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NEUROLOGICAL DISORDERS
Katherine Malanson and Karina Meiri
Welcome to the
Neurological Disorders Module!
This module focuses on how our brains work, as well as how disorders and our choices change our brains. The Neurological Disorders
(ND) Module has five units, each of which builds upon the others that
came before it. The goal of each unit is to answer a new question
about how our brains function.
To help orient you on how these topics relate to each other, we’ve
put together the following graphic that you’ll see at the beginning
of each unit. Notice how these topics relate to each other not only
in content but also in size. Our brains are composed of circuits,
which are composed of synapses, and synapses are the “junctions” between two neurons.
Outline
•
•
•
•
Unit 1: What do our brains need to do?
Unit 2: What are the building blocks of our brains?
Unit 3: How do our neurons communicate with each other?
Unit 4: How do our neurons work together to control
behaviors?
• Unit 5: How do our choices change our brains?
In Unit 1, we’ll begin our discussion by investigating what it is that our
brains need to do. From there, in Unit 2, we’ll zoom in on the neuron,
which is the basic building block of our brains. Then, in Unit 3, we’ll
focus on the synapse, which is how neurons communicate with each
other. Next, in Unit 4, we’ll take a larger approach and examine the
circuit, which is how neurons work together to control behaviors.
Finally, in Unit 5, using the example of drug addiction, we’ll look at how
our choices change our brains.
Throughout this module, you’ll have not only class lessons, but
also this workbook to guide you through your exploration of
Neurological Disorders. This workbook is designed to provide you
with readings to complement your class lessons. We have helped
make your reading of this workbook interactive by encouraging
you to take notes and answer questions throughout.
LESSON 1.1 WORKBOOK
How can we study our brains?
This unit introduces you to how we can study our
brains - both how they are built, and how they function.
In this lesson, we will begin our exploration by examining how scientists and doctors have historically tried to
study the behaving brain.
How can we study our brains?
Your brain is the most important organ in your body. It controls your organs, your behavior and your memories and emotions. Without it, none of these would function – and you wouldn’t be aware of it, because
the brain also controls the very basis for human consciousness. Perhaps the last frontier of biological
science – its ultimate challenge – is to understand the exact mental processes within the brain that allow
us to perceive and act, learn and remember – the biological basis of consciousness. Until recently, most
of what we could glean about the behaving brain came from comparing the behavior of people with brains
that had been damaged, with people apparently behaving normally. As we shall see, this approach has
provided some interesting clues, but doesn’t give an insight into normal behavior.
Today, we are at the beginning of a technological revolution. Scientists and engineers have developed
instruments that have opened unprecedented windows into the living brain. Techniques that can visualize
living neurons behaving in real time have allowed us to view the normal brain as we are thinking, feeling
and acting. Researchers can now see which parts of the brain are activated when we eat, sleep, listen
to music, dance, meditate or do any number of other activities. On top of this, advances in computing
power have allowed us to build machines that are increasingly able to function like actual brains. As young
people at the beginning of the 21st century you will be participating in the final frontier - as we gather the
tools to ask the question “What does it mean to be human?”
Wo r k b o o k
Lesson 1.1
Historically, how did scientists study the
behaving brain?
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How can scientists study the brain in the
present day?
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3
LESSON READING
What can we learn from studying cases of injury or disease?
How was Gage’s behavior affected by his
injury? ___________________________
The first – and most famous – brain injury case that scientists used to investigate the relationship
between the brain and behavior occurred in the mid-1800s. Phineas Gage was the foreman of a railway
construction crew, and by all accounts was a model citizen, serious, industrious and energetic. One day,
while using a steel rod to ram a charge of blasting powder into a hole, the charge suddenly exploded,
sending the rod into Gage’s cheek, through his brain, and out the top of his head! (Figure 1). Incredibly he survived, even walking away from the blast once he regained consciousness. But the Phineas
that woke up after the accident was a very different man. He became childish and feckless, producing
outbursts of temper that led some friends to remark that it looked as if Dr. Jekyll had become Mr. Hyde.
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The very fact that Gage
had survived such a terrible
accident put him under
intense medical scrutiny.
Add to that the dramatic
changes in personality that
resulted from the accident,
and you have one of the
most famous case studies
in neuroscience history.
After years of observing his
Figure 1: Phineas Gage (1823-1960). Phineas Gage is perhaps the most
new reactions to situations,
famous brain injury patient. In 1848, a metal rod impaled his brain his doctors came to the
entering just below the left eye socket and exiting at the top of his head.
conclusion that the front
The injury caused a dramatic change in Gage’s personality.
portions of his brain that
had been damaged must
be critical for controlling a rather subtle aspect of our personality that we now refer to as “executive function” – which is basically a filter that stops you saying the things you think, but know you shouldn’t say,
or doing the things you’d like to, but know aren’t a good idea. Gage’s accident destroyed this filter so he
just blurted out whatever came to mind, and got tangled up in all kinds of ill-advised schemes.
(You can see Phineas Gage’s skull and the iron bar at the Warren Anatomical Museum at Harvard
Medical School, 10 Shattuck St., Boston, MA – it’s open Monday – Friday, 9-5.)
Wo r k b o o k
Lesson 1.1
What part of his brain was damaged?
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What did his doctors conclude about the
part of his brain that was injured?
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4
LESSON READING
Another famous case of brain injury affecting totally different brain areas was that of Henry Gustav Molaison, known in the medical and scientific literature as ‘Patient H.M.’. Born in 1926, Molaison suffered from
severe epilepsy that left him almost totally unable to function. In 1953, surgeons attempted to treat it by
removing areas in both the right and left side of his brain just above the ears (Figure 2). The surgery was
successful and H.M.’s epilepsy disappeared. Unfortunately, the epilepsy was replaced by an equally debilitating memory impairment. H.M. woke up from the operation suffering from severe anterograde amnesia, meaning that although he could remember events from his past, he couldn’t make any new memories
and therefore couldn’t learn anything new. As a result he wasn’t able to remember people he met after the
operation, and when his family moved to a new house, he was never able to learn how to get around in
the new neighborhood.
Figure 2: Henry Gustav Molaison (1926-2008). Henry Gustav
Molaison, known as patient H.M., became a very popular case
study for learning and memory after he underwent surgery
to treat his epilepsy. The surgery removed a portion of H.M.’s
brain just above the ears on both sides of his head. We later
learned this area is critical for learning and memory.
The famous Canadian neurologist,
Brenda Milner, made it her life’s work
to study what exactly had happened
when those parts of H.M.’s brain
had been removed. By painstakingly
giving him many different kinds of
memory and recall tasks, Milner
was not only able to determine the
parts of the brain that are critical
for the formation of new memories,
she was also able to figure out that
there are several different kinds of
memory and our brains process
each kind differently. We’ll talk more
about this later.
You can hear a fascinating interview with Dr. Milner and H.M. online - see this unit on the student website
or click below:
■■ Audio: H.M.’s Brain and the History of Memory
Although no other patient has had the same surgery as H.M., similar cases of brain damage can occur
after illness. One of the most striking is Clive Wearing who was an eminent musician who contracted viral
encephalitis (an infection that destroyed part of his brain). Clive Wearing suffers from both anterograde
and retrograde amnesia so he retains memories for less than a minute, which means he is in a constant
state of believing he has just woken up.
Wo r k b o o k
Lesson 1.1
You can watch Clive Wearing and hear his wife and doctor describe what his life is like online - see this
unit on the student website or click below:
■■ Video: Life Without Memory: The Case of Clive Wearing
How was Patient H.M. affected by his surgery?
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What part of his brain was damaged?
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What did Dr. Milner and her team conclude
about the part of the brain that was damaged?
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5
LESSON READING
Can we only study the brain using cases of injury or disease?
Much of what we know about the brain and how it functions has come from scientists and doctors who
have studied cases of brain disease and injury, but we no longer have to rely on finding new cases
in order to investigate how our brains work. Dramatic new advances in technology have given us a
plethora of different tools that can be used to study the healthy, behaving brain. As we shall see, we
are now able to literally eavesdrop on the brain while subjects are involved in any number of activities,
from listening to music, reacting to a joke or watching a magic trick.
Can we use what we know to control someone else’s brain?
How likely is it that once we know exactly how the brain functions that we will be able to control another person’s brain? It sounds like science fiction, but we can actually do it right now, even with the
limited knowledge we have. Transcranial magnetic
stimulation (TMS) uses magnetic energy to send
Magne&c pulses of magnetic energy into the brain through
field the skull. In this way it can activate or disrupt the
functioning of specific brain regions (Figure 3).
Wire coil TMS is noninvasive and extensive studies have
Targeted brain region shown it to be safe, so its been approved for use
in humans by the Food and Drug Administration
(FDA), which is the drug and medical appliance
safety watchdog. TMS can be precisely aimed at
specific brain regions and has been used to trigger
ordinary people’s inner mathematical genius and
to invoke religious experiences. There are hopes
it could be used to help people with depression
Figure 3: Transcranial magnetic stimulaand other brain disorders such as schizophrenia
tion (TMS). TMS is a noninvasive proceand bipolar disorder, which have all been linked to
dure that uses magnetic pulses to stimulate
specific areas.
different brain areas.
While TMS has also been used to study the brain areas involved in moral decision making, it’s far
from the “mind control” displayed in science fiction movies, but it’ll be an invaluable tool as we continue
to study brain areas and their functions. In a later lesson, we’ll look at other techniques to visualize
specific brain areas involved in normal behaviors.
Wo r k b o o k
Lesson 1.1
How can TMS be used to control brain function?
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Can you envision any problems with using
TMS therapy? What might they be?
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6
STUDENT RESPONSES
What do you see as some of the disadvantages in trying to determine how the brain functions from studying cases of injury or
disease?
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What are some of the advantages of using modern day technologies to investigate how the brain functions?
Remember to identify your
sources
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Do you think we’ll ever get to a stage where we will be able to completely control the brain? Why or why not?
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Wo r k b o o k
Lesson 1.1
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7
LESSON 1.2 WORKBOOK
How does brain structure impact its
function?
DEFINITIONS OF TERMS
Central nervous system (CNS) –
contains the brain and spinal cord.
Peripheral nervous system
(PNS) – includes all the nerves outside the brain and spinal cord.
For a complete list of defined
terms, see the Glossary.
In this lesson, you’ll be dissecting a sheep’s brain.
During the dissection you’ll localize and identify major
brain structures. By understanding where these
structures are localized you’ll begin to appreciate how
the brain is organized spatially. Once you understand
spatial organization we can begin to investigate how
the different parts connect to control behavior.
If you have an iphone or an ipad you can download a great free app that will allow you to
look at the structures of the brain in 3D. These pictures are worth a thousand words as
we examine more closely how the brain is organized. The app is available FREE from the
itunes store. Just search ‘3D brain’.
How can we study our brains?
Before we get too much further in our discussion of how the brain is organized, let’s take a short tour of
the nervous system as a whole to orient you on all the different parts, how they’re classified and what
their functions are.
First of all we need to remember that your nervous system has basically three functions – it receives
information via our various sensory systems; it makes sense of these sensations and decides what an
appropriate response should be; and it executes that response. To complete these three functions, our
nervous system uses its two main branches - the central nervous system (CNS) and the peripheral
nervous system (PNS).
Wo r k b o o k
Lesson 1.2
Sensations come in from the environment via the PNS. The PNS delivers this information to the CNS
which then evaluates the information and decides how to respond. Finally, the CNS sends a signal the
PNS in order to be able to execute the response. Your central nervous system (CNS) includes your
brain and spinal cord while your peripheral nervous system includes all the nerves in your head, body
and limbs that lie outside the brain and spinal cord (Figure 4). Let’s start by briefly talking about the
peripheral nervous system and spinal cord, then we can concentrate on the brain for the remainder of
this lesson.
What are the three basic functions of your
nervous system?
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What is the CNS?
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What is the PNS?
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8
LESSON READING
Your Peripheral Nervous System (PNS)
The PNS can be further divided into the somatic nervous system, which controls voluntary muscles,
and the autonomic nervous system, which controls the function of organs and glands. The autonomic
nervous system has two divisions:
•
Sympathetic nervous system is nicknamed the “fight-or-flight” system because it prepares our
body when energy expenditure is necessary, such as during times of stress or excitement. This
system increases heart rate and blood pressure, stimulates secretion of adrenaline, and increases
blood flow to the skeletal muscles.
•
Parasympathetic nervous system helps our body conserve and store energy for later use. This
system increases salivation, digestion, and storage of glucose and other nutrients, as well as slowing
the heart and decreasing respiration.
DEFINITIONS OF TERMS
Peripheral nervous system
(PNS) – includes all the nerves outside the brain and spinal cord.
Somatic nervous system - part
of the PNS that controls voluntary
movement.
Autonomic nervous system –
part of the PNS that controls the
function of organs and glands.
For a complete list of defined
terms, see the Glossary.
Overall, the peripheral nervous system connects with
non-neuronal cells at one end and the central nervous
system at the other. The neurons of the PNS can be
divided into two classes:
•
•
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Which part of your autonomic nervous
system is working as you are reading this
page? What about if you heard a fire alarm?
Sensory neurons bring sensations such as
smell, touch, hearing, taste and pain to the CNS
where they are evaluated to determine what response is needed.
Motor neurons execute those responses. Motor
neurons of the somatic nervous system control
voluntary responses such as muscle contractions, whereas motor neurons of the autonomic
nervous system control involuntary responses
such as changes in heart rate.
Peripheral nerves are protected by the organs they
travel through, and in cases of injury or disease peripheral nerves are able to regenerate.
Wo r k b o o k
Lesson 1.2
Are you aware of your somatic nervous
system? What about your autonomic nervous system?
Figure 4: Peripheral and central
nervous systems. The CNS is in pink,
and contains all neurons in the brain
and spinal cord. The PNS is in blue,
and contains all neurons not in the
brain or spinal cord.
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9
LESSON READING
Your Central Nervous System (CNS)
DEFINITIONS OF TERMS
Cerebrospinal fluid (CSF) - the
fluid that bathes the brain and
spinal cord.
Meninges – protective membranes that cover the brain and
spinal cord
Ventricles - the spaces inside the
hollow brain and spinal cord that
are gilled with cerebro spinal fluid.
The central nervous system (CNS) is also divided into different parts - the spinal cord and
the brain. The sensations that are received
in the periphery via sensory neurons first
enter the spinal cord and then pass into the
brain. Then once the brain has decided on a
response, output from the brain passes into
the spinal cord before it exits to the somatic
or autonomic peripheral motor neurons in the
periphery.
The central nervous system is protected from
damage by the bony skull and vertebrae.
Both the brain and spinal cord are cushioned
by sheets of protective membranes called
meninges (Figure 5).
The brain also contains a series of hollow, interconnected chambers called ventricles which are filled with
cerebrospinal fluid (CSF). The largest of these chambers are the lateral ventricles which are located in
the center of the brain (Figure 6). The CSF serves two main functions - it provides the brain with nutrients
and it cushions the meninges to protect the brain.
For a complete list of defined
terms, see the Glossary.
Lateral ventricles Fourth ventricle Wo r k b o o k
Lesson 1.2
Figure 5: Meninges. The brain is protected in part
by the meninges which are fluid filled membranes
covering the brain. (A) The meninges have three
layers: the pia mater, the arachnoid, and the dura
mater. (B) Meningitis results from inflammation of
the meninges.
Third ventricle Figure 6: Ventricles. The ventricles are interconnected chambers that are filled with cerebrospinal fluid (CSF).
Despite these multiple levels of protection, in
cases of injury or disease, the CNS is unable
to regenerate.
What is the role of the meninges?
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What are two functions of the cerebrospinal fluid?
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10
LESSON READING
What is the function of the spinal cord?
Your Spinal Cord (CNS)
DEFINITIONS OF TERMS
Myelin – fatty substance that insluates most nerves.
White matter – portions of the nervous system that appear white in
color because they are composed
of myelinated axons.
Grey matter – portions of the
nervous system that appear grey in
color because they are composed
of neuron cell bodies and unmyelinated axons.
For a complete list of defined
terms, see the Glossary.
The spinal cord is a long, conical structure,
approximately as thick as your little finger. Its
main function is to act as a two-way track that
collects the sensory information from the periphery to pass it onto the brain, and then to
collects the motor responses from the brain
to pass onto the somatic and autonomic nervous systems.
We can divide the spinal cord into four regions, each controlling a specific region of
the body. Starting from the top (Figure 7):
• The cervical region serves the neck and
arms.
• The thoracic region serves the trunk.
• The lumbar region serves the legs.
• The sacral region serves the bowels and
bladder.
B. Brainstem Spinal cord Cervical Vertebra A. Thoracic Lumbar Sacral Figure 7: The spinal cord. The spinal cord is segmentally arranged. The segments are grouped into
4 major divisions: cervical, thoracic, lumbar, and
sacral. (A) The spinal cord is encased in vertebral
bone. (B) The spinal cord has pathways along which
sensory information can be conveyed to the brain
(indicated in red), and motor information can be
transmitted from the brain to the body (indicated in
blue).
The spinal cord is arranged so the neurons traveling up into the brain and down out of the brain are arranged on the outside. These neurons are coated with a layer of fatty insulation that appears white, called
myelin. As we will see later, myelin makes the signals that are transmitted along neurons move more
efficiently. Because of this white appearance, this area of the spinal cord is referred to as white matter.
The area where connections between the peripheral and central nervous system neurons are made is in
the middle of the spinal cord, and lacks myelin. Because of this it appears grey in comparison to the white
matter. So, this area is referred to as grey matter.
Crossing over
Wo r k b o o k
Lesson 1.2
One interesting thing to note about the neurons traveling up and down the spinal cord is that they cross
over from one side to another. Because of this cross, each side of the brain receives sensory information
from the opposite side of the body. Similarly, the spinal cord output neurons also cross from one side of
the body to the other so that each side of the brain also controls the responses of the opposite side of
the body.
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What side of the brain controls the left
side of the body? What side of the brain
controls the right side of the body?
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11
LESSON READING
Your Brain
The brain is also organized into areas of white matter where neurons travel and gray matter where connections between different neurons are made. In addition it can also be divided into distinct areas, each
of which perform a specific function. Starting from the region where the spinal cord connects to the brain,
these areas are called the brainstem, diencephalon, cerebellum, and cerebrum (Figure 8). We will take a
look at each of these areas in turn.
What is the function of the following brain
structures? What symptoms would you
see if they were damaged? Would the patient survive?
Medulla
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Pons
Figure 8: Main brain areas. The brain can be subdivided into the brainstem, diencephalon, cerebellum, and cerebrum (or cerebral
hemisphere).
The Brainstem
The brainstem is an evolutionarily old area of the brain where the spinal cord and the brain connect. Part
of the brainstem consists of sensory neurons that are traveling into the brain, and motor neurons that are
traveling out of the brain. But the brainstem also has its own functions, that divide it into 3 parts, from the
bottom, closest to the spinal cord, to the top, closest to the brain itself.
Wo r k b o o k
Lesson 1.2
•
The medulla controls breathing, heart rate and digestion. As you can imagine these are critical functions, and it is difficult to survive when the medulla is damaged.
•
The pons (from the Latin that means bridge) is a part of the brainstem that acts like a bus station
connecting upper levels of the brain (the cortex) with the spinal cord and a part of the brain called the
cerebellum. These connections allow the brain not only to give instructions about which movements
to make, but also to monitor those movements as they are happening.
•
The midbrain is also involved with coordinating movements. In this case it coordinates eye movement responses to visual and auditory stimulation.
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Midbrain
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12
LESSON READING
What is the function of the following brain
structures? What symptoms would you
see if they were damaged? Would the patient survive?
Thalamus
The Diencephalon
Moving on upwards, the diencephalon is located at the upper end of the brain stem. It has two parts
that perform functions that are critical for life:
•
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The thalamus acts as a relay station (like a post office) where all the major ascending sensory
pathways from spinal cord and brainstem connect to neurons destined for the upper parts of the
brain in the cortex. There are also reciprocal connections from the cortex to the thalamus. The
thalamus is thought to be the first area in the brain where consciousness can be experienced.
We’ll talk more about the thalamus and how important these connections are when we talk about
epilepsy and seizures.
The hypothalamus is tiny! Only 1 oz. in adult humans, yet it is the master regulator of homeostasis – controlling heart rate, blood pressure, blood composition, eating behaviors, and body
temperature to name but a few of its functions. It also links body responses to emotions. We’ll talk
more about the hypothalamus when we talk about sleep.
The Cerebellum
Wo r k b o o k
Lesson 1.2
The cerebellum lies behind and on top of the pons (Figure 9). It communicates with both the spinal cord and
the cortex. The cerebellum monitors how the intention to
perform a motor movement compares with how well the
movement is actually being executed. It can then adjust
the response to make sure the intention is being executed accurately. Amazingly, you are completely unaware of
the cerebellum as it works – it functions below the level
of consciousness.
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Hypothalamus
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Cerebellum
Cerebellum Figure 9:The cerebellum. The
cerebellum lies just behind the pons
and is critical for controlling motor
movements.
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13
LESSON READING
What is the function of the following brain
structures? What symptoms would you
see if they were damaged? Would the patient survive?
The Cerebrum
The cerebrum forms the bulk of the CNS
(Figure 10). The cerebrum consists the
three deep-lying structures surrounded by
the cerebral cortex. These three structures
also have distinct functions.
Corpus callosum •
Corpus callosum Cingulate cortex Thalamus Basal ganglia Cingulate cortex The basal ganglia are involved in the
intention to move (like when you’re lying in bed and then suddenly you’re up,
but you haven’t consciously jumped
out of bed and put your feet on the
Hypothalamus floor).
Amygdala Basal ganglia
Basal ganglia Thalamus Cerebral cortex Cerebral cortex Hypothalamus Amygdala Hippocampus Hippocampus •
The hippocampus is involved with
making memories, as we saw with
H.M.
•
The amygdala is involved in creating
emotional states. It then works with the
hippocampus to coordinate the emotional states with the correct hormonal
responses (think fight or flight).
Figure 10: The Cerebrum. The cerebrum consists
of the cerebral cortex and three deep-laying structures: basal ganglia, hippocampus, and amygdala.
The two hemispheres of the cerebral cortex are
connected via the corpus callosum. (The thalamus
and hypothalamus, which together compose the diencephalon, are also shown for spatial reference.)
The outer layer of the cerebrum is called the cerebral cortex. The cortex contains at least 30 billion individual cells. Approximately half are the neurons that transmit information around the nervous system. Just
like in the spinal cord the neurons are arranged in layers of white matter where neurons are traveling, and
grey matter where they are connecting. In the cortex these layers are alternating.
The cerebral cortex is divided into two hemispheres, one on the left and one on the right. Although they
superficially look the same they are neither structurally nor functionally symmetrical. Each hemisphere
receives sensory information from, and sends motor instructions to, the opposite side of the body. Even
though the two cerebral hemispheres perform somewhat different functions, our perceptions and our
memories are unified. This unity is accomplished by the corpus callosum, a large band of neurons that
travels between corresponding parts of the left and right hemispheres connecting them and providing both
sides of the cortex with the same information – “one world through two eyes”.
Wo r k b o o k
Lesson 1.2
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Hippocampus
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Amygdala
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Corpus callosum
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LESSON READING
Each hemisphere of the cortex can be divided into 4 lobes, each of which has a different function (Figure
11):
•
The frontal lobe is concerned with planning for future action and with control of movement.
•
The parietal lobe is concerned with receiving sensory information and with body image.
•
The occipital lobe is concerned with vision.
•
The temporal lobe is concerned with hearing, learning and memory and emotion.
Parietal lobe
Sensation, body image
Frontal lobe
Planning, motor control
Occipital lobe
Vision
Cerebellum
Temporal lobe
Hearing, memory,
learning, emotion
Brainstem
Spinal cord
Figure 11: The four lobes of the cerebral cortex.
The cerebral cortex is divided into four lobes: frontal,
temporal, parietal and occipital.
Each lobe has many characteristic folds and grooves. The folds are called gyri (singular gyrus), and the
grooves are called sulci (singular sulcus). Together the gyri and sulci increase the area of the cortex
considerably increasing the amount of information it can handle. The two most prominent sulci are:
•
The longitudinal sulcus (or fissure) which separates the left and right hemispheres
•
The central sulcus which separates the frontal lobe from the parietal lobe
Notably, mammals lower in the evolutionary scale than humans have many fewer sulci and gyri than
humans.
Wo r k b o o k
Lesson 1.2
What is the function of the following brain
structures? What symptoms would you
see if they were damaged? Would the patient survive?
Frontal lobe
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Parietal lobe
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Occipital lobe
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Temporal lobe
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15
LESSON READING
Getting information into and out of the brain
As we saw before, the brain communicates with the rest of the body via the cranial nerves (that supply
the head) and the spinal nerves (that supply the body). These nerves are part of the PNS. Since we’ve
not dealt with them before, let’s end by taking a look at the cranial nerves.
There are twelve pairs of cranial nerves that attach to the bottom surface of the brain before they enter it
via the brainstem (Figure 12).
•
Many of them deal with sensory
and motor functions in the head
and neck region in the same
way that spinal neurons do.
•
Others convey what we call the
‘special senses’ (vision, smell
and taste and hearing) to the
brain. For example, the olfactory sensory neurons transmit
olfactory information from receptors in the nose to the brain,
while the optic nerve transmits
visual signals from the eye to
the brain. The optic nerves partially cross before entering the
brain at the optic chiasm.
•
Wo r k b o o k
Lesson 1.2
What are two functions of cranial nerves?
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If the vagus nerve was damaged what
symptoms would you see?
Figure 12:The cranial nerves. Twelve pairs of cranial
nerves attach to the bottom surface of the brain and innervate the head and neck region. The three we focus on
are: olfactory (CNI), optic (CNII), and vagus (CNX).
Finally, the vagus nerve is an important autonomic cranial nerve that regulates the functions of
organs of the chest and abdomen such as the heart, lungs and digestive system.
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STUDENT RESPONSES
What differences are there between your central and peripheral nervous systems? (Be sure to address their overall functions,
and ability to regenerate).
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Remember to identify your
sources
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Given what you know about how your brain controls the function of your body, if you met a stroke patient who had difficulty
moving his left leg, what half of his brain was affected by the stroke?
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Wo r k b o o k
Lesson 1.2
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17
LESSON 1.3 WORKBOOK
How can we study the behaving brain?
We are in the middle of a technological revolution when
it comes to how closely we can look at the behaving
brain. Scientists and doctors now have many different
options if they want to investigate which parts of the
brain are linked with which function – they no longer
need to wait for a Phineas Gage to show up at their
hospital with an iron spike protruding from his head! In
this lesson, we’ll take a closer look at the most common techniques used to study the behaving brain and
investigate their advantages and limitations.
How can we study the behaving brain?
Two research areas had to come together to allow this technological revolution to occur. Firstly, noninvasive methods had to be developed to visualize the behaving brain. These methods use what doctors call markers – chemicals that had some property that can be detected, either because they’re
radioactive or fluorescent or magnetic. The markers could be injected intravenously and then observed
as they enter and accumulate in, specific brain areas. The second area was computing technology. It is
only the development of computers with huge capacities for analyzing data that make it even possible
to understand what we are seeing when we use the markers to observe the brains. The combination of
these two areas into new technologies have allowed researchers to monitor brain function in a healthy
patient, as well as to study the location and extent of brain damage while a patient is still living.
Wo r k b o o k
Lesson 1.3
What two technologies needed to be developed before we could start studying the living behaving brain/
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18
LESSON READING
What does a PET scan measure and how?
Positron emission tomography (PET)
DEFINITIONS OF TERMS
Glucose – a simple sugar
that is an important energy
source throughout the body, but
especially in the brain
Gamma rays – form of
electromagnetic wave with
shorter wavelength than X-rays
For a complete list of defined
terms, see the Glossary.
Positron emission tomography, also called PET imaging or a PET scan, is a type of brain imaging that
uses nuclear medicine. Nuclear medicine is a branch of medicine that uses small amounts of radioactive
material to diagnose or treat a variety of diseases, including many types of cancers, heart disease and
other abnormalities. PET imaging uses a radioactive chemical called a radiotracer as the marker. It is
noninvasive, and with the exception of the intravenous injection that delivers the radiotracer to the bloodstream, is painless.
When getting a PET scan, patients first receive an intravenous injection of the radiotracer – usually radioactive glucose. After the injection, the radioactive glucose accumulates in tissues that are highly active,
like the brain. Once the radiotracer becomes concentrated in these tissues, it gives off energy in the form
of gamma rays. The assumption is that the tissues that are most active will accumulate the most tracer and
therefore will show higher levels of radioactivity. Eventually the radioactive glucose is broken down and
leaves the body. The dose of radiation given is harmless.
To detect the varying levels of radioactivity in different parts of the brain, the patient’s head is placed in
a machine that contains a camera that can detect gamma rays (otherwise known as positron emission,
hence PET scan). The camera is connected to a computer that collects information about which regions
of the brain have taken up the most radioactive glucose. As the computer accumulates the information the
camera scans different areas of the brain. Together the camera and computer produce a picture that looks
like a slice through the brain, showing the level of radioactivity that have accumulated in the brain regions
found in that slice, or section.
Figure 13 shows a PET scan of a horizontal section through
the brain of a resting 54-year-old man. The computer has
colored the image to relate color directly to the tissue concentration of radioactivity: red indicates areas of higher
concentrations, and blue indicates areas of lower concentrations. Notice that high levels of radioactivity are present in
the cortex.
Wo r k b o o k
Lesson 1.3
Figure 13: PET scan taken from a normal
brain. The areas indicated in red show
high activity and the areas in blue show
low activity.
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In a PET scan, what do the warm colors usually represent? What about cool colors?
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19
LESSON READING
DEFINITIONS OF TERMS
Figure 14 shows a PET scan of a horizontal section
through the brain of an Alzheimer’s patient. This scan
shows reduced activity in the parietal lobe compared to
either the frontal lobe or the occipital lobe. Remember that
the parietal lobe is involved in language, which suggests
that this patient will have had difficulties in language processing.
Glucose – a simple sugar
that is an important energy
source throughout the body, but
especially in the brain.
Figure 14: PET scan taken from a patient
with Alzheimer’s disease. Notice the
reduced activity in the parietal lobe (indicated with red arrow) and blue coloration.
Gamma rays – form of
electromagnetic wave with
shorter wavelength than X-rays.
Hemoglobin – protein
responsible for transporting
oxygen in the blood.
Deoxyhemoglobin –
hemoglobin once it has delivered
oxygen to body tissues.
For a complete list of defined
terms, see the Glossary.
Why would an Alzheimer’s patient have a PET
scan with more areas colored in cool colors?
Figure 15: PET scan taken from a
patient with brain cancer. Notice the
areas of heightened metabolic activity (indicated with red arrows) and
yellow/red coloration.
PET scans are good at finding areas of high metabolic activity where it does not belong, and thus have been successfully
used to detect cancer in the brain, since cancer cells, because
they are dividing rapidly are very active. The yellow/red colors
in Figure 15 indicate an area of high metabolic activity detected
by the radioactive glucose, and unfortunately for the patient, the
location of a brain tumor.
PET scans are also able to detect the origins
of seizures, which show up as areas where
metabolic activity is low. In Figure 16 there
is an area of low accumulation of radioactivity, and hence low metabolic activity, in the
parietal lobe that could be due to a seizure.
Figure 16: PET scans taken from a patient with epilepsy.
Notice the area of reduced activity in the parietal lobe
(indicated with red arrow) and blue coloration.
Wo r k b o o k
Lesson 1.3
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Why would a brain tumor show up as a hot
spot on a PET scan?
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LESSON READING
The major disadvantage of PET scans is what is known as spatial resolution, i.e. the ability to detect small
areas of the brain. This means that very small abnormalities – less than 1 mm in size – may be difficult to
distinguish from the blurs simply caused by the patient shifting position. As you can imagine, even 1mm
of brain may contain thousands of neurons, hence certain abnormalities, such as small areas of damage
causing seizures, can be missed. Another problem is false positives, i.e. areas that look like they have high
areas of radioactivity, but are also artifacts. Finally, the amount of radiotracer that can be safely injected
into the body is obviously limited, and this in turn can make it difficult to see different areas that have rather
low metabolic rates.
Other problems with PET scans are that they must be completed when patients are awake. The tracer
takes between 30 and 60 minutes to reach the appropriate area in the body, and the scanning process,
during which they patient has to stay still, takes an additional 45 and 60 minutes. Therefore, patients with
limited mobility or difficulty remaining still for long periods of time may find the PET scan process uncomfortable or impossible.
A final disadvantage of PET scans is their cost. For obvious reasons of safety, the radioactive tracers used
need to be able to decay and lose their radioactivity very quickly. But because the chemicals decay so
quickly, they must be produced fresh each time they are used, in an atomic particle accelerator called a
cyclotron. Therefore, the cost of the cyclotron and the salaries of the personnel who operate it must all be
added the cost of the PET scanner.
Magnetic resonance imaging (MRI)
Wo r k b o o k
Lesson 1.3
Magnetic resonance imaging, also called MRI, is another noninvasive method that is able to image internal structure in amazing detail. It is based on the principle that the body is largely composed of water
molecules. Each of these water molecules has two hydrogen nuclei or protons. When a person is put
inside a scanner with a powerful magnetic field, some of these protons align with the direction of the field.
Then a radio frequency transmitter is briefly turned on, producing a second electromagnetic field. This
radiofrequency (RF) field has just the right energy
to flip the spin of the aligned protons in the body,
so that after the RF field is turned off, those protons
that absorbed its energy and flipped revert back to
their original state by releasing a photon. The scanner detects the released photons as an electromagnetic signal, similar to radio waves. The protons in
different tissues return to their original (equilibrium)
state at different rates. These different rates can be
detected by the MRI scanner. Figure 17 shows a
picture of an MRI scanner. Because of the extremely
Figure 17: MRI scanner.
high magnetic fields, it is critical that no ferrous (magnetizable) metal is near the scanner.
List three disadvantages of PET scans.
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What is the major difference between the
PET method and MRI?
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What does MRI measure, can you explain
how?
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LESSON READING
DEFINITIONS OF TERMS
Hemoglobin – protein
responsible for transporting
oxygen in the blood.
Deoxyhemoglobin –
hemoglobin once it has delivered
oxygen to body tissues.
For a complete list of defined
terms, see the Glossary.
The computer uses the differences in when and where
photons are released as the protons flip back at different rates to create an image of different tissues. While
MRI can be used to image every part of the body, it is
particularly useful for tissues with high concentrations
of water and therefore many hydrogen nuclei, such as
the brain, muscle, connective tissue and most tumors.
These areas of low density show up as high contrast,
while areas of high density, like bone, have much lower
contrast. Because the brain in particular has a very
high water concentration and low density, MRIs reveal
brain structures at extremely high resolution. Figure
18 shows an MRI image of a sagittal section (slice)
through the brain. The corpus callosum connecting
the two hemispheres can be seen clearly.
Functional MRI (fMRI)
Figure 18: MRI scan of brain. Structural
MRI provides good contrast between the
different soft tissues of the body, making it
especially useful for brain imaging.
Functional MRI (fMRI) is a variation of the MRI principle that measures the magnetization of oxygenated hemoglobin and deoxyhemoglobin rather than
water in order to study brain activity. When brain activity increases there is an increased demand for oxygen, and the vascular system responds by increasing the
amount of oxygenated hemoglobin relative to deoxyhemoglobin. Oxygenated hemoglobin increases the MRI signal
just like magnetized water does, while deoxyhemoglobin
decreases the MRI signal relative to the oxygenized hemoglobin signal. Therefore if blood flow in a specific area
is increased the MRI signal in that area is also increased
proportionately to the neuronal activity in that area. This is
called the BOLD signal (Blood-Oxygen-Level-Dependent)
signal. To detect a BOLD signal an area of the brain is
scanned very rapidly (typically once every 2–3 seconds).
Figure 19 shows an fMRI image of a horizontal section
through the brain after a subject had been asked to read
a single word.
Wo r k b o o k
Lesson 1.3
Figure 19: fMRI scan. One fMRI section
through the brain of a person who had been
asked to read one word aloud. The regions
indicated in red are areas of high activity.
Why are MRIs not as useful to study bone
as brain?
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What is the difference between MRI and
fMRI? What are is the main advantage of
fMRI compared to MRI?
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22
LESSON READING
What are the benefits and drawbacks of using MRI/fMRI scans?
MRI scans are good at detecting metabolic activity where it does not belong, and thus have been successfully used to detect cancer in the brain. Figure 20 shows images of a coronal section through the back of
the brain, the light-colored regions show areas of high metabolic activity, and unfortunately for this patient,
the location of a tumor. Note that MRIs show the left hand side of the brain on the right and vice versa.
Like PET scans, MRI shows a composite picture of many thousands of neurons, and so its spatial resolution, like PET is also very low. Additionally, its temporal resolution (its resolution in time) is also slow
and this is problematic. fMRI measures brain
activity indirectly, making the assumption that
areas of highly oxygenated blood correlate with
areas where neurons are very active is reasonable. However it may be difficult to pinpoint what
those pictures of areas of high blood flow are really showing: The blood flow response to a specific area of the brain takes about two seconds
to occur, but as we know a thought can happen
in thousandths of a second. So it’s difficult to say
what a picture of a rush of blood to an area actually means.
The timing issue comes up again and again Figure 20: MRI scan of patient with brain cancer.
when researchers attempt to study how brain The light colored areas indicate the presence of a
regions involved in complex behaviors commu- tumor.
nicate. Communication between brain regions
can occur very quickly - within a hundredth of a thousandth of a second – but the increased blood flow
that this increased activity would occur far too sluggishly for MRI to detect it. So, what is the increased
blood flow actually measuring – the event itself or the brain’s slower response to communication which
happened a while ago, maybe somewhere else? The analogy that has been made is that it’s like trying
to understand the process of photosynthesis in plants by measuring how much sunlight a tree or plant is
getting. You’ll see the tree grow or plant shrink based upon sunlight, but you’re still not really much closer
to understanding how photosynthesis actually occurs.
Wo r k b o o k
Lesson 1.3
How do you think MRI scans detect areas of
high metabolic activity?
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What is fMRI actually measuring? What are
the implications of this for investigating complex behaviors like reading?
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23
LESSON READING
What does EEG measure?
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Electroencephalography (EEG)
DEFINITIONS OF TERMS
Glucose – a simple sugar
that is an important energy
source throughout the body, but
especially in the brain
Gamma rays – form of
electromagnetic wave with
shorter wavelength than X-rays
Electroencephalography (EEG) examines the brain much
more directly. It involves applying a set of electrodes on
the scalp and then detecting the electrical activity of brain
beneath them. In conventional EEG, the electrodes are
placed on the scalp with a conductive gel or paste that
ensures a connection that will transmit the signal. Some
systems use individual electrodes, others (Figure 21) use
caps or nets into which the electrodes have been embedded. In most clinical applications the cap consists of 19
recording electrodes placed in standard positions (Figure
22) that are distributed over specific brain regions on the
cortex such as frontal (F), parietal (P), temporal (T) and
occipital (O) (plus ground and system reference).
Brain activity between the pairs of electrodes is then detected.
Hemoglobin – protein
responsible for transporting
oxygen in the blood
Deoxyhemoglobin –
hemoglobin once it has delivered
oxygen to body tissues
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 1.3
Figure 22: Placement of EEG electrodes.
The electrodes are placed in stereotyped
positions so that the current flow between
specific regions in the cortex can be
measured.
Figure 21: EEG cap containing electrodes to record brain activity.
Each electrode is connected to one input of an amplifier that can amplify the voltage between the active electrode and the reference electrode (typically
1,000–100,000 times voltage gain). The digital EEG
signal is stored electronically and can be filtered for
display. A typical adult human EEG signal is about
10 microvolts (µV) to 100 microvolts (µV) in amplitude when measured through the scalp and this is
increased a thousand fold to about 10–20 millivolts
(mV) if a hole is drilled in the skull and the electrodes
are placed directly on the cortex (this is sometimes
necessary to detect epileptic seizures).
You can watch an EEG being done online - see this
unit on the student website or click below:
■■ Video: Measuring Brain Waves with an EEG (Electroencephalogram)
What are two differences between EEG and
PET scans? Between EEG and MRI?
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24
LESSON READING
What does EEG actually measure? As we know,
the brain is composed of billions of neurons that
communicate electrically (we’ll see how in more
detail later). The communication between individual neurons is called the synaptic potential. The
synaptic potentials generated by single cortical
neurons are far too small to be picked up by the
EEG. Rather the EEG reflects the sum of the communication between the thousands or millions of
neurons between each pair of electrodes. This is
why each EEG trace is reported directionally (P3 T5 [parietal 3 - temporal 5] for example). Because
each pair of electrodes samples the activity of a
population of neurons between the electrodes in
different brain regions, each of the individual EEG
traces will be different (Figure 23).
Figure 23: Normal EEG. An EEG taken from a
healthy patient. Notice how each trace (wavy
line) is coded as to what pair of electrodes it was
recorded from – we’ll talk more about that later.
Wo r k b o o k
Lesson 1.3
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What behaviors do the following EEG brain
waves detect?
alpha (α)
Scalp EEGs show waves that have characteristic frequencies that correspond to different states
of brain functioning (e.g., waking and the various
sleep stages, Figure 24). The neurons that are
communicating to cause some of these characteristic waves are well known - for example
connections from the thalamus to the cortex are
known to generate the so-called theta waves
seen during sleep. Others are not – for example
the neurons that are responsible for the so-called
occipital waves are not well understood at all.
Figure 24: Typical EEG waves. The EEG shows
typical patterns of activity that can be correlated
with various stages of sleep and wakefulness. α
waves originate from occipital cortex when the
eyes are closed, β waves are associated with
intense mental activity, θ waves are associated
with drowsiness, δ waves are associated with
the deepest stages of sleep.
What are the two characteristics of and EEG
scan?
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beta (β)
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theta (θ)
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delta (δ)
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25
LESSON READING
What are the benefits and drawbacks of EEG recordings?
DEFINITIONS OF TERMS
Glucose – a simple sugar
that is an important energy
source throughout the body, but
especially in the brain
Gamma rays – form of
electromagnetic wave with
shorter wavelength than X-rays
Hemoglobin – protein
responsible for transporting
oxygen in the blood
Deoxyhemoglobin –
hemoglobin once it has delivered
oxygen to body tissues
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 1.3
Clinically, EEGs are very commonly used to monitor for seizure activity, to evaluate depth of anesthesia or
coma, and to test for brain death. The major advantage of the EEG is obviously how simple it is: EEG is
totally non-invasive and unlike PET and MRI, EEG does actually directly measure the electrical behavior
of populations of neurons. Moreover, EEGs can detect changes that occur over milliseconds, which is
much closer to the time scale of actual neuronal communication and much faster than either PET or MRI.
A major disadvantage of the EEG is its poor spatial resolution, which is worse than either PET or MRI.
Placement of the electrodes means that each pair of electrodes may be measuring activity over several
centimeters – room enough for thousands if not millions of individual neurons. Another disadvantage
is that the relationship between the activity of neurons and what is depicted on the EEG trace is quite
complex: Not only does the trace between a pair of EEG electrodes represent the sum of the activities
of thousands of neurons, but those electrodes will only detect neurons that are all communicating at the
same time (synchronously) because it can’t detect individual neurons. In order to communicate (fire)
synchronously these neurons need to be to be aligned in the same direction, i.e. to have similar spatial
orientation. If the neurons don’t line up they won’t create the waves of electrical activity that the EEC electrodes detect. Neurons connecting the thalamus and the cortex (thalamocortical neurons) have these
characteristics, as do neurons extending from the cortex to the spinal cord, but many other neurons do
not, and so they will never be detected by EEG.
Another problem with EEG is that activity from deep within the brain is more difficult to detect than currents near the skull. This is because of the simple electrical principle of the square rule – that voltage
fields decline with the square of the distance. So in cases where activity deeper in the brain needs to be
measured, a hole must be drilled in the skull, which is very invasive
Could you measure the behavior of the basal
ganglia with an EEG?
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If you wanted to measure H.M.’s seizures using an EEG, what would you have had to do
first?
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26
STUDENT RESPONSES
Which of the described imaging techniques (PET, MRI/fMRI, EEG) would you choose if you had to examine a new-born baby
who you suspected had been born with structural abnormalities in their cerebellum? _________________________________
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Which of the described imaging techniques (PET, MRI/fMRI, EEG) would you choose if a patient came to your surgery with a
bad headache, and you suspected they might have brain cancer? ________________________________________________
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Which of the described imaging techniques (PET, MRI/fMRI, EEG) would you choose if a patient came to your research lab with a
severe case of anterograde amnesia and you wanted to diagnose where the deficits originated from. What tests would you do?
Would you completely trust the results?
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Wo r k b o o k
Lesson 1.3
27
LESSON 1.4 WORKBOOK
How do our brains interpret the
environment?
DEFINITIONS OF TERMS
Sensation – immediate and basic
experience generated as sensory
stimuli fall on our sensory systems .
Perception – the higher-order
process of integrating, recognizing,
and interpreting complex patterns
of sensations.
For a complete list of defined
terms, see the Glossary.
Every day our brains are bombarded with simple and
complex sensory stimuli that they need to process,
interpret and filter. In this lesson you’ll experience firsthand how the brain senses our environment, and also
how sensations can be interpreted and processed, and
in some cases, fool our brains.
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What is the difference between sensation
and perception?
How do our brains interpret the environment?
Ask someone what the ultimate function of the brain is, and they’ll often answer with “thinking” or “reasoning”, or “remembering”, or “sensing” or “perceiving”. Certainly the nervous system performs all these functions, but they all support one fundamental function – to control your body. So the basic goal of sensation
and perception is to inform us of what is happening in our environment so that our behaviors can adapt in
a useful way.
Sensation and Perception
As you read this text, you are demonstrating extraordinary sensory and perceptual abilities. Your eyes
move along this page at a steady pace, identifying letters and words so fast as to defy explanation. If you’re
like most people, you tend to take sensation and perception for granted because you can see, hear, touch,
smell and taste so naturally and automatically. You open your eyes and see; you put a morsel of food in
your mouth and taste – what could be simpler? Perception, however, is a complex puzzle that has intrigued
researchers for centuries.
Wo r k b o o k
Lesson 1.4
If you had to describe what the ultimate
function of your brain is, what would you
say?
Before we go any further we need to define our terms because they have different meanings that ultimately
reflects how they are controlled: Sensation refers to the immediate and basic experiences generated as
stimuli fall on our sensory systems: Perception involves the interpretation of those sensations, organizing
them to give them meaning.
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28
LESSON READING
Our sensory systems
Our five basic senses are vision, hearing, taste, smell and touch. All five sensory systems receive information from the environment through specialized cells at the surface of the body and then transmit this information along peripheral sensory nerves to the central nervous system. There the information is decoded
to form a perception and used for three main functions:
DEFINITIONS OF TERMS
■■ Controlling movement
■■ Regulating the function of internal organs
Perceptual illusions – perceptions that are inaccurate representations of sensory stimuli
For a complete list of defined
terms, see the Glossary.
■■ Maintaining arousal.
While we tend to think of sensation as a conscious experience, not all sensory information reaches consciousness. When we withdraw a hand after touching a hot surface, the sensory information drives the
motor response automatically even before we are consciously aware that the surface is hot.
Our sensory systems perform incredibly well at gathering information about our environments. All of the
sensory systems are able to operate in a range of environments. For example, you can see in extremely
bright sunlight and to a degree, in moonlight – even though the light from the bright sun is 100 million times
brighter than that from the moon! Our sensory systems are also well adapted to humans’ specific needs.
For example, our visual system is especially competent at detecting motion by other humans, and our
hearing is particular sensitive to the frequency range of the human voice.
Perceptual Illusions
As good as our senses are they can occasionally be led astray by particular stimuli. For example, look at
Figure 25.
Do the two horizontal lines appear to be equal in length, or
is one longer than the other? We can learn about how our
senses function by examining cases like this in which they
fail to provide us with accurate information - perceptual
illusions – inaccurate perceptions.
Wo r k b o o k
Lesson 1.4
Our perceptions cannot always be trusted because they
can be distorted by the components of an object, or by its
surroundings. In the case of the lines in Figure 25 the pairs
of lines attached to the end fool the brain, which adds more
length to the line where the ends diverge. So our brains are
the final arbiter, deciding on the ‘truth’. Because of this we
can learn about our brains by studying how different perceptual illusions trick our brains into delivering an imaginary
‘truth’.
Figure 25: Mueller-Lyer illusion. The two
horizontal lines seem to differ in length,
but their length is actually the same.
Don’t believe us – measure it yourself.
After measuring the length of the lines in
Figure 26, does one still appear to be longer than the other? Why do you think that
might be?
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29
LESSON READING
Optical Illusions
Perhaps the most common perceptual illusions are optical. Optical illusions take advantage of basic
“weaknesses” in the visual system. Until recently, visual perception was often compared to how a camera
operates because, like the lens of a camera, the lens of the eye focuses an image on the retina. This analogy falls far short of what vision really does, which is to create a three-dimensional perception of the world
that is significantly more complex than the two-dimensional image projected onto the retina.
The visual system creates perceptions by following certain innate laws that govern how it recognizes pattern, shape, color, distance, and movement of objects in the visual field. These laws of
perception can be illustrated with examples of
visual patterning: Consider the array of dots in
Figure 26A. The dots are equally spaced, yet the
brain organizes them so that they look like they are
either in rows or in columns. Whether we perceive
Figure 26: Visual patterns. (A) The array of identione pattern rather than the other is due to the
cal dots can be seen alternatively as columns or
laws of similarity and proximity. Thus, if some of
rows. (B) Similarities in appearance of some of the
the dots in one direction look similar there is a tendots create a strong pattern of columns (top) or
dency to apply a pattern to all the dots that takes
rows (bottom). (C) Spatial arrangement alone determines whether we see vertical (top) or horizontal that similarity into consideration (Figure 26B).
(bottom) pattern.
Likewise, if some of the dots in one direction are
brought closer together, the brain will apply a pattern that takes into consideration
that proximity (Figure 26C).
A. Ambiguous pa-ern B. Law of similarity C. Law of proximity This process of perceptual organization is continuous and dynamic,
as illustrated with the well-known picture showing figures on a background apparently alternating (Figure 27). The image can either be
seen as two white profiles against a black background, or as a black
vase against a white background, but it is almost impossible to see
both images simultaneously. This winner-take-all strategy illustrates
another principle of visual perception: only part of the image is selected as the focus of attention, while the rest becomes submerged
into the background.
Wo r k b o o k
Lesson 1.4
Figure 27: Face or vase illusion.
We sometimes see a pair of
faces, sometimes a vase. A
perceptual decision must be
made between what is the figure
Optical illusions, which ‘misread’ the visual information sent to the and what is the background. By
brain, demonstrate how the brain imposes certain assumptions it has focus on the figure (face or vase)
about the visual world to the objective sensory information it receives. we cause the other to recede into
the background.
What other illusions have you experienced?
Why do you think it was that they tricked
your brain?
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30
LESSON READING
What brain areas are involved in creation of illusions?
What brain areas are responsible for “decoding” sensory illusions?
Many perceptual illusions are the result of our brains trying to reconcile conflicting sensory information.
Two areas in particular are involved (Figure 28).
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•
The frontal lobe helps resolve
conflicts between sensory inputs
(such as the two figure illustration
in Figure 27).
•
The insular cortex (which is buried deep inside the cerebral
cortex near the hippocampus) is
responsive to discrepancies between what we see and what we
touch (such as when we expect
something to be light based on
what it looks like, and then it turns
out to be heavy).
Figure 28: Processing conflicts. Our brains relay on the
frontal lobe, located at the front of the brain, and insular
cortex, located inside the brain, to help resolve conflicts
between incoming sensory information.
Are there any practical applications for sensation and perception?
Sensation and perception also have numerous practical applications in schools, medicine and industries.
Reading teachers can apply what we’ve learned about eye movements and letter identification to help
students learn to read. Physicians can use information about how to reduce the perception of pain to help
their patients and designers can use information about color and size in home decoration.
See this unit on the student website or click below to watch the following TED talk about how optical illusions help us learn how we see. Answer the question: “It’s an illusion – or is it?”
■■ Video: Beau Lotto: Optical illusions show how we see
Wo r k b o o k
Lesson 1.4
31
LESSON 1.5 WORKBOOK
How do the parts of our brains work
together?
DEFINITIONS OF TERMS
Aphasia – deficit in the ability
to use or comprehend language
caused by brain damage.
Broca’s area – area of left frontal
lobe that is critical for the production of speech.
For a complete list of defined
terms, see the Glossary.
Now that we’re becoming more familiar with all the
different parts of the nervous system, let’s turn our attention to one example of how all these different parts
work together to create complex behaviors. Maybe
one of the best illustrations is to analyze how the brain
manages language, the highest and perhaps the most
characteristically human mental function.
Looking at language
Much of what we know about language comes from the study of language disorders or aphasias most
often found in patients who have suffered a stroke that has destroyed specific areas of their brains. The last
half of the nineteenth century produced an explosion of research that gave us our most important discoveries about how and why aphasia occurs. When we look at all these studies together, they tell an exciting
story of how we got our first insight into how complex mental function actually had a simple biological basis.
Paul Broca
Wo r k b o o k
Lesson 1.5
In 1861, the neurologist Paul Broca (Figure 29) described one of
his patients who could understand language perfectly, but could
not speak. The patient had no defects to his tongue, mouth or
vocal cords, but he could only utter isolated words (in fact his
nickname was ‘Tan’ because that was one of the few words he
could say). He could whistle and sing a melody, but he could not
use the isolated words grammatically, create complete sentences nor express his ideas in writing. After he died, postmortem
examination of his brain showed damage in the posterior region
of the frontal lobe. This region became known as Broca’s area Figure 29: Paul Broca (1824-1880).
(Figure 30).
Broca was the first neuroscientist to
really examine how the structure of the
brain contributes to complex functions.
Would a patient with Broca’s aphasia be
able to understand the question “What is
your name?” How might they answer the
question?
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32
LESSON READING
Would a patient with Wernicke’s aphasia
be able to understand the question “What
is your name?” How might they answer the
question?
Broca studied a further 8 patients, all of whom had the
same symptoms, and all of whom had damage in the
same area of the left cerebral hemisphere near the
frontal cortex when their brains were autopsied. This
discovery led Broca to state: “We speak with the left
hemisphere!”
DEFINITIONS OF TERMS
Wernicke’s area – area of the
temporal lobe that is critical for
understanding language
You can watch a teenage girl, Srarah, with Broca’s
aphasia online - see this unit on the student website
or click below:
■■ Video: Broca’s aphasia - Sarah Scott - teenage
stroke
For a complete list of defined
terms, see the Glossary.
Figure 30: Broca’s area. Broca’s area
is situated next to the part of the frontal
lobe that controls movement.
Carl Wernicke
The next step was taken in 1876 by Carl Wernicke (Figure 31). He
described another kind of aphasia. Wernicke’s aphasia involved a failure to understand what was being said or written, rather than speak.
While Broca’s patients could understand language but not speak,
Wernicke’s patients could speak, but could not understand the language they heard. Their conversations were fluent, but unintelligible.
Figure 31: Carl Wernicke
(1848-1905). Wernicke noticed that not all language
deficits were the result of
damage to Broca’s area.
Wo r k b o o k
Lesson 1.5
In this case the damage was located in the posterior part
of the temporal lobe where it joins the parietal and occipital lobes. This region became known as Wernicke’s
area (Figure 32), and Wernicke might have said (but he
didn’t) “We understand language at the back of the left
hemisphere!”
Figure 32: Wernicke’s area. Wernicke’s
area is located where the parietal and temporal lobes meet. It encircles the auditory
cortex.
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What does the part of the brain that Broca’s area is found in control? What about
Wernicke’s area?
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33
LESSON READING
You can watch a patient with Wernicke’s aphasia
online - see this unit on the student website or click
below:
Broca’s area Motor cortex Wernicke’s area ■■ Video: Wernicke’s aphasia
Wernicke was the first to appreciate that different
components of a single behavior are processed in
different regions in the brain. His theory proposes
that language involves separate motor and sensory
programs, each governed by several regions of the
cortex (Figure 33).
•
•
A motor program that controls the movements
of the mouth, tongue, palate and vocal cords is
located in front of the motor area in Broca’s area.
Figure 33: Language processing. Both Wernicke’s and Broca’s areas contribute when we
hear a spoken word and then repeat it.
A sensory program that controls word perception is located in the temporal lobe area in
Wernicke’s Area. This area is surrounded by the auditory cortex, as well as the areas that integrate
auditory, visual, and touch sensation into complex perceptions and that are therefore known as association cortex.
Wernicke’s model for the organization of language has been elaborated on over the years but is still in
use today. According to the most up-to-date model, language is processed in a specialized pathway that
involves several areas of the brain, as follows:
Wo r k b o o k
Lesson 1.5
•
The initial perceptions of language are formed in separate sensory areas of the cortex specialized for
hearing words (auditory cortex) or reading words (visual cortex).
•
These perceptions are then conveyed to an area of the association cortex called the angular gyrus
that is able to transform auditory and visual information into a single code that is shared by both
speech and the written word.
•
From the angular gyrus this code is conveyed to Wernicke’s area, where it is recognized as language
and associated with meaning. Without that association, the ability to comprehend language is lost.
•
The common neural code is then relayed from Wernicke’s area to Broca’s area, where it is transformed into a motor representation that can lead to either to spoken or written language.
When this last stage, where the single code is transformed to a spoken or written motor representation
cannot take place, the ability to express language is lost.
What pathways through the brain are activated when someone says ‘Hi!’ to you and you
reply. Draw them out.
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What pathways through the brain are activated when you read this message:
“Say Hi out loud”.
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34
LESSON READING
DEFINITIONS OF TERMS
Distributed processing – theory
suggesting that information is
processed in several different parts
of the brain.
Conduction aphasia – language
disorder in which patients can
understand language, and speak
without any problem, but they omit
parts of words or substitute incorrect words.
For a complete list of defined
terms, see the Glossary.
Using this reasoning and proposed neural
pathway, Wernicke correctly deduced that a
third type of aphasia must exist, that would
result if the connection between Broca’s and
Wernicke’s area is damaged. He predicted
that patients with conduction aphasia
would be able to understand language and
would also be able to speak, but that they
would not be able to use words correctly.
Indeed patients with conduction aphasia
can understand words they hear and read
perfectly, and can also speak and write quite
fluently, yet, they cannot speak coherently.
They omit parts of words or substitute incorrect sounds. They are painfully aware of their
errors, but unable to put them right.
Our current understanding of language
processing
Figure 34: PET scans of language areas. PET scans
taken while subjects were hearing, seeing, speaking and
thinking about words. Only when patients were listening
to words, did their Wernicke’s areas show activity. The
PET scans taken while the subject was seeing, speaking and thinking show activation of the occipital cortex,
Broca’s area and frontal lobes.
Until recently, everything we knew about language came from studies of patients who had suffered brain
damage. Now PET and fMRI imaging let us look at language in behaving uninjured, healthy people. PET
scans show where individual words are coded in the brain of healthy subjects when words are read or
heard (Figure 34). The data shows that not only are reading and listening processed separately, but the
mere act of thinking about a word’s meaning activates still a different area in the frontal cortex. Thus, language processing occurs in parallel in a number of different areas as well as in serial via Wernicke’s and
Broca’s areas.
Wernicke’s discoveries also provided the first evidence for distributed processing, which is the important
concept that different types of information are routed to a number of different areas in the brain in order to
organize a response. This evidence and studies using PET scans and fMRI has led to the current thinking
that our brains organize language using a modular format that consists of processing centers each having
more or less independent functions, that are connected together in serial and in parallel.
Wo r k b o o k
Lesson 1.5
We now appreciate that all cognitive abilities, not just language, are constructed using a similar format.
This means that while specific brain regions are concerned with simple processing operations, complex
functions like perception, movement, thought, and memory are all made possible because several brain
regions, each with their own specific function, are linked together in serial and in parallel. As a result, damage to a single area need not result in the loss of an entire behavior. Even if a behavior initially disappears,
it may partially return as undamaged parts of the same functional module reorganize their linkages.
Would a patient with conduction aphasia
be able to understand the question “What
is your name?” How might they answer the
question?
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If Wernicke’s area wasn’t activated when we
read words, does that mean we need to hear
words in order to understand them?
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35
STUDENT RESPONSES
We have leearned that many areas of our brain are involved in complex behaviors. Do you consider that this is a good or a bad
thing when you are thinking about cases of brain injury or disease? What could it mean in terms of patient recovery?
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Wo r k b o o k
Lesson 1.5
36
Unit 2: What are the building
Overview
blocks of our brains?
In the last unit we discovered that complex brain functions occur as individual structures in the brain work together like an orchestra.
We also discussed one of the limitations of our new visualization techniques – that they only sample populations of hundreds or thousands of neurons, so they don’t give us any information about how the individual cells of the nervous system work together. So now
we’re going to take another step back and dial down our focus to the primary building blocks of our brains, the neurons and the glial
cells. In this unit we will explore how these basic cells are built and how they work, and importantly what can go wrong when these
building blocks are diseased and their functions are compromised.
Remember our graphic from the beginning of this workbook? This unit focuses on the neuron, which is the building block of our
brains.
LESSON 2.1 WORKBOOK
What is the structure of a neuron?
DEFINITIONS OF TERMS
Neuron – cells of the nervous
system that are specialized for the
reception, conduction and transmission of electrochemical signals.
This unit introduces you to the building blocks of our
brains: neurons and glia cells. In this lesson, we will
begin our exploration of how the brain is put together
by investigating why neurons have such complex
structures and how these structures allow the neurons
to perform highly specialized functions
What are neurons?
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 2.1
Neurons are the most important functional cells in our nervous system. The adult human brain contains
roughly 86 billion individual neurons. Each neuron is interconnected, forming a precise network. Within
that network neurons are assembled into many different kinds of functionally distinct regions (like Broca’s
area for example). As we saw in the last lesson these regions interact with each other to produce our perception of the external world, to fix our attention on the responses that need to be made, and to control our
bodily functions. Our first step in understanding the brain, therefore, has to be to understand the neuron
– how it is put together and how it works.
Neurons are cells with highly complex structures, much more complex than any other cell in the body.
Wiggle your big toe. The neuron that controls that wiggle starts off in the spinal cord somewhere in your upper chest and ends up at your big toe, a distance that would be tens of meters if you were a giraffe (which
don’t have toes, but whatever, you get the point). Neurons are different from other cells in a number of ways
especially because, unlike most cells, neurons don’t divide — the number of neurons you had when you
are born is the maximum you will ever have. This means that when a neuron is damaged the only possibility you have to restore its function is to fix it, you can’t simply make another one to take its place, like you
could in the liver. In the peripheral nervous system you can fix damaged neurons so that they’ll grow slowly
back to make their original connections. The central nervous system is different. When a CNS neuron is
damaged it cannot regrow long distances to repair its connections. Why? No one really knows. (Interestingly, CNS neurons can grow in lower vertebrates like fish). One potential reason why our CNS neurons
aren’t able to regrow lays in the hypothesis that all of our complex behaviors demand a neuronal network
with a very precise architecture. Meaning that, CNS neurons have had to trade off the ability to regrow, so
that the network remains stable. Even so, some nervous system damage can be repaired if we can induce
neurons to rewire over short distances.
Can neurons in the PNS repair themselves?
What would this mean in regards to recovery after an injury to the PNS?
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Can neurons in the CNS repair themselves? What would this mean in regards
to recovery after an injury to the CNS?
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38
LESSON READING
What are the three functional regions of the
neuron?
Neurons have three distinct functional regions
The typical neuron contains three different regions, each of which looks different
and each of which has its own specialized function (Figure 1). These regions
are:
DEFINITIONS OF TERMS
Cell body – part of the neuron
containing the nucleus, but not
including the axon and dendrites.
Also called the soma.
Endoplasmic reticulum –
organelle in the cell that forms a
network of tubules and vesicles.
It functions to synthesize proteins
and lipids as well as metabolize
carbohydrates.
Nucleus – the DNA containing
structures of cells.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 2.1
•
•
•
The cell body
The dendrites
The axon
Dendrites Axon Cell Body Ini2al Segment Synapse Presynap2c cell Postsynap2c cell Figure 1: Neuron structure. Neurons have three
distinct regions: the dendrites, the cell body, and
the axon.
The cell body
The cell body (also sometimes called the soma) is the metabolic center of the neuron (Figure 2). It
contains the nucleus, which stores the genes of the cell in chromosomes, and the smooth and rough
endoplasmic reticulum, which are the sites where proteins are synthesized. It also contains the
lysosomes that degrade proteins that have become old or damaged.
Because the ribosomes are mostly concentrated in the cell body, protein synthesis
primarily occurs there and in the dendrites
that are closest to it. Because of this, a major
role of the cell body is to package the proteins
it has made so they can be transported over
long distances down the leg and into the foot
to our big toe (or our little finger etc.). Similarly,
because the cell body is also the site were
lysosomes are concentrated, any big toe protein that has reached its sell-by date needs
to be transported back up the leg to the cell
body for destruction. Keeping all the parts of
the neuron supplied with protein is a major
task carried out by the cell body.
Figure 2: Cell body. The cell body is the metabolic center of the cell and contains all the cellular
organelles required to support cell life: the nucleus,
mitochondria, ribosomes, rough and smooth endoplasmic reticulum.
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Name two important functions carried out
by the neuron’s cell body.
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39
LESSON READING
We can identify two types of outgrowths sprouting off from the cell body, the dendrites and the axon.
The dendrites
DEFINITIONS OF TERMS
Dendrites — branched
projection(s) of a neuron that
functions as the receptive area
of a neuron.
Dendritic spines — tiny spikes
of various shapes that are
located on the surfaces of many
dendrites and are the sites of
synapses.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 2.1
Most neurons have several dendrites (Figure 3).
These dendrites branch out from the cell body in
a shape that makes them look like a tree. In fact
the dendrites are often called ‘the dendritic tree’.
The dendritic tree is the main region of the neuron
that receives signals. These signals can come in
the form of sensations from the environment. Alternatively, in the depths of the neuronal network
they may come from other neurons. The role of the
Figure 3: Dendrites. The dendritic arbor of two
dendrites is to convert these signals, which may
neurons (a Purkinje neuron on the left, and a senbe in the form of physical signals if they are from
sory neuron on the righ) illustrating the extensive
the environment (such as light, sound or touch) or
branching of dendrites..
chemicals if they are from other neurons, into an
electrical signal. Dendrites do this by changing the electrical properties of their membranes via depolarization or hyperpolarization. We will talk more about the important processes of depolarization and hyperpolarization later on in this unit.
Each of our sensory systems contains unique neurons that
are specialized to detect specific types of sensory stimuli
in the environment. The dendrites from these neurons are
able to convert these stimuli into a neural response that
the brain can understand. For example, different types of
sensory dendrites in our skin are uniquely tuned to detect
changes in pressure. They then convert the physical sensation of pressure into a neural response by depolarizing
or hyperpolarizing their membranes.
The branches of the dendritic tree often have many hundreds of thousands of little twigs that we call dendritic
spines because they look like spikes (Figure 4). Each
Figure 4: Dendritic spines. Dendrites
have small protuberances called spines.
dendritic spine usually contains one synapse, which is an
Each spine can contain a synapse.
exact area where the dendrite can receive a signal, whether from the environment or from another neuron. You can
appreciate that if a single dendritic tree has hundreds of thousands of spines, then it can have hundreds of
thousands of different inputs. Remember that there are also 86 billion neurons — makes you appreciate
that trying to understand how everything is connected is a massive task. No wonder neuroscientists were
excited by the development of supercomputers!
What is the function of the dendritic tree?
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Which kind of neuron has more inputs: a
neuron without dendritic spines, or a neuron
with dendiritc spines? Why?
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40
LESSON READING
What is the function of the axon?
The axon
DEFINITIONS OF TERMS
Action potential – the electrical
signal of the axon.
Axon – projection of a neuron that functions to conduct
electrical impulses away from a
neuron’s cell body.
Presynaptic cell – neuron
located before the synapse, and
thus sending the signal
Postsynaptic cell – neuron
located after the synapse, and
thus receiving the signal
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 2.1
The other type of sprout we can detect coming off the cell body is the axon. Unlike the branches of the
dendritic tree, which are tapered just like real branches, the axon can be identified because it looks just
like a cylindrical tube. There is usually only one axon per neuron. The axon grows out from a specialized
region of the cell body called the axon hillock or initial segment. This structure is important because
the axon is the main transmitting or conducting unit of the neuron, conveying electrical signals from the
dendritic tree down to its very tip. In our big toe analogy, the axon would convey the signal from dendrites in the spinal cord along your leg to tell your muscles to wiggle your toe. The axon hillock gathers
together all the signals the neuron has received from the dendritic tree, converts them into the single
output response and sends them down the axon. This output response is an electrical signal called the
action potential. We will focus on how the action potential is made and transported in another lesson
in this unit. Many axons split into several branches at their tips (like the roots of the tree). This means
that the action potential can affect a larger area of its target cell, for example a muscle, than it could if it
didn’t have ‘roots’.
Just as dendrites have specific points of contact called synapses, where they receive information from
the environment or other cells, so too do axons. Axons form synapses with muscles, glands, or when
located deep within a network of the CNS, with other neurons (Figure 5). In fact the synapse actually
contains both the transmitting point of contact (axon) and the receiving point of contact (dendrite).
The cell transmitting the signal is called the presynaptic cell for before the synapse, whereas the cell
receiving the signal is the postsynaptic cell for after the synapse.
Our neurons are classified into two main
groups depending on what other cells they
make connections with and what type of
information they convey. Neurons that
receive input from the environment, and
transmit that input into the CNS are called
sensory neurons. Whereas neurons that
carry information out of the CNS and make
connections with muscles and glands are
called motor neurons. If we are going to
be able to understand how neurons make
functional networks it is going to be very
important to understand exactly how the
neurons connect together.
Presynap)c cell Axon terminal Synap)c cle4 Postsynap)c cell Figure 5: Synapse. The end of the axon divides
into fine branches that swell to form axon terminals.
These axon terminals are separated from the postsynaptic cell by the synaptic cleft.
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At a synapse, the cell sending a signal is
called what? (Hint: It’s the cell before the
synapse.)
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At a synapse, the cell receiving the signal
is called what? (Hint: It’s the cell after the
synapse.)
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41
LESSON READING
DEFINITIONS OF TERMS
Within the depths of the network in the central nervous system, neurons connect to other neurons, so
the presynaptic site is usually on an axon and the postsynaptic site is usually a dendrite (we may run into
exceptions later, but for now don’t worry about them). The points of contact on the axon are specialized
swellings on the axon’s branches called axon terminals or presynaptic terminals, while the points of
contact on the dendrite are called, not surprisingly, postsynaptic terminals. It is an important characteristic
of synapses that the pre- and postsynaptic terminals do not physically touch each other. Instead, they are
separated by a space called the synaptic cleft. In order to get the signal across the synaptic cleft, and
depolarize or hyperpolarize the dendritic membrane the presynaptic terminal turns the action potential into
a chemical signal that can cross the physical space. We will talk about this process of transmitting a signal
across the synapse called synaptic transmission in another lesson.
Axon terminals/Presynaptic
terminals – swellings at the end
of the axon’s branches that serve
as the transmitting site of the
presynaptic cell.
As you might imagine, the function of the neuron critically depends on how long its axon is. Neurons with
long axons are able to convey information over long distances to your big toe and so are called projection
or relay neurons. Neurons with short axons are only able to convey information into a limited region and
integrate information within a specific local area.
Synaptic cleft – small gap in
the synapse that separates the
presynaptic cell from postsynaptic
cell.
So now we can classify neurons into three groups on the basis of their function:
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 2.1
Neuronal function
•
Sensory neurons carry information into the central nervous system for perception.
•
Motor neurons carry commands out of the central nervous system to muscles and glands.
•
Interneurons carry information from area to area within the nervous system. They are by far the largest class, consisting of all the neurons that are not specifically sensory or motor.
In summary, although all neurons contain the same three functional components, they do not all look or
behave the same (Figure 6).
Figure 6: Examples of neurons.
Neurons that perform different
functions have different shapes.
Sensory neurons receive input
from a sensory organ, like the
ear. Motor neurons control muscle
information. Local interneurons
integrate activity within a small
area. Projection neurons convey
information for long distances.
Neuroendocrine cells release
hormones into blood vessels.
Model neurons show that each of
the different types have the same
functional components.
What is the name of the site on the axon that
connects to the dendrite?
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What is the name of the site on the dendrite
that connects to the axon?
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Are the axons and dendrites in physical
contact with each other?
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42
STUDENT RESPONSES
How are neurons specialized to complete their functions?
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Remember to identify your
sources
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Given what you know about the different types of neurons, what types of neurons do you predict to be involved in your ability to
smell warm chocolate chip cookies? And then taste one after you eat it? What has to happen after you’ve smelled the cookie, but
before you make the first bite? Be as specific as you can.
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Wo r k b o o k
Lesson 2.1
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43
LESSON 2.2 WORKBOOK
How do our axons transmit electrical
signals?
This lesson introduces you to the action potential,
which is the process by which axons signal electrically. In this lesson you will learn how our axons utilize
energy stored in their membranes to send signals
throughout our bodies.
Signaling is organized in the same way in all neurons
To produce a behavior, each participating neuron in a circuit produces, in the same sequence, four types
of signals at different sites:
•
The dendrites generate electrical input signals.
•
The axon hillock (or initial segment) integrates the input signals into a single electrical signal — the
action potential.
•
The axon transmits the electrical action potential down to the presynaptic terminal.
•
The presynaptic terminals convert the electrical action potential into a chemical output signal.
We will discuss each of these signals, but it’s easiest to understand if we start with the action potential,
even though it comes in the middle. Before we discuss any of the signals though, we need to review the
electrical properties of the cell membrane that are important to understand how these signals are generated.
Wo r k b o o k
Lesson 2.2
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What are the four types of signals generated
within neurons and where are they generated?
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44
LESSON READING
Neuronal membranes store energy in the form of membrane
potentials
DEFINITIONS OF TERMS
Diffusion – the net movement
of molecules from areas of high
concentration to areas of low
concentration.
Electrostatic Pressure – the
repulsion of like charges and the
attraction of opposite charges
Potential energy – the energy a
body has because of its position
relative to others, electric charge
and other factors.
Neuronal membranes are electrically charged. This means there is a difference in electrical charge across
their cell membranes of about 70 millivolts (mV). As we shall see in a minute this difference in charge
occurs because sodium (Na+), and potassium (K+) ions and organic anions (A-) are unevenly distributed
across the membrane so that the inside of the axon is negatively charged relative to the outside (Figure 7).
This electrical charge is called the resting membrane potential. The term potential refers to the energy
stored in the membrane or its potential energy. Because the outside of the axon is arbitrarily defined as
zero, we say that the resting membrane potential of the axon is -70 mV.
The resting membrane potential is produced as a result of the forces of diffusion and electrostatic pressure
that the ions inside and outside the membrane experience. Remember that:
•
Diffusion is the net movement of molecules (such as ions) down a concentration gradient
•
Electrostatic pressure is the repulsion of like charges (positive is repulsed by positive and negative
with negative) and the attraction of opposite charges
Understanding what produces the membrane potential therefore requires that we know the concentration
of various ions inside and outside the axon and what forces of diffusion and electrostatic pressure they
are experiencing.
Resting membrane potential –
the steady membrane potential of
a neuron at rest, usually about -70
mV.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 2.2
Figure 7: Membrane potential.
(A) When both electrodes are
applied to the exterior of the
axon in the extracellular fluid, no
difference in potential is recorded. (B) When one electrode is
inserted into the axon, a voltage
difference between the inside
and the outside is recorded.
The graphs show the voltage
change when one electrode is
inside the axon.
The force of diffusion, molecules moving
down their concentration gradient, predicts the result of adding one drop of blue
food coloring to a glass of water. Immediately after adding one drop of blue food
coloring to a glass of water, that drop sits
on the top of the water in an area of high
concentration. What happens if you let the
water sit for 5 minutes?
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The force of electrostatic pressure, attraction of opposite charges and repulsion of
like charges, predicts what would happen
if you had negatively charged ions at the
top of a cup and positively charged ions at
the bottom of a cup. Where do you predict
the negatively charged ions will go?
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45
LESSON READING
Athough there are many types of ions inside and outside the axon, three are particularly important for the
membrane potential (Figure 8):
•
•
•
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Organic anions (symbolized as A-)
Potassium ions (K+)
Sodium ions (Na+)
Let’s now consider how each of these important
ions experiences the forces of diffusion and electrostatic pressure. Once we know this we will understand why each ion is located where it is when
the axon membrane is at rest.
Organic anions are negatively charged proteins
and intermediary products of a cell’s metabolism.
They are unable to pass through neuron’s membrane and so they are only found inside the axon.
Therefore, they make the interior of the axon more
negative and contribute to the negative membrane potential.
At rest Na+ Na+ K+ -­‐ Na+ Na+ Na+ -­‐ -­‐ K+ K+ -­‐ K+ Figure 8: Distribution of ions at resting membrane
potential. Na+ ions (represented by blue circles)
are more concentrated outside the neuron. K+ ions
(represented by red circles) and negatively charged
proteins (represented by black stars) are more
concentrated inside the neuron.axon, a voltage
difference between the inside and the outside is
recorded.
Potassium ions (K+) are also concentrated within
the axon, however they can move to the outside
through special channels in the cell membrane.
Thus, the force of diffusion will tend to push them
out of the cell. However the high concentration of
negative organic anions makes the inside of the cell more negative relative to the outside. Because of
this negative charge, electrostatic pressure tends to keep the potassium ions inside the cell. In the case
of potassium ions the two forces of diffusion and electrostatic pressure oppose each other and balance
each other out. As a result, potassium ions tend to remain where they are – at high concentrations inside
the axon.
Sodium ions (Na+) are concentrated outside the axon, in the extracellular fluid. Like potassium, there are
sodium ion channels in the membrane. Therefore, the force of diffusion pushes these ions inwards. In addition, sodium ions are positively charged, so electrostatic pressure also attracts them into the negatively
charged axon. However, if the sodium ions did enter the axon the charge difference across the membrane
would break down and the potential energy in the membrane would be lost.
Wo r k b o o k
Lesson 2.2
What are organic anions, and where are they
in highest concentration in our nervous systems?
Where are potassium ions in highest concentration in our nervous systems?
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Where are sodium ions in highest concentration in our nervous systems?
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46
LESSON READING
How then can Na+ overcome the two forces of diffusion and electrostatic pressure and stay on the outside
the axon, preserving the resting membrane potential? The answer is this: there is another force provided
by a pump that continuously pushes Na+ out of the axon, swapping an Na+ ion that might have leaked
inside for a K+ ion that might have leaked outside. Because the membrane is not very permeable to Na+
(there are fewer Na+ channels) the sodium-potassium pump (Na+/K+ pump) is very effective at keeping the
intracellular concentration of Na+ very low when the membrane is at rest.
DEFINITIONS OF TERMS
Sodium-potassium pump –
active transport mechanism that
pumps sodium (Na+) ions out of
neurons and potassium (K+) ions
into neurons.
Voltage-gated channels — channels that open or close in response
to changes in voltage across the
membrane.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 2.2
Just a quick side note: Sodium-potassium pumps use enormous amounts of energy – up to 40% of a
neuron’s energy is used to operate them.
The Action Potential
We just saw that the forces of both diffusion and electrostatic pressure tend to attract Na+ into the axon.
However, we also saw that the membrane is not very permeable to Na+ ions, and that the sodium/potassium pump continuously pumps Na+ out of the axon, keeping intracellular Na+ concentrations low. But
imagine what would happen if the membrane suddenly became permeable to Na+. The forces of diffusion
and electrostatic pressure would cause Na+ to rush into the cell. This sudden influx of positively charged
ions would drastically reduce the membrane potential.
This is precisely what happens to cause the action potential: A brief increase in the permeability of the
membrane to Na+ (which allows Na+ to enter the cell), is immediately followed by a transient increase in
permeability of the membrane to K+ (allowing K+ to exit the cell). The question now is – what is responsible
for these transient increases in permeability?
We already saw that there are two ways to move ions across the membrane, either through channels in
the membrane or by hooking them
up to pumps, like the sodium-potassium pump. Sometimes the passages or pores in the ion channels are
always open, but usually they are
closed and only open under specific
conditions. When the channel pores
are open they are only permeable to
a particular type of ion, which can
flow through the pore and thus enter
or exit the cell. Some ion channels
open or close depending on the
Figure 9: The membrane’s ion channels and pumps. Two ion
cell’s membrane potential. They are channels are critical in the axon’s conduction of the action
referred to as Voltage-gated ion potential: the voltage-gated Na+ channel and the voltage-gated
K+ channel. Additionally the Na+/K+ pump plays a critical role as
channels.
well. between the inside and the outside is recorded.
How does sodium remain in highest concentration outside the axon?
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How do sodium channels open in response
to changes in the cell’s membrane potential?
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LESSON READING
Two voltage-gated channels are critical in the action potential (Figure 9):
Describe the different types of voltage-gated
ion channel.
Voltage-gated Na+ channels open when
the membrane potential reaches -50 mV,
and close when the membrane potential
reaches +40 mV.
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Voltage-gated K+ channels open when
the membrane potential reaches +40 mV,
and close when the membrane potential
reaches – 70 mV.
The following numbered paragraphs describe the movement of ions across the
membrane through channels and pumps
which underlies the action potential. The
numbers in Figure 10 correspond to the
numbers in the paragraphs below.
1. The Resting Membrane potential: At
rest the voltage-gated Na+ channels and
voltage-gated K+ channels are closed and
the Na+/K+ pump is working hard, using
ATP to sustain the resting membrane potential to move three Na+ ions out of the
axon for every two K+ ions moved into
the axon. As a result the concentration
of Na+ outside the axon is high, and the
concentration of K+ inside the axon is high
(Figure 11). Because of the contribution
of the organic cations (A-) the inside of the
axon is more negative than the outside,
even though the K+ is in high concentration
there. As a result the membrane potential
at rest is -70 mV, as we saw before.
Wo r k b o o k
Lesson 2.2
Figure 10: Stage of the action potential. The opening and
closing of voltage-gated Na+ and K+ channels is responsible for the characteristic shape of the action potential.
Refer to Figures 13-17 to see what is happening at each
stage of the action potential.
Na+ Describe where the Na+ and K+ ions are when
the axon’s membrane is at rest. Why are they
located there?
Na+ Na+ Na+ Na+ Na+ Na+ K+ Na+ K+ Na+ K+ K+ K+ K+ Figure 11: Resting membrane potential (Stage 1
in Figure 10). The resting membrane potential is
maintained by the Na+/K+ pump. At rest, there is a
slow leak of K+ ions out of the cell, which the Na+/K+
pump corrects by pumping 3 Na+ ions out of the cell
for every 2 K+ ions it pumps into the cell.
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LESSON READING
2. Reaching Threshold: When the dendrites reNa
ceive a signal just a few voltage-gated Na+ chanNa
Na
Na
Na
Na
nels open and the charge across the dendritic
Na
membranes drops briefly causing small changes
in voltage or local potentials. The forces of diffusion and electrostatic pressure then pull Na+ ions
K
Na
K
into the cell through the open channels (Figure
K
K
Na
K
K
12). This inward flow of positive sodium ions starts
to reduce or depolarize the membrane potential,
meaning that the inside of the cell is becoming
more positive relative to the outside. If enough
Figure 12: Reaching threshold (Stage 2 in Figure
Na+ channels open and enough Na+ ions enter the 10). Local potentials open a few voltage-gated Na+
cell, then the membrane potential will decrease to channels, allowing Na+ ions to enter the axon.
the threshold (-50 mV) at which all the Na+ channels will open and large quantities of Na+ ions will
enter the cell. Threshold is the critical level of membrane depolarization at which the cell can actively
generate an action potential. As we see, whether threshold is reached depends on the strength of the
dendritic signal. If the dendritic signal is strong then we are more likely to reach threshold.
+ + + + + + + DEFINITIONS OF TERMS
+ + + Absolute refractory period – a
brief period after the initiation of an
action potential during which it is
impossible to elicit another action
potential in the same neuron.
Depolarize – to decrease the resting membrane potential. Decreasing membrane potential means
that the membrane potential is
becoming more positive.
Local potentials – small changes
in voltage (membrane potential)
due to dendritic signaling.
Threshold – the level of depolarization needed to generate an
action potential.
For a complete list of defined
terms, see the Glossary.
+ + + + + 3. Depolarization: When a threshold of -50 mV is reached, many more voltage-gated Na+ channels
open allowing even more Na+ ions to quickly flow
into the axon (Figure 13). This inward flow of Na+
Na
into the axon further depolarizes the membrane,
Na
reducing the membrane potential even more so
that eventually the inside of the axon becomes
positive relative to the outside.
+ + Na+ Na+ K+ Na+ K+ K
4. Hyperpolarization: When so many Na
K
Na
Na
K
Na
K
ions have entered the axon that the interior has
reached +40 mV (relative to the external value of
0 mV) the voltage-gated Na+ channels close. This
inactivates them, so they cannot open for a period
of time. This is called the absolute refractory Figure 13: Depolarization (Stage 3 in Figure 10).
Once the membrane reaches threshold (-50 mV),
period.
+
+
+ + Na+ + + + + + many more voltage-gated Na channels open, allowing even more Na+ ions to enter the axon.
Wo r k b o o k
Lesson 2.2
Describe where the Na+ and K+ ions are when
the axon’s membrane is reaching threshold.
Why are they there?
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Describe where the Na+ and K+ ions are when
the axon’s membrane is depolarizing. Why
are they there?
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LESSON READING
Remember that voltage-gated K+ channels also
open at +40 mV. This opening of K+ channels alNa
K
K
K
lows K+ ions to flow out of the axon (Figure 14).
K
K
+
Na
The K ions flow out of the axon because the prior
passage of Na+ ions into the cell has altered the
forces of diffusion and electrostatic pressure that
the K+ ions now experience. First of all, K+ is in
Na
Na
Na
Na
higher concentrations inside the axon than outNa
Na
Na
K
+
+
side the axon, so with the K channel open the K
ion is forced down its concentration gradient and
out of the cell by diffusion. Furthermore, with Na+
ions now inside the axon, the inside is now posi- Figure 14: Hyperpolarization (Stage 4 in Figure 10).
tive relative to the outside. So, electrostatic pres- At +40 mV the voltage-gated Na+ channels close and
sure also forces the positive K+ ions outside the the voltage-gated K+ channels open, allowing K+ ions
axon. This flow of K+ outside of the axon decreas- to exit the axon.
es the positive charge on the inside, and has the
effect of hyperpolarizing the axon membrane – meaning that the inside of the membrane becomes more
negative relative to the outside.
+ + + + DEFINITIONS OF TERMS
Hyperpolarize – to increase
the resting membrane potential.
Increasing membrane potential
means that the membrane potential is becoming more negative.
Relative refractory period –
period after the absolute refractory
period during which a higher-thannormal amount of stimulation is
necessary to make a neuron fire
For a complete list of defined
terms, see the Glossary.
+ + + + + + + + Due to the huge flow of K+ out of the cell, the membrane potential becomes higher than it is at rest (the
inside of the axon is more negative relative to the outside). This period of higher membrane potential is
called the relative refractory period because the sodium channels are now able to open, so if enough
positive charge came along the axon could potentially reach threshold and depolarize again. However if
you think about it, because the membrane potential is higher, more positive ions would be needed to reach
threshold than if the cell was at rest, so depolarization during the relative refractory period is less
Na
Na
Na
Na
Na
likely to occur.
Na
Na
K
+ + + 5. Returning to rest: To return the membrane
to its resting membrane potential of -70mV, the
Na+/K+ pump works hard and uses ATP to move
three Na+ ions out of the cell for every two K+ ions
moved into the cell (Figure 15).
Wo r k b o o k
Lesson 2.2
+ + + + + + + Na+ + Na+ K+ K+ K+ K+ K+ Figure 15: Returning to rest (Stage 5 in Figure 10).
The voltage-gated K+ channels close, and the Na+/K+
pump returns the membrane to rest by pumping 3 Na+
ions out of the cell for every 2 K+ ions it pumps into
the cell.
Describe where the Na+ and K+ ions are when
the axon’s membrane is hyperpolarizing.
Why are they there?
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Describe where the Na+ and K+ ions are when
the axon’s membrane is returning to rest.
Why are they there?
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50
LESSON READING
How does an axon conduct the action potential down its length?
Conduction of the Action Potential along the Axon
DEFINITIONS OF TERMS
Conduction of the action potential – movement of the action
potential down the length of the
axon
For a complete list of defined
terms, see the Glossary.
Now we have a basic understanding of what the resting
membrane potential is and how the action potential is
produced, we can turn our attention to how this electrical message moves down the length of the axon to the
presynaptic terminal. Axons do this in a process called the
conduction of the action potential.
The membrane depolarization that occurs during the action potential is localized to a small area of membrane
where the ions and channels are localized. Meaning, this
electrical signal does not move very far down the axon.
Axons therefore need to use another method, called active conduction, to prevent the electrical signal from decaying. It does this by repeatedly generating action potentials along the length of the axon.
Figure 16: Conduction of the action
potential. An action potential is generated
as Na+ ions flow in at one location along
an axon. The depolarization spreads to
the neighboring region of the membrane,
initiating an action potential there. The
original region repolarizes as K+ ions flow
out. The depolarization-repolarization process is repeated as the action potential is
propagated down the length of the axon.
Axons can use active conduction by stacking many voltage-gated Na+ channels along their membranes in close
proximity to one another. When the dendrite signal causes
the axon hillock to reach threshold and the Na+ channels
to open, the depolarization of the membrane will cause
adjacent Na+ channels to also open generating another
action potential. This process is repeated until the action potential reaches the presynaptic terminal where
it is converted to a chemical signal to cross the synaptic cleft (Figure 16).
So, essentially conduction of an action potential down the length of the axon requires many individual action potentials along the length of the axon to be generated in sequence. Each individual action potential
provides a depolarizing current which causes the next set of voltage-gated Na+ channels to reach threshold and trigger another action potential, causing a domino effect down the length of the axon.
Wo r k b o o k
Lesson 2.2
It is important to note that in order for the action potential to be conducted efficiently it is critical that the
voltage-gated Na+ channels are stacked up along the entire length of the axon. If they are not, the depolarizing current from a single action potential will get smaller as it travels down the axon, either because the
current leaks or because the proteins the axon is made of offer resistance to conduction. When voltagegated Na+ channels are in close proximity, the depolarizing current does not have enough space to decline
before the next set of Na+ channels open and initiate a new action potential.
You can watch a video about action potentials online — see this unit on the student website or click below:
■■ Video: Action Potentials
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51
STUDENT RESPONSES
Write a summary of what is happening at each stage of the action potential diagrammed below.
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Remember to identify your
sources
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Wo r k b o o k
Lesson 2.2
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52
LESSON 2.3 WORKBOOK
How fast do our neurons signal?
DEFINITIONS OF TERMS
Glial cell – several classes
of non-neuronal cells of the
nervous system.
For a complete list of defined
terms, see the Glossary.
Remember that winning goal you scored, that snowball you
dodged or the cup of coffee you managed to catch before
the cat knocked it all over your computer? Hundreds of
times a day our quick reactions improve our performance or
save us from disaster. Take a minute to think of something
that happened to you this week. Often we react so quickly
that we’ve reacted before we even know what has happened.
How can your neurons signal so quickly? In this lesson we
will find out, and to do so we need to learn about the other
important type of cell in our nervous systems – the glial cell.
Glial Cells
There are actually far more glial cells (usually referred to as glia) than neurons in the CNS of vertebrates
— between 10 to 50 times more in fact. Nerve cell bodies and axons are surrounded by them and because of this they were named from the Greek word for glue. For a long time neuroscientists thought glial
cells did behave like glue, and pretty much ignored them. Over the last few years though they have been
found to be far more active than we thought, conducting their own signals and acting more as partners
for neurons than the boring old structural cells we originally thought. Glia in fact have several vital roles
in neuronal function:
Wo r k b o o k
Lesson 2.3
•
They provide firmness and structure to the brain. This isn’t trivial. Remember from the
lesson on neural imaging that the brain has very low density. Glia beef up the density
and make the neurons more resistant to trauma. That’s important because remember
that if a brain neuron is damaged and dies it can’t be replaced.
•
Two different types of glial cells act as insulation, which as we shall see, allows the action potential to travel faster – important if we want to move a signal quickly.
•
When the brain is developing in the embryo, some glia act as guides so that the neural
network forms its connections in the right place.
•
Other glial cells help form an impermeable lining around the capillaries and venules of
the brain that prevents toxic substances in the blood from entering the brain. This lining
is called the blood-brain barrier.
What are glia cells, and what are some of
their functions?
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53
LESSON READING
Myelination increases the conduction speed of the action potential
In the last lesson we saw that if only one action potential occurred at the beginning of the axon, the depolarizing current wouldn’t reach the axon terminal. This happens because as it travels down the axon some
of the current leaks out of the axon across the membrane, and also because the materials in the axon
(chiefly protein) offer resistance to the current. We also learned that some axons solve this problem by lining up their voltage-gated Na+ channels along the axon membrane, so multiple action potentials can occur
in rapid succession, ensuring that the signal is transmitted all the way down the axon.
DEFINITIONS OF TERMS
Nodes of Ranvier – gaps
between adjacent myelin
segments on an axon.
Demyelination – the loss of
myelin insulating neurons.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 2.3
This is not a great solution because the energy required to keep the Na+/K+ pump working to repolarize
the axon membrane is huge. So axons have come up with another strategy, which is to have the action
potential jump along the axon rather than progress down it (think of the action potential pogo-sticking down
the axon rather than walking down). This how it works.
Remember that the problem with a single action potential was that the current would decay.
To prevent that decay glial cells wrap around the
axon like beads on a necklace covering the axon
tightly except for the areas in between the beads
called nodes of Ranvier which remain naked
axon (Figure 17). Two things make this strategy
work. First the glia make a substance called myFigure 17: Nodes of Ranvier. Myelin is formed
elin, which acts as an insulator. Now the parts of
from membranes of glial cells wrapping tightly
the axon that are wrapped around by the myelin
around the axon, like beads on a necklace.
are insulated and the depolarizing current can’t
Between the beads of myelin are spaces of naked
leak out. Second the sodium channels are conaxon, called the nodes of Ranvier.
centrated in the small areas of naked axon in
between each myelin ‘bead’ so the action potential can hop down the axon like a pogo stick. Let’s have a
look in a bit more detail:
Figure 18: Cross
section of myelinated axons. The glial
cell membranes
wrap so tightly
around the axon
that the cytoplasm
is squeezed out of
the glial cells.
The glial cells wrap around the axon like paper wrapping around a pencil. The glial cell membrane attaches so tightly to the axon, and to itself that there is no
extracellular fluid in contact with the axon in that area
(Figure 18). The only place where the axon comes
into contact with extracellular fluid is at a node of Ranvier, where the axon is naked. In the myelinated areas
therefore, there can be no inward flow of Na+ into the
axon because the myelin insulates the axon from the
extracellular fluid.
How does myelination increase the conduction velocity of the action potential?
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54
LESSON READING
DEFINITIONS OF TERMS
Saltatory conduction –
conduction of the action potential
from one node of Ranvier to the
next along a myelinated axon.
How then does the action potential travel along the area
of an axon covered by a myelin sheath? The answer
to this is by behaving like an electrical cable. Since the
axon is covered in myelin, there is minimal leakage of
depolarizing charge out of the axon so the depolarizing
current is able to travel passively between the nodes
of Ranvier. When the depolarizing current reaches the
next node of Ranvier, it encounters both Na+ ions and
Na+ channels, and so it can trigger another action potential at the node. The action potential gets retriggered,
or repeated, at each node of Ranvier and the depolarizing current moves passively along the myelinated portions of the axon to the next node. This type of conduction, which appears to hop from node to node, is called
saltatory conduction, from the Latin saltare, “to leap,
to dance” (Figure 19).
Figure 19: Saltatory conduction. Action
potentials are conducted down the myelinated axon via saltatory conduction. The
depolarization “jumps” from one node to the
next without decaying.
Why is myelination an advantage for the axon?
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 2.3
What are the advantages of myelination?
We can immediately see two advantages of saltatory conduction. The first is it saves energy. Sodium ions that enter axons
during the action potential must eventually be removed. You’ll
remember that the Na+ ions are removed by Na+/K+ pumps,
which use significant amounts of energy. As we mentioned
before, in axons that aren’t myelinated, these pumps must be
located along the entire length of the axon, because Na+ ions
can enter everywhere. However, in a myelinated axon, where
Na+ ions can only enter at the nodes of Ranvier, much less Na+
gets in, and consequently, much less needs to be pumped out.
Therefore, in myelinated axons much less energy is needed to
remove Na+ ions and maintain the high extracellular Na+ concentration.
Figure 20: Comparing action potential conduction in unmyelinated and
myelinated axons. The black arrows
represent current flowing down an
unmyelinated axon and the red arrows represent current flowing down
a myelinated axon. Notice how
much faster the myelinated current
travels.
The second advantage of myelin is speed. The action potential is conducted much faster in a myelinated axon because
transmission between the nodes, which occurs by means of
the axon’s cable properties, is very fast (Figure 20). Increased
speed enables us to react faster and undoubtedly to think faster. In fact, the fastest myelinated axon, 20 micrometers (µm) in
diameter, can conduct action potentials at speeds of 150 m/s,
or 335 mph!
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Think about your big toe neuron. Imagine the
axon starts under your armpit. How long will
an action potential take to travel down to your
big toe if is myelinated?
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55
LESSON READING
Under what circumstances would it be beneficial not to have myelinated axons?
Why aren’t all neurons myelinated?
Since myelin provides such important benefits – decreasing energy consumption and increasing speed –
why aren’t all of our axons myelinated? In fact, most of our axons are myelinated, but later we’ll argue that
having some unmyelinated axons is important.
DEFINITIONS OF TERMS
Demyelination – the loss of
myelin insulating neurons.
Saltatory conduction –
conduction of the action potential
from one node of Ranvier to the
next along a myelinated axon
Demyelination – the loss of
myelin insulating neurons
Take for example the so-called C fibers (fibers is just another name for nerve). C fibers are sensory neurons located in the PNS and involved in the pain response. They are not myelinated and their conduction
velocities are slow 2 m/s (or only 4.5 mph). But conducting pain information slowly, gives us an advantage
because we can respond to the source of the pain before the pain sensation becomes intense. Sometimes
it is actually beneficial for a signal to reach our brains more slowly.
What happens when myelin gets damaged?
Demyelination is the loss of the myelin sheath insulating neurons. As you might imagine, losing even a
part of the myelin sheath disrupts action potential conduction. When myelin is disrupted, conduction along
an axon may become desynchronized or even fail completely.
Demyelination is the hallmark of some neurodegenerative diseases including multiple sclerosis, (MS) and
Charcot-Marie-Tooth disease. Demyelination results in a set of symptoms that will depend on which neurons are affected.
We’ll talk more about demyelinating diseases in the last lesson of this unit, but for now remember that the
myelin sheath insulates the axon increasing the conduction velocity of the action potential, as well conserving the axon’s energy.
For a complete list of defined
terms, see the Glossary.
When does myelination occur?
Recently, research has shown that our brains
gradually add myelin as we mature. Figure 21 is
taken from one of the studies on which that statement is based. Remember, grey matter is where
neurons connect with each other and white matter is where the myelinated axons are. The study
Figure 21: Loss of grey matter and gain of white
analyzed changes in grey matter relative to white
matter from 5 – 20 years. Notice that our frontal
matter, so another way to look at the data is that
lobes are the last areas to become heavily myelinnot only does grey matter decrease, but white
ated and thus be represented as mostly white
matter also increases as we mature. Take a look
matter.
specifically our frontal lobes, which do not become fully myelinated until we are about 20. Some scientists have taken this further to argue that teenagers show poor judgment because their frontal lobes aren’t fully myelinated. This conclusion has been hotly
debated in the field, and might be one you’d like to take a minute to think about.
Mostly grey ma-er Mostly white ma-er Wo r k b o o k
Lesson 2.3
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What if your big toe neuron wasn’t myelinated? How long would it take the action potantial to reach your toe then? Would this be
an advantage or not?
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At what age does our frontal lobe become
myelinated?
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56
STUDENT RESPONSES
You just read about research that shows that the human brain, specifically the frontal lobe, is not heavily myelinated until the
age of 20. Some scientists argue that teenagers show poor judgment because their brains aren’t fully myelinated. What do you
think? Do you agree with the scientists’ arguments? Do you think there could be another explanation?
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Wo r k b o o k
Lesson 2.3
57
LESSON 2.4 WORKBOOK
What do our neurons need to work
efficiently?
We’ve learned that axons can be very long, and that most of
the proteins that make up their structures are made in the
cell body. We’ve also learned that proteins don’t last forever,
they wear out and need to be replaced – this includes all
the channels and the Na+/K+ pump that’s so important for
keeping the resting membrane potential stable, as well as
everything that’s needed to convert the action potential into
a chemical signal to cross to the other side of the synapse.
How can our neurons keep up with this relentless demand?
As you can imagine getting what’s needed to where it’s
needed, when it’s needed is a task that requires a highly
organized transport system that delivers cargo both into and
out of the axon. When this transport goes wrong, it can be a
big problem. This lesson will look at axonal transport.
Axon structure underlies axonal transport
We’ve used our big toe axons in several examples, but in fact axons can be anything from a few millimeters
to several meters long. The shortest axons belong to the interneurons that connect local areas within the
brain and can be less than 0.1 mm; the longest axons are the big toe axons that would be several meters
long if you were a giraffe. But all axons, short or long, have the same internal structure thanks to their cyto
(from the word for cell) – skeleton.
Wo r k b o o k
Lesson 2.4
The cytoskeleton is conveniently organized parallel to the length of the axon so it can provide the tracks
that transport cargo to and from the presynaptic terminal just like a railroad. The axon’s cytoskeleton has
three main protein components — microtubules, neurofilaments, and actin — each of which play different roles. Neurofilaments are like filler that hold the mature axon rigid and determine its diameter. Actin is
important when the axon is growing in the embryo and keep it flexible and able to move. Microtubules are
important for axonal transport, so we’ll focus on them here.
What are the benefits of having both short
and long axons?
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List one function for each component of the
axon cytoskeleton:
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58
LESSON READING
Microtubules provide the tracks on which cargo is transported
DEFINITIONS OF TERMS
Anterograde transport – movement of materials from cell body to
axon terminals.
Minus-end – end of microtubules
oriented toward cell body.
Minus-end directed motors –
molecular motors that travel toward
the minus-end of microtubules,
and thus carry cargo from the axon
terminal to the cell body.
Microtubules form the actual
Figure 22: Microtubule structure.
‘tracks’ that move cargo to and
Microtubules are composed of two
from the axon terminal. How
different forms of tubulin, α and β,
do they do this? They are holthat polymerize together to form a
low cylindrical polymers that
slightly polarized dimer. When the
are made from two different
dimers assemble, they then have a
forms of the tubulin protein
plus-end that is oriented toward the
axon terminal and a minus-end that
called alpha and beta tubulin.
is oriented toward the cell body.
These two tubulin isoforms
polymerize together to form a
hollow tube that is polarized,
meaning that one end is different from the other. The two different ends are called the plus-end and
the minus-end. In axons, all microtubules are oriented in the same way, with the plus-end toward the
presynaptic terminal, and the minus-end toward the cell body (Figure 22). Motors can attach to the microtubules. If they are plus-end directed motors, they will move toward the presynaptic terminal. If they
are minus-end directed motors, they will move towards the cell body. (Figure 23). We’ll talk more about
these motors in a minute. Cargo can attach directly to these motors and be transported from the cell body
into the axon and the presynaptic terminal (anterograde transport) or from the presynaptic terminal and
axon back to the cell body (retrograde transport).
Plus-end — end of microtubules
oriented toward axon terminal.
How does transport work?
Plus-end directed motors –
molecular motors that travel toward
the plus-end of microtubules, and
thus carry cargo from the cell body
to the axon terminal.
Retrograde transport – movement of materials from axon
terminals to the cell body.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 2.4
Figure 23: Axonal transport. The neuron
provides its terminal with important structural proteins and organelles via axonal
transport along the microtubule tracks.
Scientists knew that most protein synthesis occurred
in the cell body, and they deduced that there must be
a system that can transport these items efficiently to
where they were needed. Fortunately, major technological advances in microscopy occurred precisely
at the time we began to question exactly how materials are transported in the axon. One of the previous
problems had been in observing very small structures. New advances with lenses and computing allowed scientists to detect structures moving down the
axons. Using the newly developed tools that allowed
us to see the inside of living axons, scientists could
observe the movement of materials in axons and then
figure out exactly how transport works.
What kind of motors carry cargo to the axon
terminal? What motors carry cargo to the cell
body?
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Why do neurons need such an elaborate
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59
LESSON READING
Proteins are not transported down the axon individually. Instead the cell body organizes them into structures (organelles) like mitochondria or the spherical membrane vesicles that contain neurotransmitters.
DEFINITIONS OF TERMS
Anterograde transport – movement of materials from cell body to
axon terminals.
For a complete list of defined
terms, see the Glossary.
You can watch a video showing vesicles moving down an axon online — see this unit on the student
website or click the link below. In this case the particles have been tagged with a fluorescent marker
that allows them to be detected with a fluorescent microscope. The upper image shows the fluorescent
signal and the middle image shows the actual picture of the vesicles. In the bottom image they have
been merged.
■■ Video: Axonal Transport
Microtubules We knew that cargo had to get to both the preAnterograde synaptic terminal and back from it to the cell body.
transport From many different kinds of experiments that
used fluorescent and radioactive chemicals to
tag transported proteins, we found out there are
Retrograde transport basically two different ways to transport material
in the axon – fast and slow. Fast axonal transport
is used to get materials where they are needed
quickly – to the presynaptic terminal to be used
Figure 24: Fast axonal transport. There are
in neurotransmission across the synapse (antwo types of fast axonal transport: anterograde
terograde transport), or back to the cell body for
and retrograde. Anterograde transports moves
materials from the cell body towards the axon
recycling (retrograde transport). It’s fast because
terminal. Retrograde transport moves materials
it uses a lot of energy, and depends on the mifrom the axon terminal towards the cell body.
crotubule motors we talked about before (Figure
24). In contrast, slow axonal transport is used to
rebuild the axonal cytoskeleton itself – the microtubules, neurofilaments and actin polymers. Frankly, we
are still unsure about how slow transport works and it is an active area of research. Its important though
because a number of diseases affect slow transport and have serious consequences.
Fast transport – anterograde and retrograde
Anterograde transport
Wo r k b o o k
Lesson 2.4
The presynaptic terminal needs a constant supply of membrane vesicles, because as we shall see in the
next unit, it packages neurotransmitters into the vesicles so it can control their release into the synapse.
It (and the axon) also requires a constant supply of energy in the form of ATP, which is delivered by mitochondria. Hence vesicles and mitochondria need to be transported rapidly and on time, so the axon has
developed a sophisticated mechanism that directs them where they need to be.
What types of materials do you think get
transported via anterograde transport?
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What types of materials do you think get
transported via anterograde transport?
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60
LESSON READING
DEFINITIONS OF TERMS
Kinesin – plus-end directed motor
that carries cargo from the cell
body to the axon terminal along
microtubules.
Dynein – minus-end directed
motor that carries cargo from the
axon terminal to the cell body along
microtubules.
Retrograde transport – movement of materials from axon
terminals to the cell body.
Recall that fast transport uses microtuFigure 25: The plus-end diA. bules and motors, and that anterograde
rected motor protein: Kinetransport (meaning going to the presynsin. (A) Cartoon of kinesin
aptic terminal) uses plus-end directed
protein carrying organelle
down microtubule track
motors. These motors work by attaching
from the cell body to the
to and traveling along microtubles toward
B. axon terminal. (B) Electron
their plus-end which, again, is oriented
microscope photograph of
towards the presynaptic terminal. So, the
kinesin carrying a vesicle.
motors use the polarity of the microtutransport moves materibules as a cellular GPS. These plus-end
als from the axon terminal
towards the cell body.
directed motors are a family of proteins
called kinesins (Figure 25). In the cell
body, kinesins, which actually look exactly like legs and feet, attach to the cargo being transported down
the axon. The kinesin molecule then walks down the microtubule toward the plus-end at the presynaptic
terminal, carrying the cargo to its destination. Kinesin uses energy in the form of ATP to move itself and
its cargo down the microtubule. In fact it hydrolyzes one molecule of ATP for each 8 nanometer (nm) step
it takes down the microtubule. The vast amounts of energy needed to make this trip are supplied by the
mitochondria, so its clear that mitochondria will be needed in the axon as well as the presynaptic terminal.
You can watch a short video online showing how kinesin ‘walks’ down the microtubule towards the plus
end. The video was made using the actual structure of the kinesin molecule, and what is known about
how its shape changes as it hydrolyzes ATP and attaches to microtubules. The cargo would attach to the
two kinesin ‘arms’ that are sticking up.
■■ Video: Kinesin Transport Protein
Retrograde transport
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 2.4
Rapid retrograde transport returns materials from the presynaptic terminal or the axon to the cell body for recycling. As in fast
anterograde transport, cargo moves along microtubules attached
to a motor protein. In this case the motor is the minus-end directed
motor protein, dynein. Dynein works much the same way as kinesin, except it carries substances toward the cell body (Figure 26).
The combination of the polarity of the microtubules, and the specificity of the motors for the microtubules and their cargo, ensures
that cargo gets to the right place at the right time – this is crucial
if the axon terminal is going to function properly. While we’ve told
a simplified story here, keep in mind that the kinesins are actual a
family of proteins with more than 40 different kinesin proteins, each
specific for a particular cargo or particular destination.
Vesicle
Dynein
Microtubule
Figure 26: The minus end directed motor protein: Dynein.
Dynein carries cargo from the
axon terminal to the cell body
along the microtubule tracks.
What motor protein is responsible for getting
cargo from the cell body to the axon terminal? How does it work?
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What motor protein is responsible for getting
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STUDENT RESPONSES
Imagine you have nerve damage that affects your axonal transport systems, what symptoms would you have? Think about this
question in the light of what you know about the roles of axonal transport, and how neurons function to transmit signals.
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Wo r k b o o k
Lesson 2.4
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If kinesin uses one molecule of ATP for each 8 nm step, how much ATP is used to move one synaptic vesicle from a neuronal
cell body at the base of your spine to your big toe? (Assume that the distance from your spine to big toe is 3 feet (or 1 meter).
62
LESSON 2.5 WORKBOOK
What can go wrong?
Throughout this unit, we’ve discussed the basic structures and functions of the major cells that make our
nervous systems: neurons and glia. In this lesson, we’ll
investigate what happens when these functions are
compromised by disease or injury.
What if there are problems conducting action potentials?
We can make several predictions about when and how problems in conducting action potentials might
occur. For example, action potential conduction will be affected if:
•
•
The voltage-gated Na+ channels don’t function properly.
Myelination is abnormal.
If any of the above happens, we can predict what effect it will have on the neuron:
•
•
If the voltage-gated Na+ channels don’t function properly, the axon will be unable to generate action potentials properly.
If myelination is abnormal, then the axon will be unable to synchronize conduction of the
action potential and signaling may fail completely.
Diseases of axonal conduction
Let’s now investigate three diseases of action potential conduction in more depth:
Wo r k b o o k
Lesson 2.5
•
•
•
Congenital analgesia
Multiple Sclerosis (MS)
Charcot-Marie Tooth Disease (CMTD)
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63
LESSON READING
What are Gabby’s symptoms? What did her
doctor diagnose her with?
Congenital Analgesia – Case study of Gabby
Gabby is 5 years old (Figure 27). Her parents have consulted with
many specialists throughout their daughter’s life in hopes of finding
an explanation for why their daughter behaves so strangely.
DEFINITIONS OF TERMS
Congenital analgesia – disease
in which patients do not sense
pain.
For a complete list of defined
terms, see the Glossary.
Gabby’s parents first knew that something was wrong when Gabby
was only a few months old. Like other babies her age, she was teething. But unlike other babies, who would cry in pain, Gabby never
cried. One morning, her father noticed that she had been chewing Figure 27: Five year old Gabby.
on her fingers so much that they were bleeding, but again, she never
cried. Her mother described Gabby’s hand as “mangled and nasty, like raw hamburger”. After consulting
with several doctors, Gabby’s parents had all of her baby teeth removed so that she could not further harm
herself.
When Gabby was a year old, her mother noticed a white spot on her left eye. She thought it was just
something floating in Gabby’s eye, but in fact Gabby had somehow scratched her cornea. The doctor who
treated Gabby told her mother that “In most patients, this type of wound would be so painful, they would
not be able to open their eye”. To prevent Gabby from scratching her eye any more, the doctor stitched that
eye closed. But, unable to feel pain, Gabby ripped out the stitches.
These are just two of the incidents that brought Gabby’s parents into see a neurologist for further examination. The doctor diagnosed Gabby with congenital analgesia. Congenital analgesia is a very rare
inherited disease in which children, usually from birth, cannot sense pain even though their other senses
are normal. Like Gabby, children with this disease often suffer from oral damage, like biting off the tip of
their tongue, and scratches to the cornea.
Researchers have learned that the disease can be caused by a mutation in the gene that codes for a voltage-gated Na+ channel. This
voltage-gated Na+ channel (called SCN9A) is found specifically in the
specialized receptors that detect pain called nociceptors. In a normal person, when nociceptor dendrites detect a pain sensation, the
SCN9A Na+ channel will amplify the signal so it reaches threshold and
allows an action potential to fire. However, in patients with congenital
analgesia this voltage-gated sodium channel doesn’t work and thus
the input from the dendrites never reaches threshold so an action potential doesn’t fire (Figure 28).
Wo r k b o o k
Lesson 2.5
Congenital analgesia is not fatal, but patients suffering from it will
never lead a normal life. Because they can’t detect pain, they need
to closely monitor their bodies for injuries and infections. Even so, the
inability to feel pain causes complications that mean very few patients
with this disease live to a normal life expectancy.
Normal Pa)ent Congenital Analgesia X X Figure 28: Congenital analgesia. Patients do not feel pain
because a mutation in the
voltage-gated Na+ channels in
their nociceptors means an
action potential cannot fire, so
the nociceptors never detect
any pain.
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What is the neuronal defect in congenital analgesia?
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What is the treatment for congenital analgesia?
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64
LESSON READING
What are Maria’s symptoms? What did her
doctor diagnose her with?
Multiple sclerosis (MS) – Case study of Maria
DEFINITIONS OF TERMS
Multiple sclerosis (MS) – disease
in which myelin within the central
nervous system is damaged.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 2.5
Maria is 37 years old (Figure 29). She has been having reoccurring
episodes of muscle weakness in her arms and legs. The weakness
lasts for a week or two and then subsides. At other times she noticed
numbness in different parts of her body. Since the episodes came and
went, she did not think much of it until she started having changes in
her vision. First, she noticed that she was experiencing double vision,
and then she noticed that she was having problems seeing out of her
left eye. It was at this point that Maria called her doctor.
Figure 29: Maria, age 37.
Maria’s doctor started the appointment by reviewing Maria’s family history. Luckily, none of Maria’s extended family had ever suffered from a neurological disease. She then gave Maria a thorough examination. First, she checked her eye reflexes and noted that her left eye had a decreased pupillary reflex, which
means it didn’t respond to a bright light by contracting. Next, she checked Maria’s sensitivity to touch
sensation and found it was decreased in different parts of her body. The doctor ordered both an MRI to see
if there were any abnormalities in Maria’s brain, and a spinal tap to see if there were any abnormal proteins
in Maria’s cerebrospinal fluid. The MRI showed a couple of small areas in Maria’s brain where the myelin
looked abnormal (called plaques), and the spinal tap detected a high level of antibodies in her cerebrospinal fluid. The doctor gave Maria a preliminary diagnosis of multiple sclerosis, but told her that to confirm
the diagnosis; she would need to follow Maria’s condition and rule out any other neurological abnormality.
Multiple sclerosis (MS) can occur at any age, but is
most commonly diagnosed between the ages of 20
and 40. The disease affects more women than men.
MS is caused by damage to myelin within the central nervous system (Figure 30). The CNS myelin
is damaged because the immune system makes
antibodies against it, and the antibodies attack the
myelin, causing inflammation. Repeat episodes of
inflammation can occur anywhere in the brain, optic
nerve and spinal cord. We think that some aspect
of myelin’s structure must resemble an infectious
agent that previously infected the patient. The body
first made antibodies against the infection, but those
antibodies then become confused and attack the
patient’s own myelin. This is attack on self, causes
an autoimmune disease.
A. ___________________________________
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What is the neuronal defect in multiple sclerosis?
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What does the treatment for multiple sclerosis hope to do?
B. Figure 30: Multiple sclerosis. (A) Multiple
sclerosis is an autoimmune disease in which
a patient’s T cells destroy the glial cells that
myelinate CNS neurons. (B) MRI scans of
patients’ brains with multiple sclerosis show
areas of damaged myelin, appearing here as
denser plagues. Regions close to the ventricles
are commonly affected.
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65
LESSON READING
The symptoms of MS can vary based on the location of inflammation. The most common symptoms
include disturbances in vision, weakness, numbness or abnormal sensations in the arms or legs, muscle
spasms and loss of balance. The intensity of any episode and how long it lasts depends on the severity
of the inflammation in the CNS. However many patients experience even long periods without any symptoms, and during those stages they are said to be in remission. Most patients return near normal function
while they are in remission. But over time and with more episodes, function gradually declines. Even so,
most patients with MS remain able to walk and can function normally or with minor disability for 20 years
or more after diagnosis. Patients at later stages of disease may require a wheelchair to get around. MS is
a chronic disease that is currently incurable; treatment aims to slow the disease progression and lessen
symptoms. Even so, patients with MS have normal, or almost normal, life expectancies.
Charcot-Marie Tooth Disease (CMTD) – Case study of Allison
Allison is sixteen years old (Figure 31). Recently she noticed that she is
having a difficult time walking. Her feet and legs do not seem to be as
strong as they were even just a year ago. Allison considers herself to be in
good shape, but lately on her daily walks, she has been tripping frequently.
She has also been having a hard time breathing. During her yearly physical she mentioned these difficulties to her doctor.
Figure 31: Allison, age 37.
Allison’s doctor asked questions about her family history. Allison knew that
her uncle has a disease called Charcot-Marie Tooth Disease (CMTD). Her
uncle’s disease was diagnosed when he was in his early 20s and it has
made it difficult for him to walk and perform fine tasks with his fingers.
Concerned that Allison might be developing
CMTD too, her doctor examined Allison’s lower
legs carefully. He noticed that Allison’s legs look
a bit like an inverted champagne bottle because
she has lost a lot of muscle bulk in the lower
legs (Figure 32). Allison’s doctor also tested her
tendon reflexes and sensory perception. Given
Allison’s family history and worried by her poor
performance on these tests, the doctor also
ordered electrodiagnostic tests to see how well
Allison’s peripheral nerves were able to conduct
an action potential.
Wo r k b o o k
Lesson 2.5
A. B. Figure 32: Charcot-Marie
Tooth disease (CMTD).
(A) CMTD is caused
by damage to myelin in
the peripheral nervous
system. (B) “Stork legs”
seen in CMTD are due to
muscle wasting in the lower part of the leg because
innervation of skeletal
muscles is defective.
The tests are done by placing electrodes on the skin. These electrodes produce a small electric shock
which stimulates both sensory and motor nerves. A needle, inserted into the skin, measures the ability of
Allison’s nerves to conduct an action potential in response to the small electric shock. Unfortunately, Allison’s readings on this test indicate that her axons are not conducting action potentials as quickly as they
would in normal people.
What are Allisons symptoms? What did her
doctor diagnose her with?
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What is the neuronal defect in CMTD?
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66
LESSON READING
DEFINITIONS OF TERMS
Charcot-Marie Tooth Disease
(CMTD) – disease in which myelin
within the peripheral nervous
system is damaged.
Given her family history, and her results on the electrodiagnostic test, Allison’s doctor diagnosed her with
Charcot-Marie Tooth Disease (CMTD). CMTD is the one of the most common inherited neurological disorders. CMTD is commonly diagnosed when patients are in their teens or early twenties. CMTD is caused
by damage to the myelin sheath around peripheral nerves (Figure 32). Usually, the motor nerves in the
legs are affected first, causing lower leg weakness and muscle atrophy, as Allison saw. Sensory nerve
degeneration causes a reduced ability to sense heat, cold, and feel pain. In later stages of the disease,
similar symptoms may appear in the arms and hands as well as the legs. The severity of the symptoms
is variable between patients. CMTD is not fatal and patients with most forms of the disease have normal
life expectancies.
While there currently is no treatment, orthopedic shoes and braces may help patients to walk. Physical
and occupational therapy are also helpful for many patients because therapy helps to maintain muscle
strength.
You can watch a video of patients with CMTD online — click below or see this unit on the student website:
■■ Video: Charcot-Marie-Tooth Disease: A patient’s perspective
What if there are problems with axonal transport?
For a complete list of defined
terms, see the Glossary.
We can make several predictions about when and how problems in transport will occur. For example,
transport will be affected if:
•
•
•
The transport motors don’t function properly.
The microtubule tracks are disturbed.
The supply of ATP to the neuron is compromised or if mitochondria are defective.
If any of the above happens, we can predict the effect on the neuron.
•
•
If transport of organelles and mitochondria is affected, then the axon terminal will be unable to
function.
If transport of cytoskeleton is affected, then axonal structure and diameter will be abnormal.
Diseases of axonal transport
Let us now investigate three of these diseases in more depth:
•
•
•
Wo r k b o o k
Lesson 2.5
Hereditary spastic paraplegia (HSP)
Diabetic neuropathy
Alzheimer’s disease
For two of the three (diabetic neuropathy and Alzheimer’s disease) the disruptions to axonal transport occur as a result of the disease, but are not its cause. Regardless, when axonal transport doesn’t function
properly, neurons degenerate in all three diseases.
If you were going to design a drug to treat
CMTD, what would you have that drug do?
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67
LESSON READING
What are Mitchell’s symptoms? What did his
doctor diagnose him with?
Hereditary spastic paraplegia (HSP) – Case study of Mitchell
DEFINITIONS OF TERMS
Hereditary spastic paraplegia (HSP) – group of inherited
disorders that are characterized by
progressive weakness and stiffness of the legs, can be caused by
defects in axonal transport.
For a complete list of defined
terms, see the Glossary.
Mitchell is 17 years old and recently noticed that he has begun to
trip up frequently (Figure 33). As he paid more attention to why, he
noticed that he was having difficulty raising his legs to walk. Since he
thought this was odd, he mentioned it to his doctor during his yearly
physical. His doctor asked him to stand up, and then lift just his toes.
Mitchell had a really difficult time with it. The doctor prescribed physical therapy and asked Mitchell to make another appointment if his
symptoms got worse.
Figure 33: Mitchell, age 17.
A year later, Mitchell’s problem had not got better. He felt the muscles in his legs were often weak and quite
stiff. He also noticed that his sense of balance was not what it once had been. Sometimes his legs even
felt numb. He called the doctor and went back for another appointment.
After many tests, including an MRI, Mitchell’s doctor diagnosed him with hereditary spastic paraplegia
(HSP). HSP is characterized by progressive spasticity, defined as stiff or rigid muscles in the lower limbs.
Patients can also experience bladder disturbances, and impaired sensations in the feet. HSP can develop
at any age. Those patients who develop symptoms before the age of 35 have Type 1, and those patients
who develop symptoms after 35 have Type 2. For Type 1 cases, spasticity of the lower limbs is greater than
weakness of lower limbs so difficulty walking is not common. In Type 2 cases, muscle weakness, urinary
symptoms and sensory loss are more severe.
Mitchell’s doctor referred him to a specialist who was studying the genetic causes of HSP. The specialist
completed a genetic screen on Mitchell to determine if he was a carrier of the mutation his lab studied. As
it turned out, Mitchell did carry a mutation within the specialist’s gene of interest, KIF5A.
✖ ✖ KIF5A is a member of the kinesin family. Remember that Kinesins are plus-end directed motor proteins that carry cargo from
the cell body to the axon terminal. Research has demonstrated
that mutations within the motor part of the KIF5A protein can
cause HSP because fast anterograde axonal transport is disrupted, and this in turn disrupts axonal function (Figure 34).
There are currently no treatments to slow or reverse HSP. However, regular physical therapy is important for muscle strength
and to preserve range of motion.
Wo r k b o o k
Lesson 2.5
Figure 34: Hereditary spastic paraplegia can be caused by mutations within
the motor domain of kinesin proteins
that are responsible for transporting
cargo to the axon terminal.
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What is the neuronal defect in hereditary
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What does the treatment for hereditary spastic paraplegia hope to do?
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68
LESSON READING
What are Albert’s symptoms? What did his
doctor diagnose him with?
Diabetic Neuropathy – Case study of Albert
DEFINITIONS OF TERMS
Albert is 67 years old (Figure 35). He was diagnosed with type II
diabetes almost 17 years ago. Despite going on a diet and exercising, Albert has never been able to successfully manage the levels of
glucose in his blood, and get them under control, so they still remain
high (hyperglycemia). During the last year, Albert noticed a tingling
sensation in his feet. Since he is getting older, he did not think much
of it. However, when the tingling sensation developed into an actual
pain, he called his doctor.
Figure 35: Albert, age 67.
Diabetic neuropathy – disorder
in which nerves of the body are
damaged due to high blood sugar
levels resulting from diabetes
His doctor did a complete examination including testing Albert’s ability to detect sensations in his feet.
When Albert did not perform well on this test, she told him he has likely developed diabetic neuropathy, a
condition that commonly occurs in patients who have had diabetes for 10 to 20 years. Diabetic neuropathy
is a common complication of diabetes, in which nerves are damaged as a result of hyperglycemia.
For a complete list of defined
terms, see the Glossary.
Diabetic neuropathy can present with any number of symptoms, including tingling or burning sensations in
the feet, a deep pain in the arms or legs, muscle cramps, loss of sensitivity to warm or cold, loss of bladder
control, and vision changes. The symptoms vary depending on which nerves are affected. Usually feet
and legs are affected first, followed by hands and arms. While it is possible to slow diabetic neuropathy by
strictly controlling blood glucose levels, diabetes itself is incurable.
Figure 36: Diabetic neuropathy. Damage to blood vessels
in diabetes results in transport
defects because ATP supply
to the axons is compromised.
Wo r k b o o k
Lesson 2.5
Researchers have learned that diabetic neuropathy occurs when
the blood supply to nerves is reduced (Figure 36). Over an extended period of time, the high levels of glucose in the blood
damage blood vessels. These damaged blood vessels are less
able to deliver oxygen to peripheral neurons. Lack of oxygen to
nerves reduces their ability to generate ATP. Since fast axonal
transport is dependent on ATP, it is particularly vulnerable in diabetic neuropathy. When axonal transport is compromised, the
terminal degenerates, resulting in decreased sensitivity and motor control.
While there is no cure for diabetic neuropathy, the goal of treatment is to minimize the symptoms and prevent the disease from
getting any worse. It is critically important to control blood glucose
levels, and some medications can help reduce the symptoms in
the arms and legs.
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What is the neuronal defect in diabetic neuropathy? Would you expect myelinated or
unmyelinated nerves to be more affected?
How does that explain the symptoms?
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What does the treatment for diabetic neuropathy hope to do?
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69
LESSON READING
What are Yumiko’s symptoms? What did her
doctor diagnose him with?
Alzheimer’s disease (AD) – Case study of Yumiko
Yumiko is 66 years old and incredibly forgetful (Figure 37). Lately her family has
become very concerned. At a recent family dinner, Yumiko could not remember
the name of her favorite dessert – chocolate mousse pie. She also had difficulty
remembering how to get home from her son’s house. Then, later that week she
had to ask for help to balance her checkbook, something she used to do all the
time, often without a calculator.
DEFINITIONS OF TERMS
Alzheimer’s disease (AD) – major
cause of dementia in old age, characterized by neurofibrillary tangles,
amyloid plagues and neuron loss.
For a complete list of defined
terms, see the Glossary.
Figure 37: Yumiko,
When Yumiko saw her doctor, she described her symptoms and asked if her
age 67.
family’s worries were reasonable — that her forgetfulness was not normal, but
instead something to be concerned about. The doctor asked her a series of
questions about her memory, including whether or not she was having difficulty with language, misplacing
things, and thinking about abstract topics. He also asked whether or not she had noticed any changes in
her mood or behavior. Yumiko didn’t want to admit it, but after being pressed by her daughter she reluctantly answered that yes in fact she had been experiencing all of those things to some degree. The doctor
told Yumiko that yes, in fact these symptoms, together with her age were cause for further testing. He did
a complete physical exam and ordered a thorough neurological exam. The test results ruled out a brain
tumor, stroke, and thyroid disease, which all could also cause the symptoms Yumiko was experiencing, so
the doctor gave the diagnosis of Alzheimer’s disease (AD).
Alzheimer’s disease is the leading cause of dementia in the elderly. It is estimated that ten percent of people over 65 have AD, and that fifty percent of those over 85 have the disease. AD affects memory, thinking
and behavior. Problems with memory, as well as impairments with language, decision-making ability, judgment and personality must be present for the diagnosis to be made. AD is caused by an increased buildup
of tangles of neurofilaments within the cell bodies of neurons as well as increased numbers of protein
clumps called amyloid plaques at the synapse (Figure 38). Researchers have discovered that when the
plaques develop, neurons are not able to communicate with each other. Perhaps due to the accumulation
of tangles within the neural cell body, or perhaps due to defects in neuronal signaling, neurons start to die.
Patients with AD often die earlier than normal, although a patient may live anywhere from 3 to 20 years after the diagnosis.
The final phase of the disease, in which patients no longer
understand language, recognize family members, and are unable to perform basic activities of daily living, may last from a
few months to several years. Death usually occurs from an
infection or failure of other body systems. While there is no
cure for AD, treatment focuses on slowing the progression of
the disease.
Wo r k b o o k
Lesson 2.5
You can watch a video about the changes to neurons that we
see in Alzheimer’s disease online — click below or see this
unit on the student website:
■■ Video: Inside the Brain: Unraveling the Mystery of
Alzheimer’s Disease
Figure 38: Alzheimer’s disease.
Alzheimer’s disease results in an
buildup of neurofibrillary tangles within
f neurons as well as amyloid plaques
within the synapse.
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What are the neuronal defects in Alzheimer’s
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If you were designing a drug to treat Alzheimer’s disease, what would you have it do?
When would you start giving the drug?
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STUDENT RESPONSES
In the figure below, label the parts of the neuron and list a function for each part. Describe what could possibly go wrong
within the different parts of a neuron. What symptoms might a patient display should these problems arise?
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Wo r k b o o k
Lesson 2.5
71
Unit 3: How do our neurons
Overview
communicate with each other?
In the last unit we learned all about the main cells that make up our nervous system – neurons and glia – and how they work. This
unit will build on our knowledge of the neuron by exploring how neurons are able to communicate with each other. This process,
called synaptic transmission, enables neurons to send signals from one part of the brain to another and ultimately to control all of
our behaviors. This unit uses the experience of pain (something we can all relate to!) as the framework we will use to investigate how
synaptic transmission occurs.
Remember our graphic from the beginning of this workbook? This unit focuses on the synapse, which is the “connection” zone
between two neurons.
LESSON 3.1 WORKBOOK
Why do we all experience different
levels of pain?
DEFINITIONS OF TERMS
Pain – unpleasant sensory and
emotional experience associated
with actual or potential tissue
damage
This unit introduces you to the process of synaptic
transmission, which is how neurons are able to communicate with each other. We will frame our exploration in the context of how we experience pain (something we can all relate too). In this lesson we will begin
by examining how many different factors influence
how we perceive pain.
What is pain?
For a complete list of defined
terms, see the Glossary.
Pain is a curious phenomenon. It’s more than a simple sensation like hearing, because of the highly
charged emotions associated with it. Pain researchers define pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage”. Note the tight linkage between the
emotional and sensory components of pain, which is not always the case for our other senses. Both the
emotional and sensory components are clearly crucial to our perception of pain.
You might ask why we experience pain in the first place. The answer is that in most cases, pain plays
a protective role. For example, inflammation, which often accompanies skin or muscle injuries, greatly
increases how sensitive the inflamed region is to stimuli. This increase in sensitivity motivates us to minimize movement of the injured area and avoid banging it, which could cause pain. In the end, both of these
behaviors work together to reduce the likelihood of further injury.
There is a key distinction between the neural mechanisms by which we sense pain and pain itself – which
is our response to actual (or even perceived) tissue damage. The distinction is very important, both clinically and experimentally. Sensing pain does not necessarily lead to the perception of pain. In fact the intensity of the pain felt depends as much on the individual and the surrounding conditions as on the sensory
stimulus itself. Hence there is no such thing as a ‘painful’ stimulus that will always cause the perception of
pain in everyone.
Wo r k b o o k
Lesson 3.1
This first lesson of this unit focuses on the many different factors that can influence how we perceive pain.
But before we can dive into that discussion, we first need to review how the researchers who study pain
know for sure that we each experience a painful stimulus differently.
What was your most physically painful experience? What happened? And how did you
feel?
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Why do you think some people cringe at the
idea of getting a shot and others voluntarily
sign up for (and actually pay) to get tattoos?
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LESSON READING
How can we study pain?
DEFINITIONS OF TERMS
Pain threshold – the intensity of
a stimulus at which a subject says,
“It’s painful” half of the time, and,
“It’s not painful” the other half of the
time.
Pain tolerance – maximum level
of pain people will voluntarily accept .
For a complete list of defined
terms, see the Glossary.
If you wanted to ask someone to describe the pain they are experiencing, how might you do it? The task
is made difficult because we don’t have a good vocabulary to describe the experience of pain – it either
hurts a lot, or it doesn’t hurt a lot. On the other hand, we do provide good involuntary cues about the pain
we are experiencing through our facial expressions and bodily reactions. We are very good at decoding
facial expressions of pain, to the point of being able to distinguish between facial responses to genuine
pain and facial expressions that feign pain (Figure 1). Although these involuntary responses to pain
are useful, researchers have devoted a great deal of effort trying to provide people with a vocabulary to
articulate how they perceive pain.
The first thing researchers did was to determine what someone’s pain threshold is. Pain threshold is the
intensity of stimulation at which a person says, “It’s painful” half of the time, and, “It’s not painful” the other
half of the time.
Pain thresholds depend on many different factors. For instance, different parts of the body have different sensitivities to pain. The cornea, back of the knee, and neck region are particularly sensitive. On the
other hand, tip of the nose, and the inside lining of the cheek are particularly insensitive. If you’ve ever
compared the pain you feel after a tiny paper cut on the tip of a finger to the pain you feel after a gash on
the sole of your foot – you’re already well aware that different parts of your body have different sensitivities to pain.
A term related to pain threshold is pain tolerance.
Pain tolerance is the maximum pain level that
people will voluntarily accept. As you might imagine,
research on pain tolerance is even more difficult to
conduct because of ethical considerations.
We have found enormous variation in both the
threshold and tolerance individuals have to pain. For
instance, in one study in which researchers used an
electrical shock to produce consistent painful stimuli
in 40 participants, they found an eight-fold difference
between the smallest to largest pain threshold and
tolerance. That is to say any one stimulus could be
perceived by one person as being below their pain
threshold, whereas the same stimulus would be
perceived as being above someone else’s.
Wo r k b o o k
Lesson 3.1
Now, the question becomes – what causes this difference in pain threshold and pain tolerance?
Figure 1: Real and faked pain facial expressions. Can you tell which frame represents
the one where the subject was actually in pain
(hand submerged in ice water)? For both subjects, the frame on the left represents their face
when they were actually in pain. The frame on
the right represents their facial expression when
they were asked to fake being in pain. (Image
taken from Littlewort et al. 2007)
Have you ever noticed circumstances that
adjust your pain threshold? Meaning that in
one circumstance a stimulus is painful and
in another it’s not as bad? (Attitude, expectations, etc.)
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Where do you think your pain tolerance is
compared to other people? Do you think
you can withstand more pain than most,
and have a high tolerance? Or do you think
you’re fairly sensitive and have a low tolerance? Give an example.
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LESSON READING
Pain Modifiers
Our perception of pain can be modified by opiate painkillers, sugar pills, past experiences, suggestion,
hypnosis and even by activating other sensations at the same time, such as happens during acupuncture.
Environmental events can also diminish pain perception. For example, one researcher noted that many
wounded American soldiers returning from battles during World War II reported that they felt no pain from
their wounds. They did not even want pain medication. It seemed that their perception of pain was reduced
by the relief they felt that they had survived such a terrible ordeal. There are other examples in which
people report that even though they can perceive pain they aren’t bothered by it. Some tranquilizers have
this effect, and they are often used during oral surgery. Some kinds of brain damage also have this effect.
Does gender play a role?
Any mother will tell you that if men needed to go through the excruciating pain of childbirth, the human race
would have gone extinct long ago. According to feminine lore, men simply can’t handle pain. The tiniest discomfort is enough to reduce most men into helpless, whimpering heaps. Women, on the other hand, can
handle the tough stuff. The trouble with this theory is – it’s probably wrong, or at least it’s not the whole story.
Some research suggests that women actually have lower tolerance for many kinds – but not all kinds – of
painful stimuli. Other research suggests that men and women may experience pain differently because
women use estrogen to reduce how much pain they perceive. That same research is now investigating
whether a woman’s menstrual cycle plays a role in her perception of pain. So, the fact remains, no one really knows for sure if women and men perceive pain differently.
Your brain itself has no pain
Curiously enough, the outside of your brain doesn’t feel a thing. Surgeons can, and do, touch the outer
surface of brains during surgery. That’s because the perception of any stimulus, including pain, depends
on the presence of sensory neurons with receptors that respond to pain, and your brain (and other internal
organs) don’t have very many of these. In fact, your internal organs in total house only about 2 – 5 percent
of any of the sensory neurons in the body.
Because of this, while we can keep close touch (literally) with the world around us, we have limited conscious awareness of what’s going on in our innards – possibly we have evolved this way because most
threats we need to deal with come from the external environment. Pain receptors (remember they’re called
nociceptors) do exist near your brain: they’re in its blood vessels and in the meninges that surround it. In fact
one of the likely sources of migraine headache pain is from the nociceptors that are found in the meninges.
Wo r k b o o k
Lesson 3.1
Do you think men and women have different
tolerances for pain? From your own observations, would you expect that women have
a lower tolerance for pain than men?
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STUDENT RESPONSES
Why do you think so many different things are able to change our perception of pain? Why would and how could this be beneficial?
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Wo r k b o o k
Lesson 3.1
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LESSON 3.2 WORKBOOK
How do our neurons communicate
with each other?
This lesson introduces you to how one neuron communicates with another neuron during the process of synaptic transmission. In this lesson you will learn how the
electrical signal of the action potential is converted into
a chemical signal at the nerve terminal, and how this
chemical signal crosses the small gap, the synapse,
between the presynaptic and the postsynaptic neuron.
Getting pain to the brain
Pain pathways deliver information about painful stimuli (nociceptive information) using an ascending pathway that travels from the nociceptive receptors in the periphery to the brain. The pathway has four important neurons, each of which plays a different role in transmitting and interpreting the painful signal (Figure
2):
• The first, or primary, neuron is at the very beginning of the pathway. The end of its dendrites in
the periphery is where the nociceptive stimulus is first encountered. Its presynaptic terminal is
in the spinal cord and connects with…..
Wo r k b o o k
Lesson 3.2
•
The dendrites of the second neuron, which is located in the spinal cord. This neuron gathers
nociceptive information from several primary neurons into distinct pathways that ascend in the
white matter of the spinal cord. Their presynaptic terminals are in the thalamus and connect
with……
•
The third neuron, which is located in the thalamus. The thalamus is like a post office that gathers information and sends it to the right place in the cortex. So their presynaptic terminals are in
the cortex where they connect with…
•
Neurons in region of the cortex that deals with receiving sensory information about pain
(somatosensory cortex). Within the cortex these neurons also communicate with cortical areas
having other information about the environment and emotion, so that the body can initiate a
response.
Now that we know about the four neurons involved in getting pain information to the brain, let’s focus on
how the neurons communicate with each other at the synapses between them.
What are the four neurons involved in getting
pain to the brain? Where are they and what
role do they play in the pathway?
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77
LESSON READING
An introduction to synaptic transmission
DEFINITIONS OF TERMS
Neurotransmitters – chemicals
that are released by the axon
terminal and convey the message
across the synapse to another cell.
Postsynaptic potentials – small
changes in voltage (membrane
potential) due to the binding of
neurotransmitter.
Receptors – proteins that contain
binding sites for particular neurotransmitters.
For a complete list of defined
terms, see the Glossary.
Synaptic transmission is the major way that neurons communicate with each other across the small gap
between the presynaptic site and postsynaptic site called the synaptic cleft. When we left the presynaptic
terminal, an electrical signal — the action potential — had traveled down the axon. However the action
potential, being electric, can’t jump the synaptic cleft between the pre- and postsynaptic sites. To transmit
the message to the postsynaptic site the neuron must convert the electrical signal to a chemical one. This
chemical signal is carried by neurotransmitters – chemicals that are released when the axon terminal is
stimulated by the action potential.
Sensory neuron Projec'on neuron Motor neuron Interneuron Figure 2: The synapses in the pain pathway. The synapses in the
pain pathway allow for modulation of pain stimuli. The first synapse
is in the periphery, where nociceptors are initially activated. The
second synapse is in the spinal cord. The third synapse is in the
thalamus (not shown here) and the fourth synapse is in the cortex.
The neurotransmitters diffuse
across the synaptic cleft to the
postsynaptic site where they bind
to specific receptors that recognize them on the postsynaptic
membrane. Once the neurotransmitter has bound to the receptor it
can produce a postsynaptic potential – a brief depolarization or
hyperpolarization in the postsynaptic membrane that happens
because the neurotransmitter
receptors themselves are associated with ion channels.
If enough postsynaptic potentials occur, the membrane may be pushed toward or away from threshold,
depending on whether the membrane has depolarized or hyperpolarized, increasing or decreasing the
likelihood of the postsynaptic neuron firing an action potential and sending the signal down its axon to
another synapse.
Since there are obviously several steps involved in synaptic transmission, let’s investigate each one in
more detail. We’ll start our more detailed discussion of synaptic transmission by taking a closer look at the
synapse.
Wo r k b o o k
Lesson 3.2
How is synaptic transmission different from
the action potential? Compare where the two
signals occur and how the signal is sent.
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78
LESSON READING
Why do you think mitochondria are located in
the presynaptic terminal?
The Synapse
DEFINITIONS OF TERMS
The word synapse was coined in 1897 by the British physiologist
Sir Charles Sherrington (Figure 3) from the Greek word synapo,
which means “to clasp”. Using only a light microscope, Sherrington
could not see the actual point of communication between neurons, but his experiments had shown that transmission can only
occur in one direction (from what we now call the presynaptic cell
to the postsynaptic cell). Sherrington even correctly inferred that
the sending (presynaptic) and receiving (postsynaptic) cells do not
actually touch each other.
Presynap)c cell Synaptic vesicles – small spherical membranes that store neurotransmitters and release them
into the synaptic cleft
Microtubule Axon Mitochondrion Presynap)c membrane Postsynap)c membrane For a complete list of defined
terms, see the Glossary.
Figure 3: Sir Charles Sherrington
(1857 – 1952). For his work, he
was awarded the Nobel Prize for
Physiology or Medicine in 1932.
Postsynap)c cell Figure 4: Structure of a typical synapse. The presynaptic
membrane faces the postsynaptic membrane. Notice that
the presynaptic cell contains both large and small synaptic
vesicles, mitochondria and microtubules. Notice that the
postsynaptic membrane contains receptors sites that will
bind neurotransmitter.
Figure 4 illustrates a synapse. The presynaptic membrane, located at the end
of the axon terminal, faces the postsynaptic membrane, located on the neuron
receiving the information. These two
membranes face each other across the
synaptic cleft, a gap that varies in size
from synapse to synapse but is usually
around 20 nanometers (nm) wide.
The presynaptic terminal
As you may have noticed in Figure 4, the axon terminal contains two prominent structures: mitochondria
and synaptic vesicles. (We can also see the microtubules, which as you will remember are responsible
for transporting the mitochondria and vesicles from the cell body where they are made to the terminal.)
Because the terminal is often swollen to contain all this material it is often called the terminal ‘button’ or
more precisely ‘bouton’, which is simply button in French.
Wo r k b o o k
Lesson 3.2
Recall from Unit 2 that vesicles are small, hollow, beadlike structures that are transported down the axon
from the cell body. In the synaptic terminal most of them are filled with neurotransmitters and become
synaptic vesicles. Axon terminals can contain as few as a few hundred and as many as nearly a million
synaptic vesicles.
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79
LESSON READING
The postsynaptic terminal
The picture in Figure 5 was taken with a very
high resolution electron microscope, and shows
that the postsynaptic membrane appears somewhat thicker and more dense than the membrane elsewhere. This increased density occurs
because the postsynpatic membrane is loaded
with neurotransmitter receptors – specialized
proteins that detect the presence of neurotransmitter in the synaptic cleft because the neurotransmitters bind to them very specifically.
What are neurotransmitters?
Figure 5: Electron micrography of an synapse.
This photography shows a cross section of a
synapse. The axon terminal is filled with synaptic
vesicles (upper left corner). The postsynaptic
membrane on the dendritic spine appears thicker
and denser than the other membranes; this is
due to the presence of receptors.
Neurotransmitters are the chemicals neurons release in order to communicate with other cells. Scientists
first thought that only a few chemicals were involved in neurotransmission, but we have now identified over
100 different neurotransmitters. Fortunately, most of them conveniently fall into a small number of chemical
classes. See Box 3.1 for descriptions of your body’s primary neurotransmitters.
BOX 3.1: Your Neurotransmitters
There are more than a hundred different neurotransmitters, with more being discovered all the time.
Scientists are finding that many hormones can also play the role of transmitter as well. Here are some
the neurotransmitters your brain uses every day:
Acetylcholine (ACh) gets us going. It excites cells, activates muscles, and is involved in wakefulness,
attentiveness, anger, aggression, and sexuality. Alzheimer’s disease is associated with a shortage of
acetylcholine.
Glutamate is a major neurotransmitter that excites other neurons. It is dispersed widely throughout the
brain. It’s involved in learning and memory.
GABA (gamma-aminobutyric acid) is your brain’s main inhibitory neurotransmitter. It slows everything
down and helps keep your systems in balance. It helps regulate anxiety.
Epinephrine, also known as adrenaline, keeps you alert and your blood pressure balanced, and it
jumps in when you need energy. It’s produced and released by the adrenal glands in times of stress.
Too much can increase anxiety or tension. Norepinephrine (noradrenaline) is a precursor and has
similar actions.
Wo r k b o o k
Lesson 3.2
Dopamine (DA) is vital for voluntary movement, attentiveness, motivation and pleasure. It’s a key player
in addiction, so we’ll discuss it again in Unit 5.
Serotonin helps regulate body temperature, memory, emotion, sleep, appetite, and mood. Many antidepressants work by regulating serotonin.
What neurotransmitters have you heard of
before and in what context?
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80
LESSON READING
Release of neurotransmitter
When action potentials are conducted down the axon and enter the presynaptic terminal, something
happens inside the terminals – a number of small synaptic vesicles spill their contents into the synaptic
cleft (Figure 6).
DEFINITIONS OF TERMS
2. Exocytosis – process by which
the contents of membrane bound
vesicle are released to the exterior
through fusion of the vesicle membrane with the cell membrane.
For a complete list of defined
terms, see the Glossary.
3. 4. 1. 5. 6. Figure 6: Steps involved in synaptic transmission. See
text for descriptions, then write your own summary.
How does an action potential cause synaptic vesicles to release neurotransmitter
into the synaptic cleft? The process begins when an action potential invades the
presynaptic terminal (Figure 6: Step 1).
Then, some of the synaptic vesicles closest to presynaptic membrane become
‘docked’ at a region in the presynaptic
terminal called the ‘active zone’. Docking
happens when clusters of proteins on the
outside of the synaptic vesicle attach to
other proteins located on the inside of the
active zone. Once they are docked, synaptic vesicles are ready to release their
neurotransmitter into the synaptic cleft.
Synaptic vesicles only release their neurotransmitter when the action potential tells them to. How does
this happen? We need to introduce another player located at the presynaptic terminals — the voltagegated calcium channel. Voltage-gated calcium channels are similar to voltage-gated sodium channels
in that they only open when the membrane depolarizes. They are different from voltage-gated sodium
channels because they are permeable to calcium ions (Ca2+), not Na+ ions. Like Na+ ions, calcium ions
(Ca2+) are located in highest concentration in the extracellular fluid, so when an action potential arrives
at the presynaptic terminal and depolarizes the membrane, the calcium channels open and Ca2+ floods
into the presynaptic terminal, propelled by the forces of diffusion and electrostatic pressure as we talked
about in Lesson 2.2 (Figure 6: Step 2).
Wo r k b o o k
Lesson 3.2
The entry of Ca2+ into the presynaptic terminal is an essential step in synaptic transmission because it
gives the synaptic vesicles the signal to release their neurotransmitter into the synaptic cleft. The Ca2+
ions bind with the cluster of proteins that docked the membrane of the synaptic vesicles with the active
zone. The binding of Ca2+ changes the shape of these proteins, making them move apart. As they move
apart a hole or pore appears in both the synaptic vesicle and the active zone it is attached to. Both membranes then form a fusion pore so the synaptic vesicles can release their contents into the synaptic cleft.
Another name for this process of fusion and release is exocytosis (Figure 6: Step 3).
The arrival of an action potential triggers the
release of neurotransmitters. How does it
trigger this release?
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The entry calcium ions into the presynaptic
terminal is another important step in the release of neurotransmitter. What happens after calcium levels rise?
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With synaptic vesicles fusing to the presynaptic membrane, how does the presynaptic
membrane not just continually increase in
size?
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LESSON READING
DEFINITIONS OF TERMS
Endocytosis – process by which
matter is taken in by a living cell
by invagination of its membrane to
form a vesicle.
Postsynaptic potentials – small
changes in voltage (membrane
potential) due to the binding of
neurotransmitter.
For a complete list of defined
terms, see the Glossary.
What happens to the membrane of the synaptic vesicles after they have broken open and released the
neurotransmitter they contain? If the open vesicles have not completely collapsed onto the presynaptic
membrane they can simply pinch off again and drift away to be filled once more with neurotransmitter.
This has been called ‘kiss and run’. Other times the fusion pore becomes so large that the vesicles seem
to flatten down and merge entirely with the presynaptic membrane. In these cases the little buds of the
presynaptic membrane pinch off back into the terminal, effectively creating new synaptic vesicles. Another
name for this process of pinching off and recovery is endocytosis.
Activation of receptors
How does the release of neurotransmitters from the presynaptic terminal into the synaptic cleft produce
an effect in the postsynaptic cell? The answer to this question begins with the binding of neurotransmitters to their receptors on the postsynaptic cell membrane (Figure 6: Step 4). Once this binding occurs,
the postsynaptic receptors too change their shapes, and in the process open ion channels located in the
postsynaptic membrane. These ion channels, which are called receptor-gated ion channels, because
they are activated by receptors, not by voltage, permit specific ions to pass into or out of the postsynaptic
cell (Figure 6: Step 5). Thus, the neurotransmitter in the synaptic cleft, by binding to receptors, allows
particular ions to pass through the postsynaptic cell’s membrane, changing the membrane potential at the
postsynaptic site and creating postsynaptic potentials.
Termination of synaptic transmission
Postsynaptic potentials are therefore brief changes in the postsynaptic membrane potential caused by the
activation of postsynaptic receptors by neurotransmitters. They are kept brief because the neurotransmitter is rapidly removed from the synaptic cleft, and once it is removed it can no longer activate its receptors.
Neurotransmitters can be removed by two mechanisms:
•
•
Wo r k b o o k
Lesson 3.2
Reuptake
Degradation by enzymes
Almost all central nervous system neurotransmitters are removed by reuptake (Figure 6: Step 6). This
simply involves taking the neurotransmitter back into the presynaptic terminal again, using a special energy-dependent pump called a transporter. This means that from the time that an action potential stimulates
release of neurotransmitter into the synaptic cleft, until the presynaptic terminal takes it back up again,
the postsynaptic receptors only have a brief exposure to the neurotransmitter. The process of reuptake
ensures that postsynaptic potentials are also quite brief.
The binding of neurotransmitters to receptors
causes ion channels to open, thus changing
the membrane potential in the postsynaptic
neuron. Can you predict how this change in
membrane potential might affect the postsynaptic neuron? What might result from this
change in membrane potential?
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Certain drugs inhibit the reuptake of neurotransmitter from the synaptic cleft. What
would happen if this reuptake was blocked?
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LESSON READING
Neurotransmitters can also be broken down in the synaptic cleft by enzymes. As far as we know only one
neurotransmitter is dealt with in this way, but it is an important one. Acetylcholine (ACh) is the neurotransmitter used at our neuromuscular junctions, where neurons instruct our muscles to contract. It is critical
that the postsynaptic potentials produced by ACh be short-lived because the quick breakdown of ACh is
important for us to have tight control over the timing of muscle contraction. So at the neuromuscular junction the synaptic cleft is awash with the specific enzyme that can chew up ACh, and stop it binding to its
receptor.
Summary
In conclusion remember that the communication between neurons requires several steps. First the presynaptic cell must fire an action potential. Once the action potential invades the presynaptic axon terminal,
the presynaptic cell releases neurotransmitters into the synaptic cleft. These neurotransmitters then cross
the synapse and bind to receptors on the postsynaptic cell. After binding to receptors, neurotransmitters
cause postsynaptic potentials in the postsynaptic cell.
Wo r k b o o k
Lesson 3.2
What do you predict would be the effect of
drugs or toxins that stop the breakdown of
ACh in the neuromuscular junction?
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83
STUDENT RESPONSES
On the diagram below, label and describe the steps of synaptic transmission.
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The goal of synaptic transmission is to send a signal from one neuron to another. Does it matter which ions channels open and
which ions flow into the postsynaptic cell? (Hint: Think about the effect positive and negative ions would have on the chances of
the postsynaptic neuron reaching threshold.)
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Wo r k b o o k
Lesson 3.2
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LESSON 3.3 WORKBOOK
Why does applying pressure relieve
pain?
DEFINITIONS OF TERMS
Postsynaptic potentials – small
changes in voltage (membrane
potential) due to the binding of
neurotransmitter.
Receptor-gated ion channels
– ion channels that open or close
in response to the binding of a
neurotransmitter.
For a complete list of defined
terms, see the Glossary.
In the last lesson, we learned how neurons send signals
across the synaptic cleft via synaptic transmission. But two
questions remain — how does this type of signaling result
in an action potential in the postsynaptic cell? And thinking back to our pain framework, how does communication
between neurons in the pain pathway allow us to control
how we perceive painful stimuli? The answer to both questions lies in the specialized structure at the start of the axon
where the action potential originates — the axon hillock.
Postsynaptic potentials
Remember that the local changes in membrane potential created by neurotransmitters binding to their
receptors at the synaptic cleft are referred to as postsynaptic potentials. Interestingly, the kind of
postsynaptic potential a particular synapse produces does not depend on the neurotransmitter itself.
Instead, it is determined by the characteristics of the postsynaptic receptors the neurotransmitter binds
to – in particular, by the specific type of ion channel they open. Receptor-gated ion channels in the
postsynaptic membrane are much more versatile than the voltage-gated ion channels in the axon. First,
the postsynaptic membrane contains more than just Na+ and K+ channels. The postsynaptic membrane
contains anion channels (permeable to negatively charged ions) as well as other cation channels (permeable to positively charged ions). Second, receptor-gated ion channels can move ions out of the postsynaptic cell as well as into it. This means that the receptor-gated ion channels can have a varied range
of effects on the postsynaptic cell, as we shall see. The end goal of all these effects is on the threshold
that regulates whether an action potential will fire.
We can identify two major types of receptor-gated ion channels in the postsynaptic membrane: cation
channels (permeable to positively charged ions) and anion channels (permeable to negatively charged
ions):
Wo r k b o o k
Lesson 3.3
Two cation channels permeable to:
Sodium (Na+)
Calcium (Ca2+)
One anion channel permeable to:
Chloride (Cl-)
What causes receptor-gated ion channels to
open? How is that different from the voltagegated channels we saw in the axon?
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Why does opening sodium or calcium ion
channels cause a neuron to depolarize?
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Why does opening chloride ion channels
cause a neuron to hyperpolarize?
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LESSON READING
DEFINITIONS OF TERMS
Excitatory postsynaptic
potentials (EPSP) – graded
postsynaptic depolarizations,
which increase the likelihood
that an action potential will be
generated.
Inhibitory postsynaptic
potentials (IPSP) – graded
postsynaptic hyperpolarizations,
which decrease the likelihood
that an action potential will be
generated.
Integration – adding or
combining a number of individual
signals into one overall signal.
For a complete list of defined
terms, see the Glossary.
Note that these channels are different from the voltage-gated sodium and calcium channels we talked
about on the axon and the presynaptic terminal because they are stimulated to open by a neurotransmitter binding to its receptor, and not by a change in voltage. When channels open that are permeable to
either sodium or calcium, Na+ or Ca2+ ions can enter the cell, as we saw before. This entry of positive
ions depolarizes the postsynaptic membrane, making the membrane potential more positive, or phrased
another way, less negative. This is called an excitatory postsynaptic potential (EPSP) and it brings the
postsynaptic cell closer to the threshold for firing an action potential. However, when channels that are
permeable to chloride (Cl-) open, the negatively charged Cl- ions that are in high concentration outside the
cell, are pushed inside by the force of diffusion. This entry of negative ions hyperpolarizes the postsynaptic
membrane, making the membrane potential more negative. This is called an inhibitory postsynaptic potential (IPSP) and it brings the postsynaptic cell farther away from the threshold to fire an action potential.
Threshold – Voltage at which Na+ channels open Inhibitory Postsynap/c poten/als (IPSP) caused either by entry of Cl-­‐ ions, or exit of K+ ions Excitatory Postsynap/c poten/als (EPSP) caused by entry of either Na+ or Ca2+ ions Figure 7: Getting to threshold. IPSPs decrease the chance of
reaching threshold because they make the membrane potential
more negative. EPSPs increase the chance of reaching threshold because they make the membrane potential more positive.
Recall that an action potential is only
initiated after the threshold that opens
the axon’s voltage-gated Na+ channels
is reached. Because EPSPs depolarize the postsynaptic membrane, they
bring the membrane potential closer
to threshold, increasing the likelihood
that the voltage-gated Na+ channels
will open and the postsynaptic neuron
will fire an action potential. Conversely
because IPSPs hyperpolarize the
postsynaptic membrane they move
the membrane potential further away
from threshold, decreasing the likelihood the voltage-gated Na+ channels
will open and the postsynaptic neuron
will fire an action potential. (Figure 7).
Remember though that a single dendritic tree may have hundreds of thousands of synapses, all of which
receive inputs from presynaptic terminals. What happens when an EPSP and an IPSP arrive at the same
time close to each other? Do they simply cancel each other out in the membrane? Obviously this isn’t a
good solution and each neuron has the job of integrating all these many different types of inputs into a
coherent output. They do this through the process of integration.
Wo r k b o o k
Lesson 3.3
Why do EPSPs increase the likelihood of firing an action potential?
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Why do IPSPs decrease the likelihood of firing an action potential?
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LESSON READING
Excitatory Synapse: Neurotransmi4ers open Na+ or Ca2+ channels producing EPSPs. Inhibitory Synapse: Neurotransmi4ers open either K+ or Cl-­‐ channels producing IPSPs. DEFINITIONS OF TERMS
Axon hillock – specialized part of
a neuron‘s cell body that connects
to the axon. As a result, the initial
segment or axon hillock is the site
where action potentials originate.
Axon hillock reaches threshold and acDon potenDal is fired. IPSPs encounter EPSPs. Threshold is not reached and no acDon potenDal is fired. Figure 8: Axon hillock. The axon hillock generates an action potential if the excitatory inputs
reach threshold to open the voltage-gated Na+ channels. The axon hillock will not generate
an action potential if the inputs do not reach the threshold to open the voltage-gated Na+
channels.
For a complete list of defined
terms, see the Glossary.
The integration of all local postsynaptic potentials (EPSPs and IPSPs) occurs in the axon hillock (Figure
8). The goal of input integration is to put the neuron into a final electrical state whereby it can either fire an
action potential or not.
Generally:
•
The axon will only fire an action potential if the postsynaptic membrane reaches the threshold to
open the axon’s voltage-gated Na+ channels. This can only happen when the excitatory inputs
are greater than the inhibitory inputs.
•
The axon will not fire an action potential if the postsynaptic membrane does not reach the
threshold to open the axon’s voltage-gated Na+ channels. This happens when the excitatory inputs aren’t great enough, and/or when the inhibitory inputs are greater than the excitatory inputs.
The process of synaptic integration is in continuous operation in every neuron in the nervous system. Each
cell integrates all of the synaptic information it receives at any one time, and depending on the balance of
excitation and inhibition, it either fires an action potential or it doesn’t.
Wo r k b o o k
Lesson 3.3
To further explore this idea let’s examine how applying pressure can relieve pain, but before we dive into
that discussion, let’s first remind ourselves of the pathway to get pain to the brain.
Under what circumstances will the axon hillock initiate an action potential? Under what
circumstances will the axon hillock not initiate an action potential? Why?
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LESSON READING
The pain synapse in the spinal cord
Recall that the pain pathway has four neurons. The first is in the periphery, the second is in the spinal cord,
the third is in the thalamus, and the fourth is in the somatosensory cortex. Let’s take a closer look at the
synapse between the first neuron and the
second in the spinal cord.
DEFINITIONS OF TERMS
Projection neuron – neuron
whose axons make synapses in
the brain.
For a complete list of defined
terms, see the Glossary.
In the spinal cord, neurons carrying pain
stimuli make synaptic connections within
the grey matter in the area that deals with
sensory information called the dorsal horn.
Specifically, the first pain neurons connect
to projection neurons that then project up
the spinal cord, carrying pain information to
the third neuron in the thalamus (Figure 9).
But the first pain neurons aren’t the only
neurons that make connections with the
projection neurons. A different type of neuron that is sensitive to pressure, not to pain,
also connects with the same projection
neuron (Figure 9). We call these connections between pain, pressure and projection neurons a circuit. This circuit is the first
way we manage our responses to painful
stimuli. We can diagram how the circuit is
wired (Figure 10).
Figure 9: Pain and pressure synapse in
the spinal cord. Neurons carrying painful
information, as well as neurons carrying pressure information both synapse on the same
projection neuron that carries information to
the brain.
Pain neuron Projec-on neuron Interneuron To Brain Pressure neuron Figure 10: Wiring of pain and pressure synapse in
the spinal cord.
How the circuit works
Now that we know how the circuit is “wired”, let’s look at how it works.
Wo r k b o o k
Lesson 3.3
Remember, that the neurons carrying painful stimuli synapse on the projection neurons. These pain neurons make excitatory synapses with projection neurons. This means that when pain neurons are activated
by painful stimuli they will always excite the projection neurons to produce an action potential.
What is the benefit of having both pain and
pressure sensitive neurons synapsing on the
same projection neuron?
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How does applying pressure relieve some of
our pain?
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LESSON READING
However, remember that the projection neurons are also connected to pressure sensitive neurons. But
these neurons make inhibitory synapses with the projection neurons. This means that when pressuresensitive neurons are activated by pressure stimuli, they will always inhibit the projection neurons, preventing them from producing an action potential.
DEFINITIONS OF TERMS
Behavioral inhibition –
inhibition of behavior.
Neural inhibition – inhibition of
neural signaling.
For a complete list of defined
terms, see the Glossary.
We can see this circuit in action when we bang our elbow or stub our toe, and then immediately go to rub
it. By rubbing the painful area we’re applying pressure that will activate our pressure-sensitive neurons.
These neurons will then communicate with the projection neurons in the spinal cord and inhibit them so
they’ll no longer tell the brain that they’re getting painful information from the first pain neurons. It’s all a
matter of balancing excitatory and inhibitory inputs. It’s not quite the same as “No brain, no pain”, but if the
pain never gets to the brain, we certainly can’t feel it.
Excitation vs Inhibition – It’s just a bit more complicated
Note that an inhibitory postsynaptic potential, which leads to neural inhibition, does not always produce
behavioral inhibition. For example, suppose a group of neurons actually prevents a particular movement from taking place, for instance if they hold your head erect, preventing it from falling forward. If these
neurons experience enough IPSPs they won’t fire an action potential and will experience neural inhibition.
But what effect will this have on your head? In fact if these neurons are inhibited, i.e. prevented from functioning, they will no longer be able to prevent your head falling onto your chest. Thus, inhibiting inhibitory
neurons makes the behavior more likely to occur.
If we think about neural excitation we can see that the same thing occurs: If we activate neurons that
inhibit a behavior, we will tend to suppress that behavior. For example, when we are dreaming, a particular
set of inhibitory neurons in the brains becomes active and prevents us from getting up and acting out our
dreams.
It is important to remember that all neurons need to reach threshold before they can fire an action potential
and communicate with other neurons via synaptic transmission. Whether they will reach that threshold
depends on how the axon hillock integrates the hundreds of thousands of excitatory and inhibitory inputs
that fall onto the dendritic tree. If the action potential is fired, whether that neuron will have an excitatory or
inhibitory effect on the postsynaptic cells it communicates with will depend on which neurotransmitters it
releases, how they interact with their receptors on the postsynaptic side and which ion channels they open.
In summary, an action potential always precedes synaptic transmission, and an action
potential is always preceded by reaching threshold, and to reach threshold more excitatory
inputs than inhibitory inputs are required (even if the neuron is inhibitory).
Wo r k b o o k
Lesson 3.3
Can you predict the effects of damage to
our neurons that prevent us acting out our
dreams?
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STUDENT RESPONSES
What must always precede the release of neurotransmitter?
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What must always precede the firing of an action potential?
Remember to identify your
sources
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Therefore, even in the case of an inhibitory neuron, what sequence of events must occur before it can release neurotransmitter
to inhibit the postsynaptic cell?
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Wo r k b o o k
Lesson 3.3
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LESSON 3.4 WORKBOOK
What causes different pain
phenomena?
Now that we’re familiar with the process of synaptic transmission and the pain pathway, let’s turn
our attention to how these can explain some of
the most puzzling sensory perceptions we know
– pain phenomena.
Types of Pain
“First” and “Second” Pain: Why do we first feel a stabbing pain, and then later feel an aching
pain?
We’ve talked about the pain receptors or nociceptors on the dendrites of the first pain neuron that recognize pain, or nociceptive, or noxious stimuli. Nociceptors are simply free nerve endings in the skin. They
are activated after the inflammation that occurs following either pressure or extremes of temperature, so
we can identify three different types of nociceptors.
Wo r k b o o k
Lesson 3.4
•
Thermal nociceptors are activated by extreme temperatures. They transmit information very
quickly because their Aδ axons are myelinated.
•
Mechanical nociceptors are activated by intense pressure. They also transmit information
quickly via myelinated Aδ axons.
•
Polymodal nociceptors are activated by thermal, pressure or chemical stimuli. They transmit
information more slowly because their C axons are unmyelinated.
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LESSON READING
DEFINITIONS OF TERMS
Anterograde transport – movement of materials from cell body to
axon terminals.
Nociceptors will transmit noxious information
quickly if the myelinated Aδ neurons are activated and more slowly if the unmyelinated C
neurons are activated (Figure 11). Because of
this, the painful information carried by Aδ neurons is often referred to as “first” pain because
it is felt first as a sharp sensation. The painful
information carried by C neurons is often referred to as “second” pain because it occurs
later and is felt as burning or aching (Figure
12).
Figure 11: Fast versus slow pain. Fast pain is due
to the activation of myelinated Aδ fibers. Slow
pain is due to the activation of unmyelinated C
fibers.
Retrograde transport – movement of materials from axon
terminals to the cell body.
Kinesin – plus-end directed motor
that carries cargo from the cell
body to the axon terminal along
microtubules.
Dynein – minus-end directed
motor that carries cargo from the
axon terminal to the cell body along
microtubules.
Figure 12: First versus second
pain. First pain is felt as a stabbing pain, whereas second pain
is felt more as a diffuse ache or
throbbing pain.
Thus we can see that how pain is felt depends on which
nerves transmit the pain information. If only Aδ neurons respond, then only a “first” pain is felt in a sharp sensation. If
only C neurons respond, then only a “second” pain of burning
or aching is felt. If both Aδ and C neurons signal, then a sharp
sensation is felt first due to the Aδ neuron response, then a
second burning or aching pain is felt due to the C neuron
response.
Referred Pain: Why do people feel pain in their arm when they are having a heart attack?
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 3.4
Noxious information from the internal organs is detected by receptors that are activated by inflammation
and chemicals, such as toxins released by bacteria or tainted food. We talked about the first pain neurons
that make a synapse in the sensory region of the spinal cord (dorsal horn). It turns out that pain neurons
from the internal organs synapse on the same neurons (Figure 13). However, pain sensation from the skin
are usually more common than those from the internal organs. Therefore, when pain receptors from the
internal organs are activated, our cortex tends to think the pain neurons in the skin have been affected and
it localizes, or refers, the sensations to areas of the skin.
What is “first” and “second” pain? Describe
the phenomenon.
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Why does “first” and “second” pain occur?
What is it about our nervous system that
causes this phenomenon?
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LESSON READING
If a pateint described a pain in the center of
his chest, but couldn’t remember suffering
any injury to his chest, what internal organs
would you suspect might be injured?
Thus we experience pain from an internal organ
on predictable areas of the body surface. When
you feel pain in the arm following a heart attack,
this is because your brain is misinterpreting the
source of the painful stimulus, not because your
arm has also been damaged.
Why are these areas so predictable? Pain neurons from the skin and the internal organs are always coupled in the same area of the spinal cord.
Figure 14 shows the stereotyped distribution of
referred pain used to diagnose damage to internal
organs. As we already discussed, pain in the heart
is often perceived on the left arm. Pain originating
in the lung and diaphragm are similarly perceived
on the left side of the neck and left shoulder.
Figure 13: Synapse in referred pain. Nociceptive
neurons from the skin (red) and the internal organs
(green) synapse in the same place in the spinal
cord. Since the brain cannot tell where the stimulus is coming from and sensations from the skin
usually predominate, the brain incorrectly assumes
the pain is in the skin.
Figure 14: Referred
pain. The stereotyped distribution of
referred pain is used
to diagnose damage to
internal organs.
Phantom Limb Pain: Why do amputees feel pain in their missing limbs?
Wo r k b o o k
Lesson 3.4
Almost immediately following the amputation
of a limb, 90-98% of patients report experiencing a sensation coming from their missing limb, called phantom sensation (Figure
15). For some lucky patients, the phantom
limb experiences may fade, disappear or
change over time, in others, not so lucky,
the phantom limb experiences continue for
years.
Figure 15: Phantom limb. The solid lines show the
site of the amputation, the dotted lines where the
phantom limbs were experienced.
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Why does referred pain occur? What is it
about our nervous system that causes this
phenomenon?
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LESSON READING
Figure 16: Phantom sensations in the somatosensory cortex. It is believed that the experience of a phantom limb occurs because the
area of the cortex that used to receive input
from the amputated limb starts responding to
other sensations. For example, if the right arm
was amputated, the pink line shows the area of
the somatosensory cortex no longer receiving
input. If this area were to respond to other sensations, the brain might mistake that as coming
from the right arm.
This is how we explain this strange phantom limb phenomenon: When a limb is stimulated by any kind
of sensation the appropriate part of the opposite parietal lobe is activated in the somatosensory cortex.
If the limb is removed, this part of the brain no longer receives its normal input but continues to expect it,
therefore it recreates a phantom limb where that limb used to be (Figure 16). In some cases the brain
reorganizes so that the part of the brain that used to respond to the missing limb responds to other things
instead. For example, it may respond to touch in a different part of the body.
Some amputees have painless phantom limbs,
whereas others experience excruciating phantom
limb pain. Doctors do not completely understand
why this is. One factor known to be important is
whether the limb was in pain prior to amputation.
If the real limb was in pain prior to amputation, then
there is a high chance that the phantom limb will
be painful too, presumably because the brain is still
expecting that pain activation.
Many patients experience pain because the phantom limb seems to be clenched. Since phantom
limbs are obviously not under voluntary control,
unclenching them is impossible. Neurologists have
recently discovered the ability to use mirror boxes
to trick the brain into perceiving the phantom limb
is unclenched. By watching the mirror image of the intact limb, mirror box therapy provides the brain with
visual stimuli showing the “phantom” limb being unclenched (Figure 17).
Figure 17: Mirror box therapy. Neurologists
have discovered that mirror box therapy can
provide relief for phantom limb pain. The theory
is that if the brain receives visual feedback that
the limb is not in pain, then the phantom limb
pain will decrease.
Wo r k b o o k
Lesson 3.4
You can watch a video of Ramachandran talking about phantom pain online — click below or see this
unit on the student website:
■■ Video: VS Ramachandran: 3 clues to understanding your brain
If a patient who had just had his left leg amputated because of diabetes started feeling pain
in that left leg, what would you diagnose? ___
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Why does phantom limb occur? What is it
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LESSON READING
Pain and Emotions: Why do our emotions play such a large role in how we perceive pain?
How do our emotions change the way we
perceive pain? ______________________
Many areas of the brain collaborate in our
experiences of pain, including some of the
areas involved in dealing with our emotions.
This overlap probably explains why emotion is such a large component of the pain
response.
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We have seen how the sensory neurons
in the pain pathway carry pain sensations
to the somatosensory cortex located in the
Figure 18: Somatosensory cortex. Sensory input
parietal lobe. The somatosensory cortex is
from the body maps onto the parietal cortex at the
responsible for processing all tactile sensa‘somatosensory strip’. The homunculus reflect the
tions from the body, not just pain (Figure 18).
differences in sensory input from each area.
However, pain does not simply arise from
how information is processed in the somatosensory cortex. If it did, the sensation would reflect the small, well-defined areas of the skin that the pain
receptors sample. Instead, as we have seen, most clinical pain involves aches that seem to spread around
the whole body. These so-called diffuse aches occur because other areas of the cortex are also involved
in pain perception, notably the insular cortex (Figure 19), and anterior cingulate cortex (ACC) (Figure 20).
The insular cortex is found directly underneath the primary somatosensory cortex. Its role is to deal with information about
the internal state of the body and it also contributes to the emotional response to pain. Patients whose insular cortex is damaged
don’t have an appropriate emotional response to pain, they may
know its occurring but they aren’t affected by it.
Wo r k b o o k
Lesson 3.4
Figure 19: Insular cortex.
The insular cortex is directly
beneath the primary somatosensory cortex and is involved
in emotional responses to pain.
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LESSON READING
The anterior cingulate cortex (ACC) is important for processing emotion (Figure 20). It is part of an evolutionarily
ancient area of the cortex called the limbic system. The
emotional or affective component of pain that can be described by terms like “sickening”, “terrifying” and “punishing”, relates to activation of the ACC.
DEFINITIONS OF TERMS
Analgesics – drugs that reduce
pain.
For a complete list of defined
terms, see the Glossary.
Figure 20: Cingulate cortex (also
kown as Cingulate gyrus). The
cingulate gyrus is part of the limbic
system that is also important in the
emotional responses to pain. The
anterior cingulate cortex (ACC) is the
front half of the cingulate gyrus.
The insular cortex and ACC work together to determine
how we will respond emotionally to pain by associating
the current painful sensations we are experiencing with
our past experiences of pain. The insular cortex and ACC
can also control how painful sensations are processed
and thus change how we perceive pain.
Interestingly, this is not just a one-way street with emotions
affecting how we process pain. We have discovered that
the converse also happens i.e. that pain also affects how
we process our emotions. When volunteers were asked to
play a gambling card game to study how they made decisions in risky, emotionally laden situations, those
volunteers with chronic pain made 40 percent fewer good choices compared to those without pain. What’s
more, the amount of suffering correlated with how badly the volunteers played!
Medications for Pain: How do medicines that
relieve pain work?
Analgesics are a group of drugs used to relieve pain.
They work in a variety of ways, both within the brain
and within the spinal cord. Their goal is to relieve pain
without affecting any other sensation (Figure 21).
Wo r k b o o k
Lesson 3.4
How do they work? It turns out that the pain pathways
that ascend up the spinal cord to the brain are mirrored
by complementary pathways that descend from the
brain to the spinal cord. These complementary pathways have an analgesic effect. How? They release
chemicals called opioids onto the pain projection neuron in the spinal cord. The opioids inhibit the transmission of painful information to the cortex by blocking the
firing of projection neurons.
Opioids Ascending pain pathway Descending pain pathway Opioids Local anesthe5cs Local anesthe5cs An5-­‐inflammatory drugs Pain Receptors Figure 21: Descending and ascending
pain pathways. The descending analgesia pathway modulates pain perception
through actions of endogenous opioids in
the brain and spinal cord. Local anesthetics
and anti-inflammatory drugs modulate pain
perception through actions in the periphery.
Which parts of the brain are responsible for
processing the emotions related to pain?
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LESSON READING
Receptors for these analgesic opioids are found in all areas of the brain that play roles in pain regulation.
The artificial opioid morphine works the same way – it stimulates the descending pain pathway to inhibit
the pain projection neurons within the spinal cord. Giving morphine systemically can cause addiction because of all the other opioid receptors in the brain (we’ll talk about them in Unit 5). To avoid the complication
of addiction, morphine is often injected directly into the spinal cord where it can directly inhibit the pain
projection neurons without affecting receptors we want to avoid.
Local anesthetics (like Novocain if you remember from Unit 1) directly affect pain neurons close to where
they’re injected or applied. Local anesthetics block synaptic transmission by blocking voltage-gated sodium channels. When voltage-gated sodium channels are unable to open, the neurons in the area are
unable to fire an action potential. In addition to blocking neurons carrying pain information, local anesthetics also block neurons carrying other sensory information as well, which is why your whole jaw often feels
numb when you go to the dentist.
Anti-inflammatory drugs, like aspirin, block pain transmission by blocking inflammatory hormones. If you
remember, most nociceptors are activated as a result of inflammation so these inflammatory hormones
are critical for pain to be transmitted, so if they are blocked, much less pain is perceived.
In summary, medications that relieve pain work at a variety of points along the pain pathway. Some
medications work directly in the brain, while others work in the spinal cord, and finally some work right at
the site of trauma.
In Summary
It is important to distinguish between a nociceptive (noxious) stimulus and the perception
of pain. Nociceptive information is sensed in the periphery and then transmitted to the
cortex by a multi-synaptic pathway that ascends through the spinal cord. Each ascending
synapse is an important site for regulation of the response. A complementary descending
pathway can inhibit the ascending pathway by releasing of analgesic opioids that directly
inhibit the pain pathway.
Wo r k b o o k
Lesson 3.4
How do analgesics work?
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97
STUDENT RESPONSES
A single neuron receives thousands of inputs which may be conflicting or overlapping.
a.
First, describe how neurons manage all of these inputs.
b.
Second, what is the benefit of having this many connections within our nervous systems?
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Wo r k b o o k
Lesson 3.4
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98
Unit 4: How do our neurons work
Overview
together to control behaviors?
In the previous unit we learned how neurons communicate with each other using the process of synaptic transmission. This unit
further expands on that knowledge by examining how neurons work together in circuits to control behaviors. In this unit, we’ll use the
experience of sleep, something we all experience, as a guide to discuss neural circuits.
Remember our graphic from the beginning of this workbook? This unit focuses on the circuit, which is how our neurons work together
to control our behaviors.
LESSON 4.1 WORKBOOK
What is sleep?
This unit introduces you to the neural circuit, which is
how neurons work together to control our behaviors.
In this lesson, we’ll learn about sleep, a behavior that is
tightly controlled by a neural circuit.
An introduction to sleep
Sleep remains one of the great mysteries of modern neuroscience. We spend nearly one-third of our lives
asleep, and we still don’t really understand why (Figure 1). We do know that sleep occurs in all mammals
and probably all vertebrates. Sleep is crucial for concentration, memory, and coordination. Without enough
sleep, we have trouble focusing and responding quickly — in fact, sleep loss can have as big an effect
on performance as drinking alcohol. Getting enough sleep is also important for our emotional health. And
growing evidence suggests that a lack of sleep increases the risk of a variety of health problems, including diabetes, cardiovascular disease and heart attacks, stroke, depression, high blood pressure, obesity,
and infections. In animals sleep deprivation can be fatal. Disorders of sleep are among the nation’s most
common health problems, affecting up to 70 million people, most of whom are undiagnosed and
untreated. These disorders are one of the least
recognized sources of disease, disability, and
even death, costing an estimated $100 billion annually in lost productivity, medical bills, and industrial accidents.
Wo r k b o o k
Lesson 4.1
Figure 1: Sleep. We spend nearly 1/3 of our
life asleep and a considerable amount of our
time awake worrying about it, yet we still don’t
understand what it’s for.
What do you notice about your own behaviors and feelings when you don’t get enough
sleep?
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Lack of sleep increases the risk of what?
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100
LESSON READING
What are the two stages of sleep?
Sleep is an active state
DEFINITIONS OF TERMS
Electroencephalogram (EEG)
– measure of gross electrical
activity of the brain, commonly
recorded through scalp
electrodes.
Non-rapid eye movement
(NREM) sleep – sleep stages 1
through 4, during which sleepers
are still and EEG waves
decrease in frequency and
increase in amplitude.
Rapid eye movement (REM)
sleep – the stage of sleep
characterized by rapid eye
movements, loss of muscle tone,
and EEG waves similar to those
seen when awake.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 4.1
For centuries – up to the 1950’s in fact – most people thought that the purpose of sleep was simply to
give the brain a rest. This seemed to be confirmed when, in 1953, two researchers put electrodes onto
the scalp of sleeping subjects, revealing slow waves of brain activity. The slowness of the waves was
precisely what they expected a state of rest to look like. However, they were startled to find that their subjects actually spent much of their night in a wholly different form of sleep that did not look like the brain
was resting at all. In fact it was characterized by the same kind of high frequency activity that it displayed
when subjects were awake. Not only that, but the sleepers’ eyes were constantly moving rapidly. They
called this type of sleep rapid eye movement or REM sleep. For contrast, they called slow wave activity
sleep non-rapid eye movement or NREM sleep.
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Measuring brain activity during sleep
How do scientists measure brain activity in
people as they sleep?
Today we use the electroencephalogram (EEG) to measure the brain activity as people sleep. An electroencephalography involves applying a set of electrodes on the scalp.
As we saw in Unit 1, EEGs use pairs of electrodes placed in
19 standard positions distributed over specific brain regions.
(Figure 2). The encephalogram then records the voltage
that flows through the brain tissue between each pair of
electrodes (which is why each EEG trace is reported as a
pair – for example: P3 - T5 [parietal 3 - temporal 5]) (Figure
3). Because each pair of electrodes samples the activity of
a population of neurons in a different brain region, each of
the individual EEG traces will be different.
Figure 2: Placement of EEG electrodes.
The electrodes are placed in stereotyped positions so that the current flow
between specific regions in the cortex
can be measured.
If you didn’t watch how EEGs are recorded in Unit 1, you may want to watch that video now at the student
website or the link below:
■■ Video: Measuring Brain Waves with an EEG (Electroencephalogram)
Figure 3: An EEG from an
awake subject. The EEG
measures the current flow
between a pair of electrodes.
The electrodes are named
for the part of the cortex they
are over, hence F = frontal; P
= parietal; T = temporal; O =
occipital.
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What are the two characteristics of EEG
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101
LESSON READING
EEG rhythms have two characteristics – the frequency of the electrical activity and its amplitude. The frequency refers to how long a wave is from trough to trough (length). Amplitude refers to how tall the wave is
(height). Different rhythm characteristics are found during different behaviors. (For example see Figure 4.)
High frequency, low amplitude
waves occur when we are mentally
alert with eyes open.
DEFINITIONS OF TERMS
Amplitude – refers to how large
(height) a wave is from peak to
peak.
Frequency – refers to how long
(length) a wave is from trough to
trough.
For a complete list of defined
terms, see the Glossary.
High frequency, low amplitude Awake with eyes closed Medium frequency, medium amplitude Medium frequency, medium amplitude waves occur when we’re
drowsy.
Low frequency, high amplitude
waves occur when we’re asleep.
Drowsiness & sleep Low frequency, high amplitude Epilepsy High frequency, high amplitude Figure 4: Typical EEG waves. The EEG shows typical patterns
of activity that can be correlated with various stages of sleep
and wakefulness.
Can you predict what might be happening when you are in Stage 5
sleep that would cause your brain
to show an EEG that looks like it’s
awake?
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What would cause the EEG during stage 5
sleep to be similar to the EEG during wakefulness?
The EEG and sleep stages
The awake EEG is characterized by
waves that have high frequencies
and low amplitudes. The waves
slowly decrease in frequency and
increase in amplitude as we fall
asleep and progress through the
night’s sleep. That is, until we get
to Stage 5 (Figure 5). At that point
the EEG trace looks similar to the
awake brain – the waves have high
frequencies and low amplitude.
Wo r k b o o k
Lesson 4.1
Mentally alert with eyes open What happens to EEG waves as we progress through a night’s sleep?
Awake Stage 1 Non rapid eye movement (NREM) Stage 2 Stage 3 Stage 4 Rapid eye movement (REM) Stage 5 Figure 5: EEG changes during the stages of sleep. The awake
EEG is characterized by high frequency, low amplitude waves,
which slowly decrease in frequency and increase in amplitude
as we progress through a night’s sleep. That is, until we get to
REM sleep, which again has an EEG with high frequency and
low amplitude waves.
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102
LESSON READING
REM sleep, which occurs in Stage 5 is a very dynamic state. Our overall physiology is active. We experience changes in heart rate, respiration and blood pressure. But other than the muscles that control breathing and eye movements, all of our other muscles are paralyzed. As you might guess from its name, our
eyes move rapidly in REM sleep. If sleepers are woken during REM sleep, they commonly report dreams
(although they may forget them shortly thereafter).
In contrast to REM sleep, non rapid eye movement (NREM) sleep is not dynamic. Our overall physiology is
not active. We experience a decrease in heart rate, respiration and blood pressure. In NREM sleep, people
are still, and their eyes don’t move. If people are woken in this stage, they rarely describe dreams.
During the night, the cycles of NREM slow wave sleep and REM sleep alternate, with the slow wave periods
shortening and REM periods lengthening until we wake up (Figure 6).
1st Cycle Wake REM 3rd 4th 5th Stage 1 NREM Figure 6: The stages of
sleep cycle throughout the
night. Deep sleep (stages
3 – 4) predominates during
the beginning of the night.
Later on, sleep is lighter
and REM stages predominate.
2nd Cycle Cycle Cycle Cycle 30min + 40min 50min 20min 30min Stage 2 Stage 3 REM Deep sleep Stage 4 0 1 2 4 5 3 Hours A<er Going to Bed 6 7 8 Dreaming and the possible functions of REM sleep
Thanks to the EEG we can describe the stages of sleep quite well, but we still don’t really know what they
are for, especially REM sleep. Most sleep researchers accept the idea that the purpose of REM sleep is at
least in part to give the brain a rest, however we are still not at all sure how, so this idea is very controversial.
We dream for about 2 hours every night, usually during REM sleep. On the other hand REM sleep doesn’t
always mean a dream is in progress, although it does act as one of the triggers for dreams.
Wo r k b o o k
Lesson 4.1
As you well know REM dreams don’t just recall a past experience – they’re more like a movie that can
sometimes be quite lurid and surreal (Figure 7). Because of this, dreams have been intensely studied
by psychoanalysts who think they can reveal our unconscious desires. Sigmund Freud’s work ‘The Interpretation of Dreams’ published in 1899 thought dreams had deep significance, but there is little scientific
evidence to support his theory. Nonetheless many people consider the content of their dreams to be significant.
If you sleep for only 4 hours tonight, are
you primarily missing your slow wave deep
sleep or your REM sleep?
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103
LESSON READING
However, the source of this content and how
it becomes so vividly surreal is not known.
One clue might come from functional MRI
(fMRI), which shows that the areas which
regulate higher-order reasoning are inactive
during dreaming.
Figure 7: Most dreams occur during REM sleep. Most
people report dreams with a story-like description. We
dream for about 2 hours each night, mostly during REM
sleep. But no one knows where dreams come from or what
they’re for.
What is sleep for?
The bottom line is we don’t really know. We do know that if we can’t sleep we suffer. In fact, rats can only
survive three weeks if they aren’t allowed to sleep at all. In humans sleep deprivation induces paranoia and
hallucinations. Here are some current and not so current hypotheses on sleep function. None are proven
and all are flawed.
Wo r k b o o k
Lesson 4.1
•
Sleep allows body systems to recover after consuming energy during the day. In fact as we
saw previously, the brain is active during sleep and there’s no evidence that more repair
occurs during sleep than during rest or relaxed wakefulness.
•
Sleep allows us to conserve energy. Our overall metabolic rate while we sleep is lower than
while we’re awake, but species with greater sleep times have higher metabolic rates. So,
this theory doesn’t hold up either.
•
Sleep protects us from predators. But it also decreases sensitivity to external stimuli which
surely increases vulnerability.
•
Sleep allows us to consolidate our memories. Maybe. Studies have shown that people
who get plenty of deep non-REM sleep in the first half of the night, and REM sleep in the
second improve their ability to perform spatial memory tasks.
•
Sleep is needed for discharging emotions. Maybe. Activity in the brain regions that control
emotions, decision-making and social interactions is reduced during sleep, which may
provide relief from stresses that occur during wakefulness.
•
Sleep is needed during brain development. Certainly babies and infants sleep more than
adults.
Do you think your dreams have meaning?
Why or why not?
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104
STUDENT RESPONSES
Of the hypotheses listed above for the functions of sleep, which do you think is most accurate, and why?
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Wo r k b o o k
Lesson 4.1
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LESSON 4.2 WORKBOOK
Are you getting enough quality sleep?
We all know how insistent the urge to sleep can be,
and how bad we feel when we have to resist it and stay
awake. With the exception of the effects of severe pain
and the need to breathe, sleepiness is probably the
most insistent drive that we experience. So, how much
sleep do we actually need?
How much sleep do we need?
Sleep experts say most of us aren’t getting enough sleep. Here’s what the National Sleep Foundation says
we need. (But keep in mind that your sleep needs are as individual as you, your genetics, and your lifestyle.
And a timely nap may mean you need less nighttime sleep).
•
Babies take the sleep they need: sixteen to eighteen hours out of twenty-four.
•
Toddlers need about fifteen hours, young children need eleven to thirteen hours.
•
Teens need nine or more sleep hours, but seldom get it.
•
Adults need eight hours, but generally get just around seven.
•
Elders sleep a bit more, but have trouble falling asleep and staying asleep.
(By the way, small animals require
much more sleep than large animals,
with opossums craving eighteen hours
and elephants needing only three hours
a day (Figure 8).
Wo r k b o o k
Lesson 4.2
Figure 8: Different animals need different amounts of sleep.
When was the last time you woke up feeling
rested and refreshed? How much sleep did
you get that night?
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Describe your bedroom. Is your bed comfortable? Do you sleep in the dark or the light?
Do you text in bed? How long for?
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LESSON READING
What are the effects of sleep deprivation?
When we are forced to miss a night’s sleep, we become very sleepy. The fact that sleepiness is so motivating suggests that sleep is a necessity of life. If so, it should be possible to deprive people or laboratory
animals of sleep and see what functions are disrupted. From these studies we should be able to infer the
roles that sleep plays. However, the results of sleep deprivation studies have not revealed as much as
investigators had originally hoped.
Adding to uncertainty about the purposes of REM sleep is the fact that depriving people of REM sleep for
as much as 2 weeks has little effect on their behavior. They compensate by experiencing more of it after
the period of deprivation, but suffer no obvious adverse effects.
In contrast, total sleep deprivation has devastating effects. The longest documented period of voluntary
sleeplessness is approximately 12 days, chalked up by a Californian who used coffee to keep him awake
and spent his wakefulness in the window of a coffee shop. He recovered after a few days of getting sleep,
apparently none the worse for wear.
Most people who experience sleep deprivation know that it severely impacts both mental and motor functioning. Too little sleep has been linked with:
•
Increased risk of motor vehicle accidents
•
Increased body mass index – greater likelihood of obesity due to an increased appetite
caused by sleep deprivation
•
Increased risk of diabetes and heart problems
•
Increased risk for psychiatric conditions including depression and substance abuse
•
Decreased ability to pay attention, react to and remember new information.
If we don’t get enough sleep, our sleep debt progressively accumulates and leads to decreased mental
functioning. When the opportunity to sleep comes again, we will sleep much more, to “repay” the debt. Our
slow wave sleep debt is usually “paid off” first. So it seems like we can get along without REM sleep, but
need non-REM sleep in order to survive.
Wo r k b o o k
Lesson 4.2
Why is it important to get enough quality
sleep? What happens if you don’t get enough
sleep?
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107
LESSON READING
How do sleep disorders affect our quality of sleep?
Given the odds, it’s likely that we’ll each experience some form of sleep disorder in our lifetime. There are
a range of sleep disorders, but we’ll discuss the most common here. Sleep disorders affect our quality of
sleep, and if you suspect that you have one, it is important to seek medical attention. So, how do sleep
disorders affect our quality of sleep?
Narcolepsy
DEFINITIONS OF TERMS
Narcolepsy – a disorder characterized by daytime sleep attacks
and loss of muscle tone.
Insomnia – disorder of going to
sleep and staying and asleep.
For a complete list of defined
terms, see the Glossary.
Narcolepsy is a neurological disorder characterized by falling asleep at inappropriate times. Since we’ll
be focusing on narcolepsy in the next section of this chapter, we’ll save further description of this sleep
disorder for then.
Insomnia
Most people are familiar with insomnia (Figure 9). Insomnia is said to affect approximately 25 percent of
the population occasionally, and 9 percent regularly. But there is no single definition of insomnia that we
can apply to all people. Insomnia must be defined in relation to a person’s particular sleep needs, and the
amount of sleep we need is quite variable between individuals. Some people may feel fine with 5 hours of
sleep; others may still feel unrefreshed after 10 hours of sleep. Therefore, we’ll define it simply as difficulty
falling or staying asleep, such that when you do wake up, you don’t feel rested.
Some people have difficulty falling asleep initially, and others fall asleep and then awaken partway through
the night and cannot fall asleep again.
Insomnia is more common in women than men, and tends to increase with age. Short-term insomnia is
often associated with stress, the environment
(noise, light), jet lag, or medication. Long-term
insomnia may be due to other sleep disorders
or may be a secondary effect of other physical
or mental problems. Unfortunately, the shortacting sedatives, and sedating antidepressant
drugs that are available over the counter that
many people use to help themselves sleep don’t
mimic truly natural and restful sleep, because
they don’t allow the deeper stages of slow wave
sleep that are so necessary for a restful sleep.
Wo r k b o o k
Lesson 4.2
Figure 9: Insomnia. Insomnia is the difficulty falling or staying asleep, so that when you wake up,
you don’t feel rested.
What is narcolepsy? How does narcolepsy
affect our quality of sleep?
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What is insomnia? Is there only one definition of insomnia? Why or why not?
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LESSON READING
Obstructive sleep apnea (OSA)
DEFINITIONS OF TERMS
Obstructive sleep apnea – condition in which breathing stops while
you are asleep because the airway
has become narrowed, blocked, or
floppy.
REM sleep behavior disorder
– disorder in which the paralysis
that normally occurs during sleep
is incomplete or absent, allowing people to “act out” his or her
dreams.
An estimated 12 million Americans have obstructive sleep apnea (OSA) and this number is expected
to rise because OSA is made worse by the presence of excess fat. In children OSA is related to enlarged
tonsils or adenoids. OSA is a major cause of inadequate sleep, and can be life-threatening. It occurs as
sleep deepens. The airway muscles in the throat relax until collapse, closing the airway (Figure 10). This
prevents breathing, which causes the sufferer to
wake up and stops the sufferer from progressing
to the deeper stages of slow wave sleep. Sleep
apnea can cause high blood pressure, and may
also increase the risk of heart attack. Treatment
aims to stop the airway muscles collapsing and
may include approaches like losing weight, avoiding alcohol and sedating drugs, and not sleeping
on one’s back. However, most people with sleep
apnea require devices like a mask that provides
continuous positive pressure to the airway, keepFigure 10: Obstructive sleep apnea (OSA)
ing it open.
occurs when muscles at the back of the throat
relax and obstruct airflow.
Parasomnias
Parasomnias include a range of behaviors that occur during sleep
including sleepwalking (Figure 11), sleep talking, bed-wetting (enuresis) and sleep terrors. Many, including sleepwalking, talking
and terrors are more common in children than adults. Sufferers
usually have no memory of the events. Most suffers outgrow their
parasomnias, so they don’t require treatment.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 4.2
Figure 11: Sleep walking.
Sleep walking is most common in children and often
triggered by disturbances in
sleep patterns.
REM sleep behavior disorder occurs later in the night than the
other sleep disorders and usually affects middle-aged and elderly
people. REM sleep disorder appears because the muscle paralysis that normally occurs during REM sleep doesn’t happen, which
can result in sufferers acting out potentially violent dreams, even
injuring themselves or their bed partners.
What is obstructive sleep apnea? How does
obstructive sleep apnea affect our quality of
sleep?
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What are parasomnias? How do parasomnias affect our quality of sleep?
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LESSON READING
Restless leg syndrome
About 10 - 15% of the population has unpleasant leg sensations and an almost irresistible urge to move
their legs. Symptoms are usually worse in the evening and at night and often interfere with sleep. Mild
cases can be treated with exercise, leg massages and eliminating alcohol and caffeine from the diet.
What can you do to improve your sleep?
First you need to begin by assessing what you yourself need. See how you respond to different amounts of
sleep. Pay careful attention to your mood, energy and health after a poor night’s sleep versus a good one.
Ask yourself, “How often do I wake up feeling well rested?” If the answer is “not often”, then you may need
to consider changing your sleep habits or consulting a physician or sleep specialist.
To pave the way for better sleep, experts recommend that you and your family members follow these sleep
tips:
•
Establish consistent sleep and wake schedules, even on weekends.
•
Create a regular, relaxing bedtime routine such as soaking in a hot bath or listening to
soothing music – begin an hour or more before the time you expect to fall asleep.
•
Create a dark, quiet, comfortable and cool environment.
•
Sleep on a comfortable mattress and pillow.
•
Use your bedroom only for sleep (keep “sleep stealers” out of the bedroom – avoid watching TV, using a laptop or iphone or reading in bed).
•
Finish eating at least 2 - 3 hours before your regular bedtime.
•
Exercise regularly during the day or at least a few hours before bedtime.
•
Avoid caffeine and alcohol close to bedtime, and give up smoking.
If you or a family member are experiencing symptoms such as excessive sleepiness during the day, snoring, leg cramps or tingling, gasping or difficulty breathing during sleep, prolonged insomnia or another
symptom that is preventing you from sleeping well, you should consult your primary care physician or sleep
specialist to determine the underlying cause. You may also try keeping a sleep diary to track your sleep
habits over a one- or two-week period and bring the results to your physician.
Wo r k b o o k
Lesson 4.2
Most importantly, make sleep a priority. You must schedule sleep like any other daily activity, so put it on
your “to-do list” and cross it off every night. But don’t make it the thing you do only after everything else is
done – stop doing other things so you get the sleep you need.
What is restless leg syndrome? How does
restless leg syndrome affect our quality of
sleep?
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Is your bedroom a sleep-conducive environment?
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110
STUDENT RESPONSES
What could you do to improve the quality of sleep you get each night?
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Wo r k b o o k
Lesson 4.2
111
LESSON 4.3 WORKBOOK
What makes us go to sleep, and what
makes us wake up?
DEFINITIONS OF TERMS
Arousal neurons – neurons
located in the brainstem that
when active keep us awake and
alert.
Ventrolateral preoptic nucleus
(VLPO) – nucleus in the
hypothalamus that when active,
puts us to sleep.
So far we’ve discussed the nature of sleep, its functions, and problems associated with it. Now, let’s
examine what researchers have discovered about the
neural circuits that are responsible for sleep and its
counterpart, alert wakefulness.
Control of the sleep-wake cycle
The length of time we’ve been awake and active
The time of day
The Flip-Flop Switch
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 4.3
When we are awake and alert, most of the neurons in our brain – especially those in our forebrain – are
active, which enables us to pay attention to sensory information, to think about what we are perceiving,
to retrieve and think about memories, and to engage in the variety of behaviors that we have to do during
the day. The level of brain activity is largely controlled by the arousal neurons located in our brainstem
(Figure 12). A high level of activity of these neurons keeps us awake, and a low level puts us to sleep.
But what controls the activity of the
arousal neurons? What causes this
activity to fall, and put us to sleep? We
know that a region of the hypothalamus,
usually referred to as the ventrolateral
preoptic nucleus (VLPO), is critically
important for controlling when we fall
asleep (Figure 12). If this area is destroyed total insomnia results. On the
other hand, stimulating this area electrically can induce sleep.
Areas in the hypothalamus put us to sleep VLPO (Sleep neurons) ___________________________________
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What area of the brain is responsible for putting us to sleep?
Our sleep-wake cycles are controlled by two main factors:
•
•
What area of the brain is responsible for
keeping us awake and alert?
Areas in the brainstem keep us awake Arousal Neurons Figure 12: Neural control of sleep and wakefulness.
Arousal neurons in the brainstem keep us awake. VLPO
neurons in the hypothalamus put us to sleep.
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LESSON READING
The VLPO contains sleep neurons. Their axons form inhibitory synaptic connections with the brain’s
arousal neurons, and inhibit them. When our VLPO sleep neurons become active and suppress the activity of our arousal neurons, we fall asleep. The sleep neurons in the VLPO themselves receive inhibitory
inputs from some of the same regions they inhibit, including the arousal neurons in the brainstem. Thus,
when arousal neurons are active, they inhibit the VLPO sleep neurons and we remain awake. It is important to understand that the VLPO sleep neurons need to be active to inhibit the arousal neurons and vice
versa – inhibition is an active process, just like excitation.
DEFINITIONS OF TERMS
Orexin neurons – neurons
located in the hypothalamus that
use the neurotransmitter orexin.
When active, these neurons
activate the arousal neurons in
our brainstem to keep us awake.
Damage to these neurons has
been implicated in narcolepsy.
For a complete list of defined
terms, see the Glossary.
The fact that the sleep neurons inhibit
the arousal neurons and vice versa is
called a flip-flop switch that sets periods of sleep and waking. As you might
imagine the flip-flop switch can only be
in one of two states ‘on’ or ‘off’. If the
sleep neurons are active and inhibit the
arousal neurons we will be asleep. Conversely, if the arousal neurons are active
and inhibit the sleep neurons, we are
awake (Figure 13). Also because the
two switches are mutually inhibitory, it is
impossible for the neurons in both sets
of regions to be active at the same time.
A. During wakefulness B. During sleep Figure 13: The flip-flop
switch. The VLPO and
the arousal neurons are
connected to each other
by inhibitory neurons.
(A) When the arousal
neurons are active, they
inhibit the VLPO and we
remain awake. (B) When
the VLPO neurons are
active, they inhibit the
arousal neurons and we
fall asleep.
A flip-flop switch has one important advantage – when it switches from one state to another, it does so
quickly. Clearly, it is to our advantage to be either asleep or awake. A state that has some of the characteristics of both sleep and wakefulness would be quite problematic!
Controlling the switch
There is one problem with flip-flop switches however – they can be unstable. In fact, people with narcolepsy exhibit just this characteristic. They have difficulty staying awake and they also have trouble remaining asleep for an extended amount of time.
Wo r k b o o k
Lesson 4.3
We know from examining animals with narcolepsy that the problem lies in damage to a set of neurons
called orexin neurons. The orexin neurons are located in the hypothalamus and are so named because
they use the neurotransmitter orexin. Orexin neuron are connected to the arousal neurons in the brainstem
and help stabilize the sleep-wake flip-flop switch (Figure 14).
How do these two areas connect? What type
of synapse do these two areas make with
each other?
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What neurons help to stabilize the flip-flop
switch?
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113
LESSON READING
How do orexin neurons connect to the flipflop switch?
Figure 14: The orexin
neurons. Orexin neurons
in the hypothalamus send
projections to the arousal
neurons in the brainstem
to further control the flipflop switch regulating our
sleep-wake circuit.
But how do orexin neurons stabilize the flip-flop switch? Orexin neurons are activated by light, energy
balance, and the limbic system (which you’ll remember regulates emotion). These inputs cause the orexin
neurons to activate the arousal neurons, tipping the activity of the flip-flop switch toward the waking state,
thus promoting wakefulness and inhibiting sleep. When input to the orexin neurons from light, energy balance and limbic system stops, the orexin neurons stop activating the arousal neurons. Now the balance is
shifted, allowing the VLPO sleep neurons to inhibit the arousal neurons, thus promoting sleep and inhibiting wakefulness (Figure 15).
A. During wakefulness B. During sleep Wo r k b o o k
Lesson 4.3
Figure 15: The orexin neurons
are the actual switch between
being awake and being asleep.
(A) When orexin neurons are
stimulated by light, emotional
cues or energy balance they
activate the arousal neurons,
which in turn inhibit the VLPO
and we remain awake. (B)
When input to the orexin neurons from light, energy balance
and limbic system stops, the
orexin neurons stop activating the arousal neurons. Now
the balance is shifted and the
VLPO can inhibit the arousal
neurons and we fall asleep.
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What turns orexin neurons on? What turns
them off?
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114
LESSON READING
What causes narcolepsy?
So what causes narcolepsy?
Narcolepsy is a relatively uncommon condition — only one case per 2,500 people — but it is a great
example of a defect in the flip-flop switch that controls the transition between wakefulness and sleep,
particularly REM sleep.
Narcoleptics have sleep attacks during the day, in which they
suddenly fall asleep. This is socially disruptive, as well as dangerous — for example, if it strikes while they are driving. They
tend to enter REM sleep very quickly, and may even enter a
dreaming state while still partially awake. They also have attacks during which they lose muscle tone — similar to what
occurs during REM sleep only while they are awake. These
attacks of paralysis, known as cataplexy, can be triggered by
emotional experiences, even by hearing a funny joke.
You can watch a profile of a patient with narcolepsy online —
see this unit on the student website or click below:
■■ Video: Narcolepsy
Figure 16: Defects in orexin signaling
cause narcolepsy. If orexin input to
the arousal neurons doesn’t occur,
wakefulness and sleep are no longer
carefully controlled and people
transition uncontrollably from one to
the next.
Narcolepsy has been traced to defects in the orexin neurons
(Figure 16). For instance, two dog species that have narcolepsy naturally have an abnormality in the gene
that will make a receptor for the orexin neurotransmitter. Also, if we remove the gene for orexin from mice,
they immediately become narcoleptic. These mice also move directly from wakefulness to REM sleep –
which is also a characteristic of patients with narcolepsy (Figure 17). Since signaling between the orexin
neurons and the arousal neurons requires both the orexin neurotransmitter and the orexin receptors on
the arousal neurons that recognize the transmitter, removing either of the two partners in orexin signaling
between the neurons can cause narcolepsy.
Wo r k b o o k
Lesson 4.3
Figure 17: Narcoleptic mice. Normal mice
are called wild-type (top). When they fall
asleep they move through the stages of
sleep until they enter REM sleep. When
the orexin receptor is removed from
the mice by genetic engineering, this is
called Orexin-knockout (right). Orexin
knockout mice become narcoleptic, transitioning from wakefulness to sleep many
times a day. Sometimes they transition
directly from wakefulness to REM sleep
(indicated by the small arrovheads).
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115
LESSON READING
How did scientists realize that the orexin neurons were affected in narcoleptic humans?
Human cases of narcolepsy also
show problems with the orexin signaling pathway, and have abnormally low
orexin levels in the brain and spinal fluid.
However human patients don’t have the
genetic defects we saw in the dogs. Humans develop the disorder in their teens
or 20s, and we think its because the immune system attacks the orexin neurons
(like we saw in multiple sclerosis). Using
brain tissues postmortem (after people
have died), researchers have shown
that humans with narcolepsy have far
fewer orexin neurons than humans without narcolepsy (Figure 18).
Figure 18: Narcolepsy in humans is triggered by
actual loss of orexin containing neurons in the
hypothalamus. The pictures are data from normal
patients (left panel) and narcoleptic patients (right
panel). The pictures are of brain tissue after the
orexin neurons have been marked with an antibody
against them. Then the antibody itself is marked
with a dark brown color. The dark brown spots represent neurons that contain orexin. The narcoleptic
patient has far fewer orexin containing neurons than
the control patient.
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You can watch a video of a narcoleptic dog online — see this unit on the student website or click below:
Wo r k b o o k
Lesson 4.3
■■ Video: Snoozy the Narcoleptic Dog!
116
STUDENT RESPONSES
Given what you know about the causes of narcolepsy, how do you think you could treat the disorder?
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Wo r k b o o k
Lesson 4.3
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117
LESSON 4.4 WORKBOOK
Can caffeine treat narcolepsy?
DEFINITIONS OF TERMS
Adenosine – neurotransmitter that
accumulates in the brain during
wakefulness, implicated as an
important ‘sleepiness’ factor.
For a complete list of defined
terms, see the Glossary.
Remember that sleepiness is controlled by two factors:
length of time our brains have been awake and active, and
the time of day. Let’s turn our attention now to the first factor
– the length of time we’ve been awake and active.
Adenosine
The longer we stay awake, the sleepier we become and the pressure to sleep is hard to resist. Why? What
is responsible for the sleepiness that increases the longer we’re awake and mentally active? The precise
mechanism is unknown but it seems that the neurotransmitter adenosine is an important ‘sleepiness’
factor (Figure 19).
Researchers measured the levels of adenosine in the basal forebrain of cats during 6 hours of prolonged
waking and during 3 hours of sleep afterwards. They found that adenosine levels rise during wakefulness
and slowly decrease during sleep. They concluded that the accumulation of adenosine that occurs after
we have been awake for a long period may be the most important cause of the sleepiness that follows
periods of wakefulness (Figure 20).
Adenosine Wo r k b o o k
Lesson 4.4
Figure 19: Adenosine, the
‘sleepiness’ factor, is released
by neurons and glial cells.
Figure 20: Adenosine in the forebrain region of cats
during 6 hours of waking followed by 3 hours of recovery (sleep). Levels of adenosine rise during wakefulness and slowly decrease during sleep.
What is adenosine?
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What happens to adenosine levels during
wakefulness?
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118
LESSON READING
Another clue about adenosine’s role in promoting sleep came from studying caffeine, which as we all
know, decreases drowsiness and promotes wakefulness.
Caffeine Caffeine
Caffeine is found in coffee, tea, cocoa beans, and other plants. It
is a drug that produces excitatory effects (Figure 21). In much of
the world, a majority of the adult population ingests caffeine every
day – fortunately, without apparent harm.
Several studies have shown that caffeine prevents the normal
drowsiness that occurs after being awake by binding to and interfering with the receptors that recognize adenosine. One study
in particular used mice that didn’t have any adenosine receptors.
When these mice where given caffeine, it failed to keep them
awake, unlike mice with adenosine receptors, showing that indeed you need adenosine receptors for caffeine to have its normal effect.
Figure 21: Caffeine molecular structure is similar to
adenosine, so it can bind to
adenosine receptors and also
promote wakefulness.
There is now overwhelming evidence that caffeine’s effect as a stimulant occurs because it binds to adenosine receptors and blocks the action of adenosine (Figure 22). You can see now why that first cup of
coffee in the morning helps shake off the lingering sleepiness of the previous night, how a midafternoon
coffee break helps bring you back to an alert state during a post-lunch period of drowsiness, or how that
late night cup of coffee keeps you awake (unless you’ve already built up a tolerance to caffeine).
A.  Adenosine binds to its receptors. When levels are high enough, it promotes sleep Wo r k b o o k
Lesson 4.4
B. Caffeine also binds to adenosine receptors and stops adenosine binding. Sleep is prevented Figure 22: Adenosine signaling. (A) When adenosine levels are high they bind to adenosine receptors and cause us to fall asleep. (B) Caffeine also binds to the adenosine
receptors, which stops adenosine from binding. By preventing adenosine from binding
to its receptors, caffeine keeps us awake.
How much caffeine do you drink in an average day? When do you have it? Do you recognize any effects it’s having?
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How does caffeine keep us awake?
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LESSON READING
Let’s take a minute now to introduce the concepts of tolerance and withdrawal – two topics we’ll spend a
lot more time talking about in Chapter 5. The concepts may make more sense in the context of a drug that
probably everyone has used — caffeine.
We can define a drug as a chemical that changes behavior. So caffeine is a drug, but it does not produce
the compulsive drug-seeking behavior that people who abuse amphetamine, cocaine or other opiates
show. Therefore, it poses minimal risk and is not controlled by government laws and regulations – so it’s
readily available, and legal, to consume. Now, let’s look at tolerance and withdrawal with caffeine, our most
popular drug.
DEFINITIONS OF TERMS
Tolerance – decreased response
to a drug as a direct result of
repeated drug exposure.
Withdrawal – the condition
brought on by the elimination from
the body of a drug on which the
person has become physically
dependent.
For a complete list of defined
terms, see the Glossary.
Tolerance is what happens when we are repeatedly exposed to a drug – we become less susceptible to
its effects. Prolonged use of caffeine does lead to a moderate amount of tolerance. Tolerance explains why
those of us who consume caffeine regularly do not experience the same stimulating effects as nonusers,
and why those of us who regularly use caffeine need more of the it to get the same effects.
Withdrawal is what happens if we try to stop using a drug we’ve become dependent on. People who suddenly stop taking caffeine often complain of headaches, drowsiness and difficulty concentrating. These
withdrawal symptoms will stop after consuming more caffeine, but if the person continues to abstain, they’ll
disappear within a few days. Often, especially with drugs of abuse, these withdrawal symptoms are so
severe that individuals continue to consume the drug simply to avoid the withdrawal symptoms.
Could caffeine be used to treat narcolepsy?
If caffeine is a stimulant that keeps us awake, could it be used to treat narcolepsy – a disorder characterized by falling asleep at inappropriate times? Although, some patients with mild narcolepsy do report that
caffeine helps them overcome their daytime fatigue, caffeine is not currently an approved treatment because it is not strong enough to override the defects in orexin signaling that cause narcolepsy. But, luckily
other drugs have been developed that do.
Not surprisingly one drug, modafinil, which has been used to treat narcolepsy, is thought to act on orexin
neurons. Researchers found that giving modafinil increased orexin neuron activity, but whether this is a direct or indirect effect is still not clear. Other drugs used to treat narcolepsy include central nervous system
stimulants and antidepressants that are much stronger than caffeine. The sleep attacks can be reduced
by stimulants such as methylphenidate (Ritalin). The untimely episodes of REM sleep can be helped by
antidepressant drugs.
Wo r k b o o k
Lesson 4.4
What is tolerance? How would you know if
you’ve developed tolerance to a drug?
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What is withdrawal? How would you know if
you’re experiencing withdrawal symptoms?
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120
STUDENT RESPONSES
Would caffeine be an adequate treatment for narcolepsy? Why or why not?
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caffeine?
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Lesson 4.4
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121
S
LESSON 4.5 WORKBOOK
How do circuits regulate their output?
DEFINITIONS OF TERMS
Homeostasis – tendency to
relatively stable equilibrium.
Feed-forward inhibition –
control mechanism whereby the
output of one pathway inhibits
the activity of another pathway.
Negative feedback/Feedback
inhibition – control mechanism
whereby activity of a circuit ends
up inhibiting the activity of the
circuit.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 4.5
Now that we have discussed an example of a neural circuit,
let’s take a closer look at how these circuits regulate their
output. Circuits do this through the use of different arrangements of excitatory and inhibitory connections.
What are the two factors that control sleepiness?
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What is homeostasis?
The other sleep clue: time of day
Recall that sleepiness is controlled by two factors: time of day and length of time our brains have been
awake and active. We’ve already discussed the first factor, so let’s now explore the second – time of day.
Before we dive into our discussion of how time of day regulates sleep, let’s first remind ourselves how our
body regulates the activity of cells, tissues and organs.
The activity of all of our bodies’ cells, tissues, and organs are regulated and integrated with each other.
Homeostasis is the name given to the body’s overall response to different stimuli. Because a number of
different responses are integrated together the overall state is quite stable.
For example, take a room whose temperature is regulated by a heater that is controlled by a thermostat.
When the room is colder than the temperature the thermostat is set to, the thermostat turns the heater
on, and the heater warms the room. Once the room reaches the set temperature, the thermostat turns
the heater off. Because the production of heat feeds back to the thermostat and causes it to turn off, this
process is called negative feedback or feedback inhibition. Negative feedback control systems are the
most common homeostatic control mechanisms in our bodies, so it shouldn’t come as a surprise that our
nervous system uses negative feedback to control the output of neural circuits.
Another type of regulatory process frequently used together with feedback inhibition is feed-forward inhibition. Feed-forward inhibition anticipates changes, improves the speed of the homeostatic responses,
and minimizes fluctuations in the level of the variable being regulated. Feed-forward inhibition learns the
meaning of cues from the external environment and responds to them. For example with our room analogy, feed forward control might learn that opening a particular door to the outside would make the temperature in the room drop faster than the opening an inside door. So it would learn to make the heater work
faster if that door were opened. Not surprisingly, the first time the outside door were opened feed forward
control would not know what the result would be, and the first fluctuations in temperature would be much
larger than after it learns to anticipate the change.
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What are the two types of regulatory processes that our bodies use to control circuit
activity?
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LESSON READING
One very well characterized negative feedback loop occurs within our biological clocks which keep track
of the time of day and help control our sleep-wake cycles.
The signals for sleep – the biological clock
Our internal biological clock regulates the timing for sleep, keeping us awake during the day and making us
sleepy at night. The clock cycles with approximately a 24-hour period, and so it is called circadian (circa
diem is the Latin for ‘about the day’).
DEFINITIONS OF TERMS
Circadian – recurring naturally
on a twenty-four-hour cycle.
Melatonin – so-called ' hormone
of darkness' released by the
pineal gland. When light levels
fall, melatonin levels rise.
Preoptic nucleus (PON) –
nucleus in the hypothalamus
that signals the pineal gland to
release melatonin when light
levels fall.
Suprachiasmatic nucleus
(SCN) – nucleus in the
hypothalamus that controls that
circadian cycles of various body
functions
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 4.5
The major brain structure regulating the clock is in the tiny hypothalamus. The hypothalamus has many different brain nuclei that control many aspects of homeostasis. One of these nuclei – the suprachiasmatic
nucleus (SCN) – coordinates the timing of sleep with the light-dark cycle (Figure 23). The SCN consists of
two pinhead structures, one on each side of the brain, and acts as a master clock. The SCN nucleus sets
the pace for daily cycles of activity, sleep, hormone release, and other bodily functions
The SCN is linked to many different brain regions. The SCN receives information about the
outside world’s light-dark cycle through direct
input from the eye via the retina. The SCN then
passes on this information to the following brain
areas, each of which is also involved in controlling our sleep-wake cycles:
■■ The preoptic nucleus (PON) located
in the hypothalamus. When it is active
the PON stimulates the pineal gland to
release melatonin. Melatonin has been
called the hormone of darkness because
its levels rise at night. It is responsible
for causing drowsiness. Thus, when light
levels fall, melatonin levels rise and we
feel drowsy.
How are these regulatory processes similar? How are they different?
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What is melatonin? How is it involved in our
need for sleep?
Figure 23: The circadian clock in the hypothalamus.
The suprachiasmatic nucleus (SCN) receives information about light levels from the retina. When light
levels are high, output from the SCN that regulates
the timing of sleep is switched off.
■■ The sleep neurons in the ventrolateral preoptic nucleus (VLPO) located in the hypothalamus. As
we’ve already seen, when active the VLPO sleep neurons inhibit arousal neurons, causing us to go
to sleep.
At times when light levels are high, such as during daylight, the retina signals to the SCN, which then
inhibits the pineal gland, preventing it from secreting melatonin. Because the hormone of darkness is not
present, we feel awake.
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LESSON READING
However, when light levels fall, the retina no longer signals to the SCN, and the SCN can no longer inhibit
the pineal gland, which is now able to secrete melatonin (Figure 24). Because the hormone of darkness
is present, we feel drowsy.
A. During light B. During darkness Inhibits Inhibits Figure 24: The SCN also controls the flip-flop switch. Light activates the SCN which
inhibits the VLPO and prevents the pineal gland from secreting the hormone melatonin. However, in darkness, the SCN is not activated and therefore no longer inhibits
either the VLPO or the pineal gland, which can now secrete melatonin. Together, the
activity of the VLPO and the hormone melatonin promote sleepiness.
SCN activity is regulated by genes that are called ‘clock genes’. The clock genes synthesize ‘clock proteins’. The clock proteins slowly enter the cell nucleus and stop the clock genes from synthesizing more
clock proteins (Figure 25). But over a period of about 24 hours, these clock proteins break down and so
the clock genes become active again and are able to synthesize more clock proteins. They slowly enter
the nucleus etc. etc. This control of clock gene expression is a good example of feedback inhibition at the
level of the individual cells in the SCN.
Wo r k b o o k
Lesson 4.5
Figure 25: Feedback inhibition controls the production
of clock proteins. Clock genes express clock proteins which then affect behavior and other activities.
When levels of clock proteins are high, they enter the
nucleus and suppress the genes responsible for their
production. Over time the levels of clock proteins fall,
which removes the inhibition on the clock genes, so
they can again synthesize more clock proteins.
The circadian clock in humans actually
cycles at just over 24 hours, so the cellular
clock must match the light-dark cycle. The
cue for matching the cellular clock to the circadian clock is light. Neurons in the eye that
are sensitive to light (photoreceptors) transmit signals to the SCN, which sets the clock
genes so they match the environmental
cues. If the clock genes fail to reset properly,
the neurons in the SCN become out of sync
with the environment and can produce various problems such as jet lag, seasonal affective disorder, and Monday morning blues.
How does the SCN connect with the flip-flop
switch?
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What is the biological clock? Where is it
located? How does it control our need for
sleep?
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LESSON READING
How does jet lag happen? How does jet lag
affect our sleep-wake cycles?
Biological clock disorders
Jet Lag
Travelers who cross multiple time zones rapidly (such as by
plane) often suffer from jet lag (Figure 26). Jet lag has many
unwelcome effects, including disrupting sleep, causing loss of
concentration, poor motor control, slowed reflexes, nausea, and
irritability. Jet lag happens because our circadian clock can’t immediately adjust to the changes in the light cues that result from
crossing time zones quickly. So, the clock is out of step with the
cues in the new time zone. This conflict between external and
internal clocks affects more than just the sleep-wake cycle. All
the rhythms are out of sync, and they take a number of days to
re-match (also known as re-entrain to) the new time zone. Eastward travel generally causes more severe jet lag than westward
travel, because traveling east requires that we shorten our day
and adjust to time cues occurring earlier than our clock is used
to.
Figure 26: Jet lag is the bane of frequent travelers because our circadian
clocks can’t automatically readjust to
changes in light-dark cycles that happen rapidly with modern day travel.
Seasonal affective disorder (SAD)
Seasonal affective disorder (SAD) is a form of depression that
occurs at a certain time of year, when the hours of daylight decrease i.e. winter (Figure 27). The change of seasons in the
fall brings on both a loss of daylight savings time (fall back one
hour) and a shortening of the daytime. During this season of
short days and long nights, too little bright light reaching the
biological clock in the SCN causes some individuals to develop
symptoms similar to jet lag – but more severe. These symptoms include decreased appetite, loss of concentration and
focus, lack of energy, feelings of depression and despair, and
excessive sleepiness. Treatment with light boxes that artificially Figure 27: Seasonal affective disorder
(SAD) is caused by lack of sunlight to
increase the length of daylight are very effective.
Wo r k b o o k
Lesson 4.5
reset our biological clocks. It can be
helped by light therapy to stimulate
summer, or at least brighter light
conditions.
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How does SAD happen? How does SAD affect our sleep-wake cycles?
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LESSON READING
How do the Monday morning blues happen?
How do they affect our sleep-wake cycles?
Monday morning blues
By staying up later and sleeping in more than usual on the
weekends, we provide our biological clocks with cues that
push it toward a later nighttime phase. If we keep a late sleep
schedule on both weekend nights, our internal clock can become two hours or more behind our usual weekday schedule.
This delay in our clocks (not to mention facing another work
week) makes it very difficult to wake up on Monday morning – a condition called the Monday morning blues (Figure
28). To cure the Monday morning blues, it is recommended
we stay on our weekday sleep schedules on the weekends.
(We know it’s hard, but it’s what recommended in order to not
throw off your biological clock.)
Figure 28: Monday morning blues.
The circadian clock is not set exactly at 24 hours, so if we go to bed
and sleep late on the weekends,
our internal clock becomes behind
schedule, making Monday mornings particularly miserable.
Shift work
Figure 29: People who work the night
shift often encounter behavioral problems like jet lag and SAD.
Wo r k b o o k
Lesson 4.5
Humans are normally active during daylight hours and
sleep at night. This pattern is called diurnal activity. For humans and other diurnally active animals, light signals the
time to awake, and sleep occurs during the dark. People
who work the night shift may experience mental and physical difficulties similar to jet lag and SAD because their internal clocks and external daylight and darkness signals, are
no longer synchronized (Figure 29).
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How does shift work affect our sleep-wake
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STUDENT RESPONSES
What are the benefits of using feedback and feed-forward inhibition to control circuit activity?
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How do our biological clocks use feedback and feed-forward inhibition to control our sleep-wake cycles?
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Wo r k b o o k
Lesson 4.5
127
S
LESSON 4.6 WORKBOOK
What causes epilepsy?
DEFINITIONS OF TERMS
Generalized seizures –
seizures that involve the entire
brain.
Partial seizures – seizures that
do not involve the entire brain.
Positive symptom – symptom
in which one acquires an
abnormal behavior.
Negative symptom – symptom
in which one loses a normal
behavior.
For a complete list of defined
terms, see the Glossary.
So far in this unit we’ve seen how the activity of circuits
regulate behaviors, as well as how the activity of circuits can
be regulated by feedback inhibition and feed-forward inhibition. In this lesson, we’ll turn our attention to a disorder in
which the control of circuit activity is abnormal – epilepsy.
When neuronal activity is unregulated
All complex behaviors rely on precisely ordered communication between neurons in circuits. What happens to the circuit when the ordered communication between neurons breaks down? The result is called
a seizure – one of the most dramatic examples of disordered electrical behavior in the mammalian brain.
Epilepsy is the chronic neurological condition that results from unprovoked seizures. It affects approximately 50 in every 1000 people in developed countries. In the US, about 3% of all people living to the age
of 80 will be diagnosed with epilepsy. Three to four times that number will have epilepsy in developing
countries – why the discrepancy? No one knows.
How seizures are classified
Not all seizures are the same, and they must be sorted out according to their clinical features before any
treatment program can begin. Seizures can include both ‘positive’ and ‘negative’ motor or sensory symptoms. A positive symptom involves acquiring an abnormal behavior – like jerking an arm for instance.
A negative symptom involves losing a normal behavior – like briefly losing sight for instance. What
symptoms appear depends on the effected region of the brain and the extent to which the normal brain
tissue is involved.
Seizures can be classified clinically into two categories: partial seizures and generalized seizures. This
simple classification is very useful because the effectiveness of the treatment depends on the category of
seizure being treated.
Wo r k b o o k
Lesson 4.6
What is a seizure? What is epilepsy?
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What are the two main types of symptoms
associated with seizures? And what determines what types of symptoms will appear
with a seizure?
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What are the two main types of seizures?
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LESSON READING
Partial Seizures
DEFINITIONS OF TERMS
Complex partial seizures –
partial seizure in which patient
loses consciousness.
Seizure focus – specific area of
the brain where partial seizures
begin.
Simple partial seizures –
partial seizure without the loss of
consciousness
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 4.6
Partial seizures originate in a small group of
neurons that are called
the seizure focus. The
seizure focus can be
any small group of excitatory neurons that are
damaged in some way –
for example because of
a blood clot, a tumor, or
a scar. The symptoms of
a partial seizure depend
on where the seizure
focus is located (Figure
30).
Somatosensory What is the seizure focus?
Motor in limbs Visual Motor in face and head Auditory Figure 30: The symptoms of seizure depend on where the seizure focus
is located. Symptoms may include visual, auditory, somatosensory and
motor abnormalities depending on where the abnormal electrical activity
is located.
If the activity in the focus is intense, the inhibitory neurons surrounding the area can’t keep up with the
excitation. The excitatory electrical activity then begins to spread to other brain regions (Figure 31). This
spread follows the normal connections in the affected circuit. The cortex is heavily interconnected. Therefore seizure foci in the cortex are more likely to spread within that hemisphere of the cortex, then to the
other hemisphere, and finally to the thalamus, which can redirect the seizure throughout the entire brain.
Partial seizures are further classified into two categories: simple and complex. Simple partial seizures
often cause changes in consciousness,
but do not cause loss of consciousness.
A. B. Simple partial seizures involve localized
symptoms, such as jerking of the arm. The
simple partial seizure becomes a complex
partial seizure if it progresses so that the
patient loses consciousness.
People who experience partial seizures
often describe symptoms that precede the
actual seizure called auras. Common auras include a sense of fear, a rising feeling
in the abdomen, or a specific odor.
Figure 31: Secondary spread of the seizure. (A)
Seizure activity may spread within the same lobe of the
cortex, to the opposite lobe via the corpus callosum or
throughout the entire brain via the thalamus. (B) Once
the thalamus is involved, the seizure is likely to spread
widely throughout the brain. This is known as secondary
spread.
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What causes the abnormal activity in a seizure focus to spread?
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What is the difference between simple and
complex partial seizures?
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LESSON READING
What is a generalized seizure? How is it different from a partial seizure?
Generalized seizures
In contrast to partial seizures that originate in the cortex, generalized seizures involve connections to the
cortex from subcortical structures like the thalamus, and connections from the cortex to subcortical structures like the thalamus (Figure 32). Generalized seizures begin without an aura or a seizure focus and involve both hemispheres of the brain from the onset. They can be divided into non-convulsive or convulsive.
DEFINITIONS OF TERMS
Absence seizure – seizure
in which patients have a
transient loss or impairment of
consciousness.
Convulsive seizure – seizure
involving uncontrollable jerking
of the body.
Grand mal seizure – (also
known as tonic-clonic seizure)
type of generalize seizure that
affects the entire brain.
The best understood non-convulsive generalized seizure is the absence seizure (formerly called petit
mal). These seizures begin abruptly, usually last less than 10 seconds and are characterized by repeated
loss of attention or consciousness without any physical symptoms. Absence seizures can happen many
times a day and are most common in children. In this case the issue is not a defective area in the brain
but a sudden generalized cortical hyper-excitability. This hyper-excitability then synchronizes with the excitatory input from the thalamus to the cortex, which causes a massive depolarization. In response, the
inhibitory neurons in the thalamus try to control the output. The resulting prolonged hyperpolarization
causes the neurons to take a long time to repolarize, but once they do, the synchronized depolarization
can happen again. Interestingly, the EEG in absence seizures is very similar to the EEG in the deep stages
of sleep known as ‘sleep spindles’.
The most common convulsive generalized seizure is the tonic-clonic or grand mal seizure. These seizures also begin abruptly, often with a grunt or a cry as the thorax and diaphragm contract suddenly. The
patient may fall to the ground with a clenched jaw, lose bladder or bowel control, and become blue in the
face (cyanotic). This tonic phase typically lasts 30 seconds before evolving into jerking of the extremities
lasting 1 - 2 min. This active phase is followed by an ictal phase during which the patient is sleepy and may
complain of headache and muscle soreness.
What is an absence seizure?
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What is a grand mal seizure?
Non-convulsive seizure –
seizure without jerking.
Thalamus For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 4.6
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Figure 32: Generalized seizures involve connections
both to and from the cortex via the thalamus and
other subcortical structures. Since the thalamus is
involved, the seizure activity immediately spreads to
the entire brain.
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130
LESSON READING
You can imagine that it is often difficult to distinguish a generalized seizure from a complex partial seizure
with a brief aura. The distinction isn’t academic – it’s vital to choosing the proper treatment as well as
pinpointing the underlying cause.
Electrical activity and seizures
As you can imagine, the most accurate way
to pinpoint the region that initiates a seizure
would be to impale the brain with electrodes and then measure where activity is
defective. This is obviously not feasible in
human patients. So, the EEG is called into
service. The EEG provides a non-invasive
way of examining brain activity.
EEG recordings made during partial seizures show abnormal neuronal firing beginning first in a single region. This abnormal
activity then may spread to other regions,
but initially only one region is affected (Figure 33).
How do doctors diagnose the origin of a seizure?
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What would an EEG trace look like during a
partial seizure?
Figure 33: EEG of partial seizure. Seizure activity shows
up initially on only some the EEG leads, indicating that
initially only one area is involved, but may recruit others if
the seizure spreads.
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What would an EEG trace look like during a
generalized seizure?
Conversely, EEG recordings made during generalized seizures show abnormal
neuronal firing beginning simultaneous
throughout many, if not all, brain regions
(Figure 33).
Wo r k b o o k
Lesson 4.6
Figure 33: EEG of generalized seizure. Seizure activity
shows up simultaneously on all the leads of the EGG,
indicating that the entire cortex is involved.
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LESSON READING
Treatments
Seizure disorders are treated with anticonvulsant drugs, many of which work
by increasing the effectiveness of inhibitory synapses. Most patients respond well
enough to drugs that they can lead a normal life. In a few instances, drugs provide
little or no help. Sometimes, seizure foci
remain so irritable that despite drug treatment, brain surgery is required (Figure
34). In these cases, the surgeon removes
the seizure foci and some of the region of
the brain surrounding the focus. Most patients recover well from surgery, with their
seizures eliminated or greatly reduced in
frequency.
Wo r k b o o k
Lesson 4.6
Figure 34: Most patients with epilepsy respond well to
anticonvulsant medications which increase the effectiveness of inhibitory synapses. In some cases surgery
is required to remove a seizure focus. Surgery often
means removing a considerable amount of brain tissue,
but it can be extremely effective.
Figure 35: Vagus nerve stimulation (VNS). VNS
is a treatment option for patients who do not
respond well to medications and are not considered good candidates for surgery. VNS involves
the implantation of a pacemaker like device that
provides electrical stimulation to the brain via the
vagus nerve.
For those patients who do not respond to anticonvulsant medications, and who are not
considered good candidates for surgery (because their seizures are produced throughout
the brain), vagus nerve stimulation (VNS) is
another treatment option (Figure 35). VNS involves the implantation of a pacemaker device
that generates pulses of electricity to stimulate
the vagus nerve. While it is not exactly known
how VNS works, it is thought that by stimulating
the vagus nerve, electrical energy is discharged
upward into a wide area of the brain, disrupting the abnormal activity that causes seizures.
Another theory suggests that stimulating the
vagus nerve causes the release of inhibitory
neurotransmitters that decrease seizure activity.
What treatments are available for epilepsy?
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132
STUDENT RESPONSES
If a friend of yours was diagnosed with epilepsy, what questions would you ask to find out whether it caused partial or general
seizures?
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How would you tell the difference between a partial seizure that has spread or a generalized seizure?
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Wo r k b o o k
Lesson 4.6
133
Unit 5: How do our choices
Overview
change our brains?
In the previous units, we learned about the neuron, synaptic transmission, and neuronal circuits. In this key culminating unit, we’ll
bring all of that knowledge together with a discussion of drug addiction, to understand how our choices affect our brains, as well as
how our brains affect our choices.
Remember our graphic from the beginning of this workbook? This unit focuses on how our choices change our brains – so we’re
pulling all the information from the previous units together.
LESSON 5.1 WORKBOOK
What circuit do drugs affect in our
brains?
DEFINITIONS OF TERMS
Addiction — chronic,
relapsing brain disease that is
characterized by compulsive
drug seeking and use, despite
harmful consequences
Ventral tegmental area
(VTA) – brain region containing
dopamine neurons that form
connections with nucleus
accumbens and prefrontal cortex
Nucleus accumbens (NAc)
– brain structure that plays an
important role in rewarding
and reinforcing effects of many
abused drugs
Prefrontal cortex (PFC) – part
of the frontal lobe that receives
emotional and motivational input
and is necessary for logical
decision making
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 5.1
To start our discussion of drug addiction, in this lesson
you’ll be introduced to the circuit that controls how we
experience pleasure — the neural reward circuit.
What is drug addiction?
Drug addiction poses a serious problem to our society. Consider the disastrous effects caused by the
abuse of one of our oldest drugs, alcohol: automobile accidents, fetal alcohol syndrome, increase rate of
liver disease, increased rate of heart disease, and increased rate of stroke. Or take smoking which causes
addiction to nicotine. It greatly increases the chances of dying of lung cancer, heart attack, and stroke.
The term addiction is derived from the Latin word addicere, “to sentence”. Someone who is addicted to
a drug is, in a way, sentenced to a term of involuntary servitude, because they are shackled to their drug
dependency, which defines how they live their lives.
Addiction is defined as a chronic, relapsing brain disease that is characterized by compulsive drug seeking and use, despite harmful consequences. It is considered a brain disease because drug use changes
brain structure and function. These changes can be long lasting, and can lead to the harmful behaviors
seen in people who abuse drugs.
How do drugs of abuse work in the brain?
Drugs of abuse interfere with neurotransmission. They do this by altering signaling in the pathway that
controls our feelings of reward and pleasure. This pathway is called the dopamine reward pathway. The
dopamine reward pathway originates in a subcortical area of the brain near the midline called the ventral
tegmental area (VTA). Dopamine neurons whose cell bodies are in the VTA end up in the nucleus accumbens (NAc) and the prefrontal cortex (PFC).
What is drug addiction? It’s important to be
familiar with the complete definition.
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What brain pathway do drugs of abuse affect? What brain structures are involved in
this pathway?
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LESSON READING
The connections between the VTA and the nucleus accumbens are called the reward pathway because
the pathway is activated during pleasurable experiences such as eating, sex or receiving praise. Researchers have learned that this pathway is well conserved among animals, making the same connections in our
brains as it does in a rodent’s brain (Figure 1).
Human Brain Rat Brain DEFINITIONS OF TERMS
PFC Reward pathway – neural
circuit that plays an important
role in rewarding and reinforcing
effects of behaviors, including
the VTA, NAc, and PFC.
Intracranial self-stimulation –
method that involves implanting
electrodes into an animal’s brain
and then allowing the animal
to electrically stimulate the
electrode to activate that brain
region.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 5.1
NAc VTA Figure 1: Reward pathway.
The reward pathway connects
the ventral tegmental area
(VTA) with the nucleus accumbens (NAc) and prefrontal
cortex (PFC). This pathway
is well conserved in animals,
having the exact same connections in a rodent brain as it
does in the human brain.
Since these structures are buried deep within the middle of the brain, you might want to take a look at a 3D
model to get a better understanding of where these structures actually are. (We really like the free smart
phone app called ‘3-D Brain’.)
Methods to study drug effects in the brain
The reward pathway was discovered using the technique of intracranial self-stimulation (Figure 2). In
these experiments, scientists implanted an electrode
in different areas of rats’ brains, and then trained the
rats to press a lever to active the electrode. When the
electrode was implanted in the VTA, the rats spent
their time compulsively pressing the lever, even at the
expense of eating and drinking. The rats didn’t behave
like this if the electrode was implanted in areas other
than the VTA. Knowing that rats only compulsively
repeat behaviors that are pleasurable, the scientists
concluded that stimulation of the VTA must activate a
pathway that stimulates feelings of pleasure or reward.
Figure 2: Intracranial self-stimulation. When
the animal presses the lever it receives an
electrical shock directly to an area of its brain
via an implanted electrode. Alternatively, the
experiment can be setup so that the animal
receives a drug after pressing the lever. This
drug self-administration method predicts
abuse potential.
You can watch a video about intracranial self-stimulation online — see this unit on the student website or
click below:
■■ Video: Brain Mechanisms of Pleasure and Addiction
How did intracranial self-stimulation experiments help scientists discover the reward
pathway?
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What do scientists use the drug self-administration method for?
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LESSON READING
DEFINITIONS OF TERMS
Self-administration method –
test used to measure the abuse
potential of a drug by allowing
an animal to give itself doses of
the drug.
Breaking point – the point at
which an animal will no longer
expend the effort required to
receive a reward.
For a complete list of defined
terms, see the Glossary.
A modification of intracranial self-stimulation has been used very effectively in identifying drugs that have
the potential to be abused by humans. Based again on the idea that animals only compulsively repeat
pleasurable behaviors, if an animal compulsively presses a lever in order to receive an injection of a
drug into either their blood or their brain, we can conclude that the drug must have reinforcing properties
(meaning that the drug activates the reward pathway and encourages animals to keep repeating the
behavior). Using animals and this drug self-administration method, scientists have been able to very
accurately predict whether or not a drug is likely to be addictive in humans. For example, rodents will
readily self-administer morphine, cocaine and amphetamines, drugs that we know are readily abused by
humans. In contrast, drugs like aspirin, antidepressants, and drugs that are used to treat psychoses like
schizophrenia, are neither self-administered by animals nor abused by humans.
We can also use this self-stimulation method to ask the animal which of several drugs it prefers by placing
two levers in the chamber and training the animal to press lever A for one drug, and lever B for the alternative. Given free access to the levers, the animal’s choice will indicate which drug the animal prefers,
because that drug will have greater reinforcing properties.
Additionally, we can ask how much the animal really “likes” a particular drug by varying how hard the animal needs to work to get the drug. For example, we can make the animal press the lever ten times for one
injection or sixty-five times for one injection. We can tell how reinforcing the drug is by how many times the
animal will press the level for a single injection. The point at which the effort required exceeds the reinforcing value is called the breaking point – the higher the breaking point, the greater the reinforcement of the
drug, and presumably the greater the abuse potential in humans. Drugs like cocaine sustain incredibly
high rates of responding: animals will lever-press for drug reinforcement until exhaustion.
Addicted to _____
You’ve probably suspected that addiction is not limited to drugs. Many brain parts are interlocking and
overlapping, so the reward pathway can get turned on by – well, just about anything.
In addition to the usual physical suspects, you can get hooked on a feeling as well, and that includes (but
is not limited to) compulsive behavior such as eating, gambling, shopping, risk taking, and sex. That’s because these feelings, thoughts and sensations hijack our reward pathways. (See Box 5.1 for a description
on how food effects our reward pathway.)
Wo r k b o o k
Lesson 5.1
Certainly many events and experiences register pleasure, but some things are much more potent than
others. All drugs of abuse, for example, prompt a tsunami of dopamine signaling in the reward pathway –
a reaction much more powerful than any natural reward. Eventually these reactions overwhelm, capture,
and change the reward pathway, leaving us craving more and more.
Would you expect a rat to self-administer an
antibiotic? Why or why not?
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137
LESSON READING
BOX 5.1 Controlling the desire to eat: The Reward Pathway
Various feeding and satiety messages from the body do not single-handedly determine what we
eat. Almost everyone has encountered a mouth-watering dessert and devoured it, even on a full
stomach. We have an innate taste for sweet and acquire a taste for fat. We often eat because food
confronts us. It smells good, tastes good, and looks good. We might eat because it is the right time of
day, we are celebrating, or we are trying to overcome sadness. After a meal, memories of pleasant
tastes and feelings reinforce appetite, our desire to eat.
Our desire to eat is controlled by the dopamine reward pathway. Scientists have learned that the
reward pathway is activated by all pleasurable stimuli, including food. Our reward pathways are particularly sensitive to high-calorie food, containing sugar and fat. This makes sense evolutionarily
because as hunters, we did not always succeed in finding something to eat. So high-calorie foods,
which contained a lot of energy, offered a survival advantage. In that environment, it was in our best
interest to consume as many high-calorie foods as we could find. So our bodies adapted a mechanism to find high-calorie foods rewarding, which motivated us to consume them. But today, when we
no longer need to hunt to find our food, our reward pathways are still guiding our food selection to
high-calorie foods that are full of sugar and fat.
The involvement of the reward pathway in food selection and consumption is an area of much scientific research. Research indicates that even in the absence of hunger, the sight, smell and even the
thought of high-calorie foods can activate the reward pathway and motivate us to consume these
foods. Consuming foods to please appetite but not hunger, is one reason why we intake more food
than is needed to maintain an energy balance.
Wo r k b o o k
Lesson 5.1
What was the evolutionary advantage of
having high calorie food stimulate the
reward pathway, and how is that advantage
actually maladaptive today?
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STUDENT RESPONSES
Recently, different celebrities have blamed transgressions on ‘addictions’ (i.e. Tiger Woods addicted to sex) – to what extent
do you believe that people get addicted to different behaviors? To what extent do you think people are using ‘addiction’ as an
excuse?
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Remember to identify your
sources
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Since anything that is pleasurable activates the reward pathway, it is technically possible to become addicted to anything that is
pleasurable – for example running. Describe how an addiction to running would occur.
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Wo r k b o o k
Lesson 5.1
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LESSON 5.2 WORKBOOK
How do drugs alter synaptic transmission?
DEFINITIONS OF TERMS
Reuptake – process that involves
transport of neurotransmitter out of
the synaptic cleft by the same cell
that released the neurotransmitter.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 5.2
Now that we know which neural pathway is activated in
response to rewarding stimuli, let’s take a closer look
at the synapses in the pathway and see how different
drugs of abuse change their synaptic signaling.
Dopamine signaling
All the natural reinforcers that have been studied
so far (such as food for a hungry animal, water for
a thirsty one, or sexual contact) have one physiological effect in common – they cause the release
of dopamine in the nucleus accumbens. The release of dopamine appears to be a necessary
condition for positive reinforcement to take place.
What do all natural reinforcers have in common?
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How does the dopamine synapse clear dopamine from the synaptic cleft?
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Addictive drugs – including amphetamine, co___________________________________
caine, opiates, nicotine, alcohol, PCP, and canna___________________________________
Figure
3:
Dopamine
synapse.
The
dopamine
bis – trigger the VTA to release dopamine in the
___________________________________
synaptic cleft does not contain an inactivating
nucleus accumbens. Different drugs stimulate the
___________________________________
enzyme, therefore in order to turn off doparelease of dopamine in different ways. Before we
___________________________________
mine signaling, dopamine must be recaptured
get into the specifics of how different drugs stimu___________________________________
and transported back into the presynaptic
terminal by transporters in a process known as
late dopamine signaling, we need to mention one
___________________________________
reuptake.
important feature of the dopamine synapse.
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Once dopamine has been released, moved across the synaptic cleft and interacted with its receptors, ___________________________________
the dopamine synapse clears dopamine from the synaptic cleft by pumping it back into the presynaptic ___________________________________
terminal using specific transporters. This process is known as reuptake (Figure 3). This means that any ___________________________________
drug inhibiting the reuptake of dopamine from the synaptic cleft will cause dopamine levels to stay high,
and its effects to persist, because it can’t be taken back up by the presynaptic terminal. Keep this in mind
140
as we discuss how specific drugs change dopamine signaling.
LESSON READING
What are the psychological and behavioral
effects of taking cocaine?
Stimulant drugs: Cocaine and Amphetamine
Cocaine and amphetamine have similar behavioral effects: both are stimulants and both act as potent dopamine agonists. However, their sites of action are different. Cocaine binds with and inactivates the dopamine transporter proteins, thus blocking dopamine reuptake and keeping dopamine levels in the synaptic
cleft high. Amphetamine has two effects: It also inhibits the reuptake of dopamine, but its most important
effect is to directly stimulate the release of dopamine from axon terminals.
DEFINITIONS OF TERMS
Agonist – drug that facilitates the
effects of a neurotransmitter on the
postsynaptic cell .
Stimulants – class of drugs that
increase the activity of the central
nervous system.
For a complete list of defined
terms, see the Glossary.
Cocaine
When people take cocaine (Figure 4), they become euphoric, active and talkative. They say that they feel powerful and alert. Some of them become addicted to the drug,
and obtaining it becomes an obsession to which they devote more and more time and money.
Laboratory animals, which quickly learn to self-administer
cocaine, also act excited and show intense exploratory activity. If animals are given continuous access to self-inject
cocaine, they often self-inject so much that they die from
an overdose.
Figure 4: Cocaine. When people take
cocaine they become euphoric, active
and talkative. Once addicted to cocaine,
obtaining it becomes an obsession.
One of the alarming effects seen in people who abuse
either cocaine or amphetamine is psychotic behavior: hallucinations, delusions of persecution, mood disturbances, and repetitive behaviors. These behaviors so closely resemble those of paranoid schizophrenia
that even trained mental health professionals cannot distinguish between them unless he or she knows
about the person’s history of drug abuse. These effects disappear once people stop taking the drug.
As mentioned previously, cocaine use increases alertness, energy, motor activity and feelings of well-being. But feelings of anxiety, paranoia and restlessness are also common effects of cocaine. With excessive
use, cocaine can cause tremors, convulsions, stroke and even death.
Cocaine effects dopamine synaptic transmission by altering the way in which dopamine is removed from
the synaptic cleft. Under normal conditions, the VTA releases dopamine onto the nucleus accumbens.
Dopamine binds to receptors within the nucleus accumbens and this initiates downstream signaling in the
nucleus accumbens neurons. As we saw before, dopamine signaling is normally stopped when the dopamine transporters (also known as pumps) in the dopamine reuptake system pump dopamine back into the
presynaptic neurons, thus decreasing the levels of dopamine in the synaptic cleft.
Wo r k b o o k
Lesson 5.2
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Where does cocaine act within the reward
pathway?
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141
LESSON READING
What is the effect of cocaine on dopamine
levels in the nucleus accumbens?
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Cocaine ___________________________________
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Figure 5: Mechanism of cocaine action. Cocaine
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increases synaptic dopamine by binding to the dopamine
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transporter and inhibiting dopamine reuptake.
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Compare the healthy brain at the top with the
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brain of a cocaine abuser at the bottom of Fig___________________________________
ure 6. Didn’t we say cocaine is a stimulant?
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Why then does cocaine reduce brain activity
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if it increases the activity of dopamine neuro___________________________________
transmission at the nucleus accumbens syn___________________________________
apse? This is because the output neurons from
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the nucleus accumbens are actually inhibitory.
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That is to say when they are activated they shut
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down signaling in the regions they synapse
Figure 6: PET scans showing decreased activity
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with. When they are stimulated by cocaine the
in cocaine addict. Cocaine reduces brain activity
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because output from the nucleus accumbens is
inhibition is even more intense.
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largely inhibitory.
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You can watch an animation describing how cocaine affects the brain online — see this unit on the student ___________________________________
website or click below:
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■■ Video: How Does Cocaine Affect the Brain?
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Cocaine blocks the activity of dopamine
transporters. Since dopamine transporters are responsible for removing excess
dopamine from the synaptic cleft, when
they are blocked, dopamine cannot be
removed from the synaptic cleft, and dopamine levels increase which increases
dopamine signaling at the nucleus accumbens (Figure 5).
Wo r k b o o k
Lesson 5.2
142
LESSON READING
Amphetamine
Amphetamines include methamphetamine, crystal meth, and crack. Amphetamines are also central nervous system stimulants, increasing alertness and focus, while decreasing fatigue and appetite. They also
produce hyperactivity and anxiety. With chronic use and/or high doses, amphetamines can also cause
seizures, stroke, coma, and death.
Amphetamine (Figure 7) has two effects on the VTA-nucleus
accumbens synapse: The first effect is similar to cocaine – it
also prevents dopamine reuptake. The most important effect
of amphetamine however is to stimulate release of dopamine
into the synaptic cleft (Figure 8).
Figure 7: Amphetamines include methamphetamine, crystal meth and crank.
Amphetamines are CNS stimulants.
Under normal conditions, the VTA releases moderate amounts
of dopamine onto the nucleus accumbens. Dopamine then
binds to receptors within the nucleus accumbens and effects
downstream signaling, as we have seen before. Then, to stop
dopamine signaling, dopamine transporters (also called dopamine reuptake pumps) pump dopamine back into the presynaptic neurons, which decreases the levels of dopamine in the
synaptic cleft.
Amphetamines can alter dopamine synaptic transmission by blocking dopamine transporters like cocaine
does. When the dopamine transporters are blocked, dopamine cannot be removed from the synaptic cleft,
and dopamine levels remain high, which increases dopamine signaling in the nucleus accumbens, just as
we saw for cocaine.
Wo r k b o o k
Lesson 5.2
The second way amphetamines can alter synaptic transmission is by entering
the presynaptic terminals of the VTA’s
neurons and causing dopamine to be released even in the absence of action potentials. This release also increases the
level of dopamine signaling to the nucleus accumbens. Scientists are still trying
to figure out exactly how amphetamines
cause the release of dopamine in the absence of action potentials, but somehow
this mechanism gives amphetamines another way to alter dopamine signaling in
the reward pathway.
Amphetamine Figure 8: Mechanism of amphetamine action. Amphetamine (AMPH) increases synaptic dopamine in two ways.
First, it binds to the dopamine transporter and inhibits
dopamine reuptake. Second, it enters the presynaptic
terminal and stimulates dopamine release. The combined
effect is a massive increase in synaptic dopamine levels.
What are the psychological and behavioral
effects of taking amphetamine?
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Where does amphetamine act within the reward pathway?
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How does amphetamine alter synaptic signaling of the reward pathway? What is the
drug target?
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What is the effect of amphetamine on dopamine levels in the nucleus accumbens?
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143
LESSON READING
What are the psychological and behavioral
effects of taking heroin?
Opiates: Heroin and Morphine
Opium, derived from a sticky resin produced by the opium poppy, has been eaten and smoked for centuries, and in 1847 scientists figured out to make it themselves, producing heroin, the most commonly abused
opiate. Addiction to opiates, like heroin, has several high personal and societal costs.
• First, because heroin (Figure 9) is an illegal drug is
most countries, an addict becomes by definition, a
criminal.
DEFINITIONS OF TERMS
• Second, because of tolerance, a person must take
Opiates – class of drugs with pain
reducing qualities.
increasing amount of the drug to achieve a “high”.
The habit thus becomes more and more expensive, and the person often turns to crime to obtain
enough money to support his or her habit.
• Third, addicts that inject opiates often don’t have
For a complete list of defined
terms, see the Glossary.
Where does heroin act within the reward
pathway?
Figure 9: Heroin is the most commonly
abused opiate.
access to sterile one-use needles, so a substantial
percentage of people who inject illicit drugs have been exposed to hepatitis or HIV.
• Fourth, if the addict is a pregnant woman, her infant will also become dependent on the drug, which
easily crosses the placenta barrier. The infant must be given opiates right after birth, and then weaned
off the drug with gradually decreasing doses.
• Fifth, the uncertainty about the strength of a given batch of heroin means that a user could unwittingly
take an overdose, with possibly fatal consequences.
Heroin and morphine are both opiates. They are analgesics, meaning they reduce pain without producing
unconsciousness. Heroin and morphine produce a sense of relaxation and sleep, and at high doses can
cause coma and death.
Heroin and morphine increase the activity at the nucleus accumbens in two ways, both are different from
how cocaine and amphetamines act. Both heroin and morphine work on a group of inhibitory neurons that
normally inhibit the VTA. Under normal circumstances these neurons decrease the activity of the VTA.
However when heroin and morphine bind to their receptors, they can no longer decrease the activity of the
VTA. When the inhibition to the VTA is blocked, the VTA’s activity is increased, which results in an increase
in dopamine signaling to the nucleus accumbens. Thus when either heroin or morphine are present, more
dopamine is released by the VTA to the nucleus accumbens because the VTA is no longer inhibited.
Wo r k b o o k
Lesson 5.2
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Heroin and morphine can also affect the nucleus accumbens directly by binding to receptors for opiates
found on the nucleus accumbens itself. The body itself produces natural opiates, which play an important
role in reducing pain sensations and many neurons have receptors for these natural opiates. The nucleus
accumbens is no exception. Both heroin and morphine can bind to these receptors and in this way can
directly affect the activity of the nucleus accumbens.
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How does heroin alter synaptic signaling of
the reward pathway? What is the drug target?
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What is the effect of heroin on dopamine levels in the nucleus accumbens?
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144
LESSON READING
Nicotine
While nicotine (Figure 10) might seem rather tame in comparison to cocaine, amphetamine and opiates, it
is still an addictive drug, and it accounts for more deaths than all the other so called “hard” drugs combined.
The combination of nicotine and other substances in tobacco smoke is carcinogenic and leads to cancer
in the lungs, mouth, throat and esophagus. The World Health Organization (WHO) estimates that 50% of
people who begin to smoke as adolescents and continue to smoke will die from smoking-related diseases.
Nicotine is extremely addictive; many people continue to smoke even when their health is seriously affected. Although tobacco companies and others with vested interests have tried to argue that smoking is a
“habit” rather than an “addiction”, it is clear that people who regularly use tobacco behave like compulsive
drug users. Smokers tend to smoke regularly or not at all; few smoke just a little. Male smokers smoke an
average of 17 cigarettes per day, while female smokers smoke an average of 14. Nineteen out of twenty
smokers smoke every day, and only 60 out of 3500 smokers surveyed smoke fewer than 5 cigarettes a day. Of those who attempt
to quit smoking by enrolling in a special program, only 20% manage to abstain for one year. The record is much poorer for those
who try to quit on their own: one-third manage to stop for one day,
Figure 10: Nicotine is the active
one-fourth manage for one week, but only 4% manage to stop for
ingredient in cigarettes and chewing tobacco.
six months.
What are the psychological and behavioral
effects of taking nicotine?
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Where does nicotine act within the reward
pathway?
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How does nicotine alter synaptic signaling of
Ours is not the only species that will willingly self-administers nicotine, laboratory animals will too. Nicotine the reward pathway? What is the drug target?
binds to and stimulates nicotinic acetylcholine receptors in the VTA. Once nicotine binds to these receptors,
the neurons in the VTA fire action potentials. These action potentials cause the VTA to release dopamine
onto the nucleus accumbens, thus increasing dopamine levels in the synaptic cleft.
Scientists have also learned that nicotine can increase the actual amount of dopamine that the VTA releases, although they do not understand how. They do know that when nicotine binds to its receptors, the
VTA releases more dopamine than normal. Thus nicotine binding to its receptor not only causes dopamine
to be released in response to an action potential, but also the amount of dopamine released is greater.
Wo r k b o o k
Lesson 5.2
Through binding to nicotinic receptors, nicotine stimulates the central nervous system, causing increased
alertness, and decreased appetite. Like other drugs nicotine also has unpleasant effects such as nausea,
vomiting, diarrhea, and confusion.
When people stop smoking, they often start overeating and gain weight. One lab discovered why: As you
will see in the Metabolic Diseases module, eating and changes in metabolism are regulated by the activity
of two different types of neurons whose cell bodies are located in the hypothalamus. One of these sets of
neurons secretes the peptide called melanocyte-stimulating hormone (MSH). MSH affects neurons that
normally increase appetite. When nicotine is present, it inhibits these neurons, suppressing appetite. However when nicotine is removed, such as when people try to stop smoking, this inhibition is removed and the
MSH neurons can stimulate eating again — so people overeat and gain weight.
You can watch a video about nicotine’s effect on the brain online — see the student website or click below:
■■ Video: Visualization award winner in Science - Nicotine addiction and molecule diffusion
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What is the effect of nicotine on dopamine
levels in the nucleus accumbens?
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145
LESSON READING
Alcohol
DEFINITIONS OF TERMS
Apoptosis – type of cell death in
which the cell uses specialized
cellular machinery to kill itself.
Depressant – class of drugs that
decrease the activity of the central
nervous system.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 5.2
What are the psychological and behavioral
effects of taking alcohol?
Alcohol (Figure 11) also has enormous
costs to society. A large percentage of
deaths and injuries caused by car accidents are related to alcohol use. Additionally, alcohol contributes to violence and
aggression. Chronic alcoholics often lose
their jobs, homes, and families; and many
Figure 11: Alcohol is the most commonly used drug in
die of cirrhosis of the liver, exposure, or
the United States.
diseases caused by poor living conditions
and abuse of their bodies. Alcohol consumption by pregnant women leads to fetal alcohol syndrome, one
of the leading causes of mental retardation in the Western world today. Therefore, understanding the physiological and behavioral effects of alcohol is an imporant issue.
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Alcohol acts as a depressant in the central nervous system. Alcohol consumption produces a decrease in
anxiety, disinhibition, intoxication, memory impairment and sleep. At high doses, alcohol can cause vomiting, unconsciousness and even death due to the inhibition of the brain’s breathing center.
Alcohol is considered a sedative because it reduces the excitability of neurons. Alcohol has this effect by
increasing the activity of the brain’s main inhibitory neurotransmitter, GABA. Alcohol can bind to the GABA
receptor and increasing its activity. When alcohol is present, GABA signaling is increased, thus increasing
inhibition.
How does alcohol alter synaptic signaling of
the reward pathway? What is the drug target?
Where does alcohol act within the reward
pathway?
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Alcohol’s serious effects on fetal development occur during the brain growth spurt period, which occurs
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during the last trimester of pregnancy and for several years after birth. One study found that exposure of an
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immature rat brain to alcohol triggered widespread death of neurons called apoptosis. This resulted in the
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death of various areas of the immature brain, and abnormal brain development.
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Alcohol can also affects the brain’s reward system. It does this by inhibiting the same inhibitory neurons that ___________________________________
project to the VTA that opiates work on. Recall that when they are active these inhibitory neurons decrease ___________________________________
the activity of the VTA, which decreases the levels of dopamine the VTA releases onto the nucleus accumbens. However, when alcohol is present, the activity of these inhibitory neurons is blocked which removes What is the effect of alcohol on dopamine
their inhibition of the VTA. This removal of inhibition increases the activity of the VTA. The VTA is then able levels in the nucleus accumbens?
to increase dopamine signaling to the nucleus accumbens. Thus when alcohol is present, more dopamine ___________________________________
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is released by the VTA onto the nucleus accumbens because inhibition is removed.
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146
LESSON READING
What are the psychological and behavioral
effects of taking marijuana?
Marijuana
Another drug that people regularly self-administer is THC, the active ingredient in marijuana (Figure 12).
THC comes from the flowering hemp plant, Cannabis sativa, and is a class of chemical called cannabinoids. THC is found in several different forms such as marijuana and hashish, both of which may be
smoked or eaten. The consumption of cannabis for its intoxicating effects is thought to date back thousands
of years to Eastern cultures. The practice of marijuana smoking was introduced in the United States in the
early 1900s by Mexican and West Indian immigrants.
Marijuana is the most heavily used illicit drug in the United
States. Marijuana use causes euphoria, disinhibition,
relaxation, altered sensations and increased appetite.
Long-term use of marijuana has been associated with
deficits in cognitive function, respiratory problems and
impaired immune function.
Studies with laboratory animals show that in rodents THC
produces changes in motor activity, catalepsy (inability to
move), hypothermia, and analgesia. Cannabinoids disrupt
memory in several kinds of learning tasks, an effect that
is thought to be related to activation of the hippocampus.
Where does marijuana act within the reward
pathway?
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Figure 12: Marijuana. The active
When marijuana is smoked, THC rapidly passes from
ingredient in marijuana, THC is regularly
self-administered, resulting in euphoria,
the lungs into the bloodstream which carries THC into the
disinhibition, relaxation, altered sensabrain. Once in the brain, THC binds to receptors, called
tions and increased appetite.
cannabinoid receptors. These receptors are particularly
concentrated on the VTA. The binding of THC to cannabinoid receptors on the VTA stimulates them to fire an action potential. These action potentials cause the
VTA to release dopamine, thus increasing dopamine signaling at the nucleus accumbens.
There are many concerns about the adverse effects of chronic cannabis use. In young people the amount
of cannabis use directly correlates with poor educational performance, although whether this is a causal
effect is not clear. Long-term use has been associated with at least temporary decrements in cognitive
function, although whether these effects persist has been disputed. Likewise, it has been suggested that
heavy cannabis use produces persistent cognitive deficits and/or apathy, loss of achievement motivation
and decreased productivity, but the evidence supporting these suggestions is not strong. Because of this,
researchers currently favor the hypothesis that early cannabis use is linked to lifestyles that devalue educational achievement.
Wo r k b o o k
Lesson 5.2
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On the other hand, there are real health risks associated with marijuana smoking that involve respiratory
problems.
How does marijuana alter synaptic signaling
of the reward pathway? What is the drug target?
___________________________________
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___________________________________
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What is the effect of marijuana on dopamine
levels in the nucleus accumbens?
___________________________________
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147
LESSON READING
Drugs of abuse have similar effects
All drugs of abuse increase dopamine activity at the synapse between the VTA and the NAc, but they do
it in slightly different ways:
•
Cocaine and amphetamine both inhibit dopamine reuptake transporters, thus increasing the
amount of dopamine remaining in the synaptic cleft.
•
Heroin and other synthetic opiates, like morphine, effect dopamine signaling in two ways. First,
they inhibit inhibitory neurons projecting to the VTA. By removing this inhibition, the drugs increase
VTA activity and the release of dopamine. Second, the drugs can also directly affect the nucleus
accumbens by binding to opiate receptors.
•
Alcohol, like the opiates, inhibits inhibitory projections to the VTA, thereby increasing VTA activity
and its release of dopamine.
•
Nicotine stimulates the VTA, where the dopamine neurons originate, directly, increasing dopamine release.
•
THC the active ingredient in marijuana binds to cannabinoid receptors on the VTA which stimulates it to release dopamine.
Drugs of abuse can increase the amount of dopamine in the synaptic cleft between 2 - 10 fold more than
normal. In some cases, this occurs almost immediately (as when drugs are smoked or injected), and the
effects can last much longer than those produced by natural rewards.
Wo r k b o o k
Lesson 5.2
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148
STUDENT RESPONSES
On the diagram of the reward circuit below, draw in where each drug of abuse affects the pathway. Make sure to include: cocaine,
amphetamine, heroin & morphine, nicotine, alcohol, and marijuana.
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Inhibitory _____________________________________________________________________________________________________
Neuron _____________________________________________________________________________________________________
_____________________________________________________________________________________________________
_____________________________________________________________________________________________________
Prefrontal _____________________________________________________________________________________________________
Cortex VTA _____________________________________________________________________________________________________
_____________________________________________________________________________________________________
_____________________________________________________________________________________________________
_____________________________________________________________________________________________________
NAc _____________________________________________________________________________________________________
_____________________________________________________________________________________________________
_____________________________________________________________________________________________________
What do all drugs of abuse have in common? In terms of their activity on the reward pathway? In terms of their abuse potential?
_____________________________________________________________________________________________________
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Wo r k b o o k
Lesson 5.2
149
LESSON 5.3 WORKBOOK
Should animals be used in scientific research?
In the last couple of lessons we have referred to experiments in which laboratory animals have been used to test
the adverse effects of drugs. The question of whether or not
animals should be used in scientific research is one that triggers quite a debate. In this lesson, you will explore the issue
as a class, reading various perspectives on the issue and
debating the merits of each.
Various perspectives
The relationship of animals and humans has been the subject of differing philosophical views for thousands of years. The controversy continues today in many aspects of contemporary life. Some people
believe that a vegan lifestyle is the only moral choice. Others believe that humans should treat animals
“humanely”, but that we should be able to use animals and animal products at will, including for biomedical or other scientific research. Others believe that humans have no moral responsibilities to animals and
we are free to treat animals however we want.
Advocates of animal rights believe that animals have legal rights and are members of the moral community. Therefore, they believe that animals should not be used by humans for any purpose. Advocates
of animal welfare believe that non-human animals should be treated humanely and without unnecessary
suffering, but otherwise are available for humans to use for food, clothing, research and entertainment.
To determine where you stand on the issue, you need to learn about the historical views on the relationship between humans and animals, current views, and in particular the role of animals in biomedical
research. In groups, you will learn about these concerns from multiple perspectives, including:
Wo r k b o o k
Lesson 5.3
•
•
•
•
•
National Institutes of Health (NIH)
People for the Ethical Treatment of Animals (PETA)
Americans for Medical Progress (AMP)
Understanding Animal Research
Humane Society of the United States
A brief summary of each perspective is included here, but you are encouraged to do your own research
to learn more about each perspective’s stance on the use of animals in biomedical research.
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150
LESSON READING
From the NIH’s perspective, what historical
precedents justify contemporary use or nonuse of animals in scientific research?
National Institutes of Health (NIH)
NIH is the steward of medical and behavioral research for the
nation. Its mission is to support science in the pursuit of fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to extend healthy
life and reduce the burdens of illness and disability.
NIH-supported scientists study diseases that cause pain and
suffering and threaten the quality and length of life. NIH-supported scientists also study basic biological processes, expanding our knowledge of the origins and causes of disease.
Through such research, involving both humans and animals,
scientists identify new ways to treat illnesses, extend life, and
improve health and well-being.
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Figure 13: National Institute of
Health (NIH).
From the NIH’s perspective, what benefits
and problems have developed because of
the use or non-use of animals in scientific
Both people and animals have unique and important roles as research subjects. Many medical advances research?
that enhance the lives of both humans and animals originate from animal studies. The types of animals
used in research are chosen for their similarity to humans in anatomy, physiology, and/or genetics. Not only
can we learn how to prevent, treat, and cure human diseases by studying animals, but often the treatments
developed can also be used to improve the health of animals.
When new thinking about diseases and treatments are developed from this research, they must be evaluated very carefully so that benefits and risks from the proposed approach are clear. When necessary, new
hypotheses are tested in animals first in order to gather sufficient evidence of these benefits and risks
before considering possible use in humans.
We can study animals in ways that we cannot study people for many reasons. Animal studies conducted in
the laboratory allow scientists to control factors that might affect the outcome of the experiments—factors
like temperature, humidity, light, diet, or medications. Even the genetic composition of many animal models
can be known and understood completely. These rigorous controls allow for more precise understanding
of biological factors at hand and provide greater certainty about experimental outcomes when developing
treatments.
All animals used in federally-funded research are protected by laws, regulations, and policies to ensure
the smallest possible number of subjects and the greatest commitment to their welfare. Fulfilling these
protections is a collaborative effort between NIH, federally-supported scientific investigators, and research
institutions.
Wo r k b o o k
Lesson 5.3
You can learn more about the NIH’s perspective on animal use in research at their website — see this unit
on the student website or click below:
■■ NIH Website: OER Animals in Research
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From the NIH’s perspective, should animals
be used in scientific research? If so, what
considerations should be given to their care
and well-being? If not, why not?
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151
LESSON READING
People for the Ethical Treatment of Animals (PETA)
Each year, more than 100 million animals—including mice, rats, frogs, dogs, cats, rabbits, hamsters, guinea pigs, monkeys, fish, and birds—are killed in U.S. laboratories for chemical, drug, food, and cosmetics
testing; biology lessons; medical training; and curiosity-driven experimentation. Before their deaths, some
are forced to inhale toxic fumes, others are immobilized in
restraint devices for hours, some have holes drilled into
their skulls, and others have their skin burned off or their
spinal cords crushed. In addition to the torment of the actual
experiments, animals in laboratories are deprived of everything that is natural and important to them—they are confined to barren cages, socially isolated, and psychologically
traumatized. The thinking, feeling animals who are used in
Figure 14: People for the Ethical Treatment of Animals (PETA).
experiments are treated like nothing more than disposable
laboratory equipment.
Human clinical, population, and in vitro studies are critical to the advancement of medicine; even animal
experimenters need them—if only to confirm or reject the validity of their experiments. However, research
with human participants and other non-animal methods does require a different outlook, one that is creative and compassionate and embraces the underlying philosophy of ethical science. Animal experimenters artificially induce diseases; clinical investigators study people who are already ill or who have died.
Animal experimenters want a disposable “research subject” who can be manipulated as desired and killed
when convenient; clinicians must do no harm to their patients or study participants. Animal experimenters
face the ultimate dilemma—knowing that their artificially created “animal model” can never fully reflect
the human condition, while clinical investigators know that the results of their work are directly relevant to
people.
Human health and well-being can also be promoted by adopting nonviolent methods of scientific investigation and concentrating on the prevention of disease before it occurs, through lifestyle modification and the
prevention of further environmental pollution and degradation. The public needs to become more aware
and more vocal about the cruelty and inadequacy of the current research system and must demand that
its tax dollars and charitable donations not be used to fund experiments on animals.
You can learn more about the PETA’s perspective on animal use in research on their website — see this
unit on the student website or click below:
■■ PETA Website: Animals Used for Experimentation
Wo r k b o o k
Lesson 5.3
From PETA’s perspective, what historical
precedents justify contemporary use or nonuse of animals in scientific research?
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From PETA’s perspective, what benefits and
problems have developed because of the use
or non-use of animals in scientific research?
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From PETA’s perspective, should animals be
used in scientific research? If so, what considerations should be given to their care and
well-being? If not, why not?
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152
LESSON READING
From the perspective of Americans for Medical Progress, what historical precedents jusAmericans for Medical Progress
tify contemporary use or non-use of animals
Animal research plays a crucial role in scientists’ understanding of diseases and in the development of in scientific research?
effective medical treatments.
Research animals provide scientists with complex living systems consisting of cells, tissues and organs.
Animal models can interact and react to stimuli, giving researchers a picture of a compound
moving through a living system and an idea of
how that stimuli might react in a human being.
Animals are biologically similar to humans in
many ways and they are vulnerable to over
200 of the same health problems. This makes
Figure 15: Americans for Medical Progress (AMP).
them an effective model for researchers to
study.
The majority of research animals are used in experiments focused on disease treatment and prevention,
and the treatment of injuries. Laboratory animals are also used in basic medical research, breeding other
research animals and diagnosis.
Rats and mice account for about 95 percent of all animals used in research. Most of the remaining research animals are rabbits, guinea pigs, hamsters, farm animals, fish and insects. Combined, less than
one percent of the remaining research animals are cats, dogs and non-human primates. The overwhelming majority of research animals are specifically bred for laboratories.
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From the perspective of Americans for Medical Progress, what benefits and problems
have developed because of the use or nonuse of animals in scientific research?
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Before conducting research on animals, most scientists make absolutely certain animals are needed for
their experiments. For more than 50 years, scientists have relied on the “3Rs”: refinement of tests so animal
distress or pain is minimal, reduction of the number of animals used in one particular study, and the replacement, whenever possible, of animal experiments with non-animal experiments.
From the perspective of Americans for Medical Progress, should animals be used in scientific research? If so, what considerations
should be given to their care and well-being?
As living beings with a conscience mind, we cannot ignore human or animal suffering. Each day scientists If not, why not?
use their knowledge to minimize suffering in both humans and animals by conducting medical research
that will benefit the greater good. They work to provide research animals with a clean environment, food,
water and minimal pain and suffering.
You can learn more about the perspective of Americans for Medical Progress on animal use in research on
their website — see this unit on the student website or click below:
■■ AMP Website: Animal Research Benefits
Wo r k b o o k
Lesson 5.3
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153
LESSON READING
From the perspective of Understanding Animal Research, what historical precedents
justify contemporary use or non-use of animals in scientific research?
Understanding Animal Research
Animals are essential in scientific research, medicine development and safety testing. They are necessary to understand the
body in health and disease, and to develop new and improved
medical treatments. But their use is not undertaken lightly. Both
the potential scientific and medical benefits of the research, and
the possible suffering of the animals used, are weighed up carefully before any animal research project can proceed.
Figure 16: Understanding
Animal Research.
No one wants to use animals in research, and no one would use them unnecessarily. Animal research
is considered a last resort, to be used only when there is no alternative method. Strict regulations and a
licensing system mean that animals must be looked after properly and may not be used if there is any other
way of doing a piece of research.
Non-animal methods are used for the majority of biomedical research. Animal studies are used alongside
these other types of research. Such ‘alternative’ methods include the study of cells and tissues grown in the
laboratory, computer-modeled systems, and human patients, volunteers or populations.
You can learn more about the perspective of Understanding Animal Research on animal use in research
on their website — see this unit on the student website or click below:
■■ Website: Understanding Animal Research
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From the perspective of Understanding Animal Research, what benefits and problems
have developed because of the use or nonuse of animals in scientific research?
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From the perspective of Understanding Animal Research, should animals be used in scientific research? if so, what considerations
should be considered for their care and wellbeing? If not, why not?
Wo r k b o o k
Lesson 5.3
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154
LESSON READING
Humane Society of the United States
Picture the dog at your feet, the guinea pigs or mice you had as pets growing up, or the birds at the feeder
in your yard. Now imagine 25 million animals just like these living in small laboratory cages and being deliberately sickened over the course of weeks, months, or even years — and then killed.
If animal experimentation was the hallmark of 20th century biomedical research, sophisticated non-animal methods are likely to
characterize 21st century research. Many humane state-of-the-art
alternatives to animal experiments have already been shown to be
effective in advancing medical progress, cutting research costs,
and eliminating animal suffering.
The Humane Society of the United States (HSUS) is at the forefront
of promoting these research methods and their continued develFigure 17: Humane Society
of the United States.
opment, as well as ending some of the most inhumane research
practices. Until the day when animals are no longer used in harmful
experiments, the HSUS, with your help, also strives to gain stronger legal protection for animals used in
research, and seeks to limit animal use and suffering. Right now, approximately 95% of the animals used
for research aren’t afforded even the minimal protections of the Animal Welfare Act.
You can learn more about the Humane Society’s perspective on animal use in research on their website
— see this unit on the student website or click below:
■■ Humane Society Website: Biomedical Research
Wo r k b o o k
Lesson 5.3
From the perspective of the Humane Society,
what historical precedents justify contemporary use or non-use of animals in scientific
research?
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From the perspective of the Humane Society,
what benefits and problems have developed
because of the use or non-use of animals in
scientific research?
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From the perspective of the Humane Society, should animals be used in scientific research? If so, what considerations should be
given to their care and well-being? If not, why
not?
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STUDENT RESPONSES
Do you think animals should be used in scientific research? If so, what considerations should be given to their care and wellbeing? If not, why not?
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Do humans have moral responsibilities for animals or are animals destined to serve humanity?
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Lesson 5.3
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156
LESSON 5.4 WORKBOOK
How is dopamine involved in addictive
behaviors?
Now that we’re familiar with the reward pathway and how different drugs of abuse increase the levels of dopamine in the
nucleus accumbens, let’s turn our attention to new research
indicating that dopamine is also involved in drug seeking
behaviors.
DEFINITIONS OF TERMS
Appetitive phase – phase of
motivated behavior where subject
seeks out a goal.
Consummatory phase – phase of
motivated behavior where subject
actually consumes the goal,
whether that goal be a drug, food,
or sex.
Intracranial self-stimulation – a
method that involves implanting
electrodes into an animal’s brain
and then allowing the animal to
electrically stimulate the electrode
to activate that brain region.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 5.4
Two phases of motivated behaviors
Motivated behaviors are any behavior directed toward receiving a reward or goal. The reward may be
natural (food, sex, etc.) or artificial (electrical stimulation, drugs, etc.). Drug addiction, like sexual behavior,
is a kind of motivated behavior.
There are two phases of motivated behavior:
•
Appetitive phase
•
Consummatory phase
During the appetitive phase, motivated behavior consists of those behaviors related to approaching the
goal. In sexual behavior, for instance, the appetitive phase consists of behaviors that establish, maintain or
promote sexual interaction. Generally speaking, appetitive behaviors allow an animal to come into contact
with its goal. The consummatory phase represents the actually attaining the goal. In the case of sexual behavior, the consummatory phase is sexual intercourse. Collectively, appetitive and consummatory aspects
characterize motivated behaviors.
Neurobiology of motivated behaviors
The neurobiology of motivation is a field that seeks to identify which neuronal circuits are responsible for
motivated behavior. In the first section of this unit, we described the classic experiment of intracranial
self-stimulation. This experiment was used to demonstrate the existence of the brain’s reward pathway.
The VTA and nucleus accumbens play central roles in this pathway. Through dopamine projections from
the VTA to nucleus accumbens, this pathway carries signals about motivational and emotional information. Thus, dopamine neurons terminating in the nucleus accumbens play an important role in motivated
behavior. Not unexpectedly, the activity of these dopamine neurons changes as rewards are sought out
and consumed.
What behaviors does the appetitive phase
include?
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What behaviors does the consummatory
phase include?
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LESSON READING
DEFINITIONS OF TERMS
Microdialysis – technique used
to measure neurotransmitter
release in the brain of an
awake, freely moving animal
by collecting samples of
extracellular fluid and then
analyzing the samples
biochemically.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 5.4
Intracranial self-stimulation leads to dopamine increases in the nucleus accumbens
Let’s go back and take a second look at the classic experiment of intracranial self-stimulation. As we previously mentioned, intracranial self-stimulation helped researchers to identify and map the reward pathway.
During the experiment, a stimulating electrode was implanted in the VTA to activate dopamine neurons
using electrical pulses. The stimulating electrode and the instrument generating the electrical pulses were
connected to a lever that the animal could press. When the animal pressed the lever, electrical pulses were
delivered to the stimulating electrode. Thus, the animal controlled the stimulation of its dopamine neurons.
To obtain the rewarding electrical stimulation, rats pressed the lever at astonishing rates, sometimes pressing continuously for hours.
These early studies with intracranial self-stimulation were very informative. Indeed, the highest rates of
lever pressing during intracranial self-stimulation occurred when the stimulating electrode activated dopamine neurons directly in the VTA. Collectively, these experiments led neuroscientists to conclude that
dopamine was the transmitter responsible for reward.
New experiments examine the appetitive and consummatory phase
Recent studies challenge that traditional view. One of the key considerations is this – to fully understand
dopamine’s role in each phase of motivated behavior (appetitive and consummatory), we must be able to
monitor dopamine levels very quickly. The experiment we use to monitor dopamine levels must be able to
distinguish between the appetitive and consummatory phases, which are separated by less than a second.
The original studies used a technique called microdialysis (Figure 18). In this technique, samples of extracellular fluid are removed from the brain and analyzed biochemically to determine what neurotransmitters
are present. These experiments showed that dopamine levels increased when animals pressed a lever
and received a rewarding electrical stimulation.
The problem is that animals will press
the lever at rates of upwards of 5 times
per second, and microdialysis is not
able to sample at rates fast enough to
detect what dopamine levels are doing
with each press of the lever. Nor can
it detect what happens to dopamine
levels just before the animal presses
the lever. Therefore, microdialysis is
not an appropriate technique to distinguish between dopamine’s role in the
appetitive and consummatory phases
of motivated behavior.
A. B. Figure 18: Method of microdialysis. (A) Microdialysis allows
the collection of samples from deep within the brain. The
collected samples are identified and measured by one of
several techniques, such as HPLC. (B) Typical microdialysis
probe which uses flexible tubing that is sealed except at its
tip, where it is semipermeable and is able to collect samples.
It is held in place by dental plastic on the animal’s skull.
What did the initial experiments using intracranial self-stimulation teach us about the
involvement of the reward pathway and dopamine in addictive behaviors?
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Why is microdialysis an inappropriate tool
to examine dopamine involvement in the appetitive and consummatory phases of motivated behavior?
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158
LESSON READING
A. DEFINITIONS OF TERMS
Fast-scan cyclic voltammetry
– technique used to measure
neurotransmitter release in
the brain of an awake, freely
moving animal by inserting
a microsensor that detects
the presence of specific
neurotransmitters at very fast
rates.
For a complete list of defined
terms, see the Glossary.
B. Figure 19: Method of in vivo voltammetry. (A) In vivo
voltammetry uses implanted electrodes to measure chemicals in extracellular fluid. (B) In voltammetry, a very fine
electrode is implanted and a small electrical potential is applied. Changes in the current flow at the electrode tip reflect
changes in the concentration of electroactive substances
such as neurotransmitters and their metabolites. A major
advantage is that because the measurements are made
continuously, researchers can evaluate neurotransmitter
release as it’s occurring in real time.
Luckily, scientists developed a new technique that allowed more rapid sampling of
dopamine levels in the brain. This chemical microsensor technique, called fastscan cyclic voltammetry uses carbonfiber electrodes and is able to measure
dopamine levels 10 times per second
(Figure 19). Finally, we have a suitable
technique for monitoring dopamine levels
during the appetitive and consummatory
phases of motivated behavior.
When researchers used voltammetry to
monitor dopamine release during motivated behavior, some very interesting
findings were obtained. The researchers
found that dopamine levels increase at two different times – first, at 5 seconds before the animal pressed
the lever, and then again 36 seconds after the animal pressed the letter (Figure 20).
The increase in dopamine 36 seconds after the animal pressed the lever was rapid and substantial. This
time point coincides with the delivery of cocaine to the animals’ brains. So, it is consistent with previous
studies showing that dopamine levels increase rapidly when cocaine is consumed (consummatory phase).
The new and very interesting finding was that dopamine increased before the animal even pressed the
lever. Approximately 5 seconds before the animal pressed the lever, researchers saw a small increase in
dopamine levels. The dopamine levels then increased gradually until 2 seconds before the animal pressed
the lever, and then there was a rapid and sizable increase. Approximately 10 seconds after a lever press,
dopamine levels returned to normal, which was still 26 seconds before the researchers observed the very
rapid and substantial increase due to cocaine consumption. Because dopamine levels rise while the rat
was engaged in cocaine seeking behavior, but before it receives its cocaine reward, the researchers concluded that dopamine also plays a role in cocaine seeking (appetitive phase).
A. B. Wo r k b o o k
Lesson 5.4
Figure 20: Dopamine increases as measured by in vivo voltammetry during
self-administration. (A) The solid blue trace represents dopamine concentrations during the experiment. Notice how dopamine levels increase as the
animal approaches the bar (inverted red triangle). These levels drop as the
animal presses the lever (inverted black triangle), and then sore after infusion
of cocaine (light-blue bar). (B) The solid blue line is the mean dopamine
changes across all animals around the lever press, and the dashed blue line
is the mean plus standard error. Increases in dopamine before the lever press
are highlighted by the arrows. (Figure adapted from Phillips, et al. 2003.)
What new technique did scientists develop in
order to be able to detect changes in dopamine quickly enough to distinguish between
the appetitive and consummatory phases of
motivated behaviors?
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What did scientist observe about dopamine
levels during motivated behavior when using
voltammetry?
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LESSON READING
You might be asking – why would dopamine levels rise during the appetitive phase? The researchers
hypothesized that before a cocaine-addicted animal receives cocaine, it thinks about its need for cocaine.
Thinking about cocaine then activates the reward pathway, and stimulates the release of dopamine. Thus,
the brain of the cocaine-addicted animal responds not only to the physical presence of cocaine in the brain,
it also responds to any stimuli associated with seeking out cocaine.
Dopamine signaling in appetitive phase may underlie relapse
DEFINITIONS OF TERMS
Remissions – drug free periods.
Relapses – reoccurring drug
use after periods of abstinence.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 5.4
In terms of the reward pathway, a rat’s brain is very similar to a human brain. Since the brain of a drugaddicted rat responds not only to the physical presence of the drug, but also to the activity of drug seeking,
it is possible that human drug addicts react to drug seeking behavior with a spike in dopamine levels. If
so, then breaking the addiction will be more difficult for addicts who spend time in activities and locations
associated with past drug seeking behavior.
Researchers have in fact shown that exposing addicts to stimuli associated with past drug use will lead to
drug-like effects. These drug-like effects (that is, responses similar to those produced by the drug itself)
may serve as primers, promoting subsequent drug seeking and drug consumption by reminding the individual of how the drug feels. This phenomenon may be what underlies the strong cravings addicts feel
when presented with stimuli that remind them of the previous drug use. This also means that individuals
stay addicted for long periods of time, and that drug-free periods (remissions) are often followed by relapses in which drug use recurs.
Why would dopamine levels increase before
receiving a reward (appetitive phase)?
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160
STUDENT RESPONSES
What do these findings about dopamine levels in the appetitive phase mean for addicts trying to break their addiction?
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How could we use these findings to help people overcome their addictions?
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Wo r k b o o k
Lesson 5.4
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161
LESSON 5.5 WORKBOOK
When does abuse become addiction?
So far in this unit, we’ve talked about how drugs affect our
brains, including their effects on neural circuitry, synaptic
signaling and neurons. In this lesson, we’ll start getting to
the bigger picture of drug abuse and addiction by talking
about the different risk and protective factors that underlie
addiction.
S
Why do people start using drugs?
People being taking drugs for a variety of reasons:
•
To feel good – As we’ve already seen, drugs of abuse produce intense feelings of pleasure by
activating the reward pathway.
•
To feel better – Some people who suffer from social anxiety, stress-related disorders, and depression begin abusing drugs in an attempt to lesson feelings of distress. Stress can play a major role in
beginning drug use, continuing drug abuse, or relapse in patients recovering from addiction.
•
To do better – The increasing pressure that some individuals feel to chemically enhance or improve
their athletic or cognitive performance can similarly play a role in initial experimentation and continued drug abuse.
•
Curiosity and peer pressure – In this respect, adolescents are particularly vulnerable because
of the strong influence of peer pressure, they are more likely, for example to engage in thrilling and
daring behaviors.
If taking drugs makes people feel better, what’s the problem?
At first, people may perceive what seem to be positive effects with drug use. They also may believe that
they can control their use. However, drugs can quickly take over their lives. Consider how a social drinker
can become intoxicated, put himself behind a wheel and quickly turn a pleasurable activity into a tragedy
for him and others. Over time, if drug use continues, pleasurable activities become less pleasurable, and
drug use becomes necessary for abusers to simply feel “normal”. Drug abusers reach a point where they
seek and take drugs, despite the tremendous problems they cause for themselves and their loved ones.
Wo r k b o o k
Lesson 5.5
What reason do you think is the most common for people to start using drugs?
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You can watch two stories of young people who became addicted to cocaine online — see this unit on the
student website or click on the link below:
■■ Video: Council on Drug Abuse: Crossroads (Parts 1 - 2)
162
LESSON READING
Is continued drug abuse a voluntary behavior?
DEFINITIONS OF TERMS
The initial decision to take drugs is mostly voluntary. However, when drug abuse – the overuse of a drug
by an individual – takes over, a person’s ability to exert self-control can become seriously impaired. Brain
imaging studies from drug-addicted individuals show physical changes in areas of the brain that are critical
to judgment, decision-making, learning and memory, and behavior control. Scientists believe that these
changes alter the way the brain works, and may help explain the compulsive and destructive behaviors
of addiction. Remember that addiction is defined as the continued compulsive use of drugs in spite of
adverse health or social consequences.
Why do some people become addicted to drugs, while others do not?
Addiction – the continued
compulsive use of drugs
despite adverse health or social
consequences.
Drug abuse – overuse of a drug
by an individual.
Risk factors – factors in a
person’s life that increase the
risk of developing addiction .
Protective factors – factors in a
person’s life that reduce the risk
of developing addiction.
For a complete list of defined
terms, see the Glossary.
As with any other disease, vulnerability to addiction differs from person to person. There are many factors
that can influence either the likelihood of someone becoming a drug addict, or the probability that they will
be able to achieve stable abstinence once addicted. In general, the more risk factors an individual has, the
greater the greater the chance that taking drugs will lead to abuse and addiction. Conversely, “protective”
factors reduce a person’s risk of developing addiction.
No single factor determines whether a person will become addicted to drugs. The overall risk for addiction
is impacted by the biological makeup of the individual, and it can be influenced by gender or ethnicity, his
or her developmental stage, and the surrounding social environment (for example conditions at home, at
school, and in the neighborhood). Risk factors can therefore be environmental, social, psychological or
biological.
Environmental, social, and psychological risk factors
One important environmental risk factor is the occurrence of stress and the ability of the person to cope
with such stress. The life histories of drug addicts often show instances in which stressful events either
promoted increased drug use or triggered relapse from a previous period of abstinence. Numerous animal
studies confirm that stress can increase self-stimulation of abused drugs, as well as trigger renewed drugtaking after periods of relapse. For this reason, many treatment providers teach their clients new coping
skills to deal with life stresses without relapse.
Family and socio-cultural influences also influence the risk of developing a pattern of drug abuse or addiction. Family factors have been studied most in conjunction with alcoholism. For example, adult children of
alcoholics are at increased risk for having alcohol or other substance abuse problems. In the case of alcohol, this may be related in part to modeling (imitation) of the parent’s drinking behavior or to a heightened
expectancy that drinking will lead to positive mood changes.
Wo r k b o o k
Lesson 5.5
Socio-cultural studies have identified at least four different functions served by drug abuse. The first involves the ability to fit into a social situation. Alcohol and other drugs are often consumed in a group setting
where the substance may appear to enhance social bonds – like at a frat party where everyone is drinking.
Is continued drug abuse a voluntary behavior?
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The second function is to remove the user from normal social roles and responsibilities, thereby allowing
an escape from the burdens associated with responsibilities. Third, substance use may promote group
solidarity within a particular ethnic group. A good example of this phenomenon is the association of the
Irish culture with heavy alcohol use and a high rate of alcoholism. Finally, substance abuse sometimes
occurs with a “drug subculture” that embraces social rituals surrounding a particular subculture and rejects
conventional social norms and lifestyles. Sociological studies have identified distinct subcultures for many
different drugs of abuse, including heroin, cocaine, alcohol, marijuana, and methamphetamine.
Biological risk factors
While social and environmental factors contribute to the risk of addiction,
the finding that several genes are
linked to specific addictive behaviors
indicates that there is also a genetic
susceptibility (Figure 21). Scientists
estimate that genetic factors account
for between 40 and 60 percent of a
person’s vulnerability to addiction, including the effects of environment on
gene expression and function.
Wo r k b o o k
Lesson 5.5
Fortunately the reward pathway is
located in a part of the brain that is
evolutionarily very old, so all aspects
of the pathway are almost identical in
mice, rats and humans. This means
that mice, which are a valuable genetic tool, are also useful animal models to investigate genetic susceptibility. Mice have the same number of
genes as humans (20,000 – 25,000)
and each mouse gene is about 85%
identical to its human counterpart
(or homolog). Among the genes now
identified to be involved in susceptibility to addictive behaviors are dopamine receptors.
According to sociocultural studies, what are
the four different functions served by drug
abuse?
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Why are animal models useful tools in investigating the biological risk factors for addiction?
Figure 21: Addictive behaviors are associated with defects
to a number of genes, indicating genetic susceptibilities.
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Dopamine receptors
Since all drugs of abuse modulate dopamine signaling, it is necessary to consider how dopamine receptors
mediate drug effects and addiction potential. Intriguing results have come from studies involving dopamine
receptors. These studies suggest that animals with higher the levels of dopamine receptors are more prone
to addiction, presumably because they experience greater effects from dopamine binding.
Levels of dopamine released
Low baseline dopamine release High baseline dopamine release The greater the “high” experienced
by drug users, the more likely addiction will develop. In the case of
Cocaine Cocaine cocaine, one biological factor that
influences the experienced “high” is
the baseline level of dopamine activity in the reward pathway. Imagine two subjects – A and B. Due to
Figure 22: Role of baseline DA release. If baseline levels of
individual differences in dopamine
dopamine release are low (left), then partial inhibition of dopamine
signaling, subject A starts with a
transporters by cocaine or amphetamine has relatively little effect
relatively low level of baseline doon synaptic levels of dopamine. However, if baseline dopamine
pamine release, whereas subject
release is high (right), then the same inhibition results in much
B starts with a relatively high level
greater synaptic levels and receptor activation.
of release. Both subjects are now
given cocaine which inhibits dopamine transporters. Even with equivalent amounts of reuptake blocked,
the effect of this blockage on stimulating postsynaptic dopamine receptors will be greater in subject B than
in subject A because of the higher initial concentration of dopamine in the synaptic cleft (Figure 22).
Protective factors
There are two different ways that we can think about protective factors in drug addiction. First, an absence
of the various risk factors described previously would confer some protection in respect of developing a
drug addiction. Put another way, individuals who do not suffer from preexisting personality or mood disorders, who come from a stable family without any substance abuse, who do not belong to an ethnic group
that promotes substance use, and who do not become involved in social rituals surrounding drug use are
at a reduced risk for becoming addicted.
Wo r k b o o k
Lesson 5.5
The second way that protective factors can operate is to help maintain a stable abstinence in previously
drug-abusing or addicted individuals. Once the decision to abstain has been made, the risk of relapse is
reduced by such actions as avoiding drug-associated cues (for example, moving to a new area and developing new social relationships with nonusers), and engaging in substitute activities like physical exercise
or mediation.
Why would having increased levels of dopamine receptors be a risk factor for developing addiction?
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Why would having a “high” baseline level of
dopamine activity be a risk factor for developing an addiction to cocaine?
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What are protective factors and how do they
help people remain drug free?
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Do you think these risk and protective factors tell the whole story of the development of drug addiction? Why or why not?
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In addition to risk factors, one’s motivation for taking drugs is a critical factor in the development of addiction. Why would your
motivation to taking a drug play such a critical role? (Think about people who are prescribed drugs by doctors, versus people
who take drugs for recreation.)
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Wo r k b o o k
Lesson 5.5
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LESSON 5.6 WORKBOOK
What are the long-term effects of drug
abuse and addiction?
DEFINITIONS OF TERMS
Tolerance – decreased
response to a drug as a
direct result of repeated drug
exposure.
Dependence – state of drug use
in which user requires drug to
maintain normal bodily function.
Withdrawal symptoms — the
condition brought on by the
elimination from the body of a
drug on which the person has
become physically dependent.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 5.6
Now that we’re familiar with the reasons why people start
taking drugs, and the factors that can influence the likelihood of someone becoming addicted, let’s turn our attention to the long-term effects of drug abuse and addiction.
How does long-term drug abuse affect our brains?
Just as we turn down the volume on a radio that is too loud, our brains adjust to the overwhelming surges
in dopamine caused by drugs of abuse by producing less dopamine and/or reducing the numbers of dopamine receptors that receive the signals. As a result, dopamine’s impact on the reward circuit can become
abnormally low, and the ability to experience any pleasure is reduced. This is why abusers eventually
feel flat, lifeless, and depressed, and why they are unable to enjoy things that previously brought them
pleasure. Now, they need to take drugs just to try and bring their dopamine function back up to normal.
And, they must take larger amounts of the drug than they first did to create the same dopamine high – an
effect known as tolerance.
We know that the same sort of mechanisms involved in the development of tolerance can eventually lead
to profound changes in neurons and brain circuits that can severely affect the brain’s long-term health. The
early stages of addiction are characterized by tolerance and dependence. After a drug binge, an addict
needs more of a substance to get the same effect on mood. This increase in tolerance then provokes an
escalation of drug use that develops into dependence – needing a drug to function normally. Once dependent, if an addict abstains they face withdrawal symptoms – painful emotional, and at times, physical
reactions that result from stopping drug use (Figure 23). Both tolerance and dependence occur because
frequent drug use can, ironically, suppress parts of the brain’s reward circuit.
How do our brains adjust to the overwhelming surges of dopamine in the case of drug
addiction?
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What causes tolerance?
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What is dependence?
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LESSON READING
A. B. DEFINITIONS OF TERMS
Transcription factors —
proteins that bind to DNA and
influence the expression of
particular genes.
For a complete list of defined
terms, see the Glossary.
Figure 23: Model of tolerance and withdrawal. (A) Theoretical
model suggesting that the nervous system adapts to the disturbing presence of a drug, so tolerance develops, but if the
drug is suddenly stopped, the adaptive mechanisms continue
to function, causing disturbed homeostasis characterized by
withdrawal symptoms. (B) Application of model to morphine
addiction. Morphine acutely inhibits cAMP, but the effect
becomes less as tolerance develops and neural adaptation
occurs. If morphine is suddenly withdrawn, a larger than
normal amount of cAMP is produced, resulting in withdrawal
effects and suggesting that the adaptive mechanism is still
operating. With time, cells once again adapt, this time to the
absence of the drug.
At the heart of this cruel suppression lie molecules known as transcription factors, proteins that regulate
the expression, or activity of genes and thus the overall behavior of neurons. When drugs of abuse are
consumed, specific transcription factors are switched on. After these transcription factors are switched on,
they bind to a specific set of genes, triggering the production of the proteins those genes encode.
What causes relapse?
Chronic exposure to cocaine and other
drugs of abuse is known to induce the dendrites of nucleus accumbens neurons to
sprout more dendritic spines (Figure 24).
Increasing the number of dendritic spines,
bolsters the cell’s connections to other neurons. In rodents, this sprouting can conFigure 24: Chronic exposure to drugs of abuse
tinue for months after drug use stops. It’s
results in neurons changinf their structures, including
suggested that specific transcription facincreased dendritic spines, which increases the contors may be responsible for these added
nections between neurons
spines. It is speculated that the extra connections can amplify the signal in the nucleus accumbens for years and that the heightened signaling might
cause the brain to overact to drug-related cues. These dendritic changes may, in the end, be the key to
adaptation that accounts for how hard addiction is to break. These changes in dendritic spines and thus
connections between neurons may also underlie relapse.
Wo r k b o o k
Lesson 5.6
What are withdrawal symptoms?
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What are transcription factors?
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How do neurons in the nucleus accumbens
change in response to chronic exposure to
drugs?
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LESSON READING
Additionally, learning may also be involved in relapse. Conditioning is one example of this type of learning
and memory, in which environmental cues become associated with the drug experience and can trigger uncontrollable cravings if the individual is later exposed to these cues, even without the drug being
available. This learned “reflex” is extremely robust and can emerge even after many years of abstinence,
leading to relapse.
Drugs of abuse change our brains
In summary, researchers have discovered that long term drug abuse changes our brains. Drug abuse
activates transcription factors, which in turn stimulate the production of different proteins that ultimately
increase the number of dendritic spines, thus increasing the number of synapses and altering our synaptic
connections. This response lasts long after drug use stops. The synaptic connections created are stable
additions to our neural circuits, and may underlie relapse.
How might these changes in NAc neurons
explain relapse?
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Put the following in order: Protein, DNA,
RNA.
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Wo r k b o o k
Lesson 5.6
169
STUDENT RESPONSES
How does drug abuse and addiction change our neurons and thus our brains?
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Lesson 5.6
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LESSON 5.7 WORKBOOK
Is addiction a chronic disease?
DEFINITIONS OF TERMS
Addiction is a disease – idea
that states drug addiction is
no different from other chronic
diseases, like diabetes and heart
disease, and thus needs to be
treated as a distinct medical
disorder.
For a complete list of defined
terms, see the Glossary.
In this last lesson, we will explore the idea of addiction as a
chronic disease.
Drug Addiction as a disease
Throughout much of the last century, scientists studying drug abuse labored in the shadows of powerful
myths and misconceptions about the nature of addiction. When scientists began studying addiction in the
1930s, people addicted to drugs were thought to be morally flawed and lacking in willpower. Those views
shaped society’s responses to drug abuse, treating it as a moral failing rather than a health problem, which
led to an emphasis of punitive rather than preventative and therapeutic actions. Today, thanks to science,
our views and responses to drug abuse have changed dramatically. Groundbreaking discoveries about
the brain have revolutionized our understanding of drug addiction, enabling use to develop more effective
responses to the problem.
As a result of scientific research, we know that addiction is a disease that affects both the brain
and behavior (Figure 25). We have identified
many of the biological and environmental factors, and are beginning to search for the genetic
variations that contribute to the development and
progression of the disease. Using this knowledge,
scientists are developing more effective prevention and treatment options that reduce the toll drug
addiction takes on individuals, families and communities.
Wo r k b o o k
Lesson 5.7
Figure 25: Addiction is a disease. PET scans
comparing decreased metabolism in diseased
brain and diseased heart. Just as a heart attack
causes decreased metabolism in the heart,
addiction causes decreased metabolism in the
brain.
Why would the myths and misconceptions
about drug addiction in the 1930s hinder research on and treatment of drug addiction?
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Why is drug addiction considered a disease?
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LESSON READING
Can addiction be treated?
Yes. Addiction is a treatable disease. Discoveries in the science of addiction have led to advances in drug
abuse treatment that help people stop abusing drugs and resume their productive lives. Like other chronic
diseases, addiction can be managed successfully. Treatment enables people to counteract addiction’s
powerful disruptive effects on the brain and behavior and regain control of their lives.
Figure 26: Comparison of relapse rates.
Relapse rates for drug-addicted patients
compared with those suffering from diabetes,
hypertension and asthma. Relapse is a common and similar across these illness (as is
adherence to medication). Thus, drug addiction should be treated like any other chronic
illness, with relapse serving as a trigger for
reinstated or adjusted treatment.
Relapse does not mean treatment has failed. The
chronic nature of addiction means that relapsing back
to drug abuse is not only possible, but likely. Relapse
rates for drug addiction are similar to those for other
well-characterized chronic medical illnesses, such as
diabetes, hypertension, and asthma, which also have
physiological and behavioral components (Figure
26). Treatment of chronic diseases involves changing
deeply embedded behaviors, and relapse does not
mean treatment failed. For the addicted patient, lapses
back to drug abuse indicate that treatment needs to
be reinstated or adjusted, or that alternative treatment
is needed – and again, not that treatment has failed.
Research shows that combining treatment medication, where available, with behavioral therapy is the
best way to ensure success for most patients. Treatment approaches must be tailored to address each
patient’s drug abuse patterns and drug-related medical, psychiatric and social problems.
How can medications help treat drug addiction?
Different types of medications may be useful at different stages of treatment to help a patient stop abusing
drugs, stay in treatment, and avoid relapse (Figure
27).
Wo r k b o o k
Lesson 5.7
Figure 27: Medications used to treat drug addiction. With scientific research, we’ve been
able to develop a variety of medications to
aid in the treatment of addiction.
When patients first stop abusing drugs, they can experience a variety of physical and emotional symptoms, including depression, anxiety, and other mood
disorders, restlessness, and sleeplessness. Certain
treatment medications are designed to reduce these
symptoms, which makes it easier to stop abuse.
How can drug addiction be treated?
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How can medications be used to help treat
drug addiction?
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LESSON READING
Some treatment medications are used to help the brain gradually adapt to the absence
of the abused
drug – for example nicotine patches or gum in the case of cigarette smokers, or methado
ne in the case
of heroin addicts. These medications act slowly to stave off drug cravings, and have
a calming effect on
body systems. They can help patients focus on counseling and other psychotherapies
related to their drug
treatment.
Science has taught us that stress, cues linked to drug experience (for example – people,
places, things,
moods), and exposure to drugs are the most common triggers for relapse. Medications
are being developed to interfere with these triggers to help patients sustain recovery.
How do behavioral treatments help drug addiction?
Behavioral treatments help engage people in drug abuse treatment (Figure 28). Behavio
ral treatments
aim to modify attitudes and behaviors related to drug abuse. They also focus on increasi
ng life skills to
handle stressful circumstances and combat environmental cues that may trigger intense
drug cravings
and prompt another cycle of compulsive abuse. Moreover, behavioral therapies can
enhance the effectiveness of medications and help people remain in treatment longer.
How do the best treatment programs help patients recover?
Wo r k b o o k
Lesson 5.7
Getting an addicted person to stop abusing drugs is just one part of a long and complex
recovery process.
When people enter treatment, addiction has often taken over their lives. The compuls
ion to get drugs,
take drugs, and experience the effects of drugs has dominated their every waking
moment, and drug
abuse has taken the place of all the things they used to enjoy doing. It has disrupted how
they function in
their family lives, at work and in the community, and has made them more likely to suffer
from other serious illnesses. Because addiction
can affect so many aspects of
a person’s life, treatment must
address the needs of the whole
person to be successful. This is
why the best programs incorporate a variety of rehabilitation services into their comprehensive
treatment regimens. Treatment
counselors select from a “menu”
of services for meeting the individual medical, psychological, social, vocational, and legal needs
of their patients to foster their recovery from addiction.
Figure 28: Variety of behavioral therapies. A variety of behavioral therapies aim to help drug addicted patients beat their
addictions.
How do behavioral treatments help to treat
drug addiction?
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Summary
Research has shown that addiction is a disease that affects brain structure and impacts behavior. Many of
the biological and environmental factors that contribute to addiction have been identified, and the search
has begun to identify the underlying genetic variations that predispose and contribute to its development
and progression.
Addiction occurs when the activity of the reward pathway is disturbed. The reward pathway is composed
of the connections between the ventral tegmental area (VTA) and the nucleus accumbens (NAc). Drugs of
abuse act on this pathway in various ways to increase dopamine neurotransmission across this synapse.
Dopamine neurotransmission can lead to transient effects on the postsynaptic cell membrane, but also effects gene transcription. Effects on gene transcription result in longer acting effects on neuronal structure,
including building more synapses on the post-synaptic cell. Finally, addiction is considered a chronic disease because it causes long term changes in the brain, it is characterized by the compulsive, non-voluntary
use of drugs, and people are never completely cured of their addictions.
Wo r k b o o k
Lesson 5.7
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STUDENT RESPONSES
Pretend you are an advisor to a government agency that needs to decide whether or not insurance companies should be
required to cover treatment for addiction. Write an opinion piece to help the agency make the right choice.
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Wo r k b o o k
Lesson 5.7
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