Download Physiology 2 - Sheet #6 - Dr.Loai Al-Zgoul - Done by: Yara

Physiology 2 - Sheet #6 - Dr.Loai Al-Zgoul - Done by: Yara Zreiqat
*Please note that this lecture and the upcoming two lectures are not
present in the book. Hence, these notes are your primary resource.
This lecture is basically about the cerebral cortex and higher
intellectual functions, neurotransmitters and the fast
neurotransmitter glutamate.
The Cerebral Cortex and Higher Intellectual Functions:
The cerebral cortex is the outermost layer of the brain which consists of
FIVE lobes:
12345-
Frontal
Parietal
Temporal
Occipital
Insula (A hidden lobe found deep behind the parietal and frontal
lobes)
Each lobe of the cortex has a function. The frontal lobe, for instance,
has the prefrontal cortex (will be discussed further later on) which is
responsible for the personality of the individual, his thinking abilities
and behavior. The occipital lobe is divided into several functional visual
areas and is therefore responsible for the vision.
Giving each lobe a certain function is quite challenging so the cortex of
the brain was divided into three types according to their function.
These three are:
1) Primary cortex
2) Secondary cortex
3) Association cortex
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Physiology 2 - Sheet #6 - Dr.Loai Al-Zgoul - Done by: Yara Zreiqat
1) Primary cortex
- It’s the site that first receives the information as an impulse. This
impulse is in the form of an action potential. If there is an action
potential then the primary area receives information if not then there is
no information received and hence no sensation.
e.g. primary visual cortex in the occipital lobe enables you to see ,
primary somatosensory (postcentral gyrus- colored blue in the slides),
primary motor (precentral gyrus- refer to slides), primary gustatory (to
taste) and so on…
2) Secondary cortex
- It’s responsible for the processing of the information received by the
primary cortex. In other words, it helps in understanding the sensation
received.
- The primary visual area 17 enables you to see but the secondary areas
18 and 19 help you understand what you’re seeing.
- Together, the primary and secondary cortex, receive and process the
sensation. For example, you can smell food and know the source of the
smell- does it smell good or not?
3) Association cortex
- It’s a large part and forms most of the cortex and each area has a particular
function. (Almost all areas are association except 17,18,19, 1,2,3,4,… which are
primary and secondary areas)
- It’s responsible for the higher order processing.
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Physiology 2 - Sheet #6 - Dr.Loai Al-Zgoul - Done by: Yara Zreiqat
- Your primary and secondary areas help you see, smell and hear. But it’s the
association area that connects the sensations together. For example, someone
speaking to you in Arabic, you hear (auditory) that he’s speaking in Arabic and so
you respond to him (speech) in the same language. Another examples are Broca’s
area and Wernicke’s area (responsible for the language).
- Most common association areas in the brain are the prefrontal and parietal
areas that link more than one sense to produce higher complex information.
- Prefrontal cortex refers to the anterior part of the frontal lobe. It contains areas
(9,10,11). As mentioned earlier in the first page, the functions of the prefrontal
cortex are thinking, determining the personality, behavior, intentions…
Consequences of damage of any of the areas:
 Primary cortex damage: No sensation.
e.g. damage to visual primary area  blindness
damage to primary auditory area  deafness
damage to somatosensory area  no touch or pain sensation
 Secondary cortex damage: There is sensation but no
understanding of it.
e.g. One can hear a sound but doesn’t understand what it is.
One can smell something but can’t tell if it’s pleasant or
unpleasant?
*** What happens when the primary motor area is damaged? What
happens when the secondary motor area is damaged?
In the motor areas, unlike the sensory, the processing happens BEFORE
the action. The primary area is responsible for the simple movements.
The secondary is responsible for the processing and more skillful
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Physiology 2 - Sheet #6 - Dr.Loai Al-Zgoul - Done by: Yara Zreiqat
moves. So, when the primary area (Area 4) is damaged it causes
paralysis. On the other hand, when the secondary area is damaged
simple movements (voluntary- writing, pushing, pulling…) remain while
skilled and complex moves are lost since they require planning and
processing. The secondary area (Area 6) is called the premotor area
because processing happens before (pre-) the motor action. Area 6
receives the information and then 4.
Damage to the secondary sensory cortex is called Agnosia.
Damage to the secondary motor cortex is called Apraxia.
 Association Area Damage  loss of higher complex abilities
** Damage to the prefrontal cortex (Recall: the functions of the
prefrontal cortex are personality determination, behavior, higher
functions…etc)
In the 1860s, a railroad construction worker had an
accident where a large iron rod was driven into his head
destroying his prefrontal cortex. Since the respiratory
and cardiovascular centers are in the medulla and the
pain, sensory and motor areas are behind the
prefrontal cortex; he survived and didn’t lose any of his senses or
motion. However, his personality and behavior changed severely as a
result of his injury.
Note: The subcortical is responsible for one’s emotion but what
controls the emotion is mainly the prefrontal cortex. An example to get
a better understanding of this is when you feel angry-- it’s the
subcortical’s job. However, whether you respond to this feeling of
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Physiology 2 - Sheet #6 - Dr.Loai Al-Zgoul - Done by: Yara Zreiqat
anger by hitting someone or not, for example, is controlled by your
personality which is the prefrontal cortex’s role.
Therefore, damage to the prefrontal cortex causes lack of foresight (no
predicting), frequent stubbornness, inattentive and moody behavior,
lack of ambitions, sense of responsibility and sense propriety(rude) and
finally less creativity and inability to plan for the future.
Synapses and Neurotransmitters
•
We know that the brain consists of neurons in which an action
potential is transmitted. These neurons intercommunicate by
synapses. A synapse is a specialized site of contact, and
transmission of information between a neuron and an effector
cell.
• There are two types of synapses: Chemical and Electrical. The
main synapses present in the brain are chemical synapses.
Chemical Synapses:
One neuron
releases neurotransmitter molecules
into a small space (the synaptic cleft)
that is adjacent to another neuron.
Steps: The process begins with a wave
of electrochemical excitation called
an action potential travelling along the membrane of the presynaptic
cell, until it reaches the synapse. Calcium ion channels open allowing
the entry of calcium ions into the presynaptic neuron. This high
concentration of Ca-ions causes the release of neurotransmitters by
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Physiology 2 - Sheet #6 - Dr.Loai Al-Zgoul - Done by: Yara Zreiqat
exocytosis via synaptic vesicles which bind to their chemical receptors
and transmits its effect on the postsynaptic neuron. Finally, the
neurotransmitter is either reabsorbed by the presynaptic cell, and then
repackaged for future release, or else it is broken down metabolically
by enzymes.
Synapses depend greatly on the postsynaptic neuron’s receptors rather
than on the type of neurotransmitters. The type of receptors
determines the effect of the released neurotransmitter.
There are two types of receptors (both are ligand-gated, ligand
receptors and neurotransmitter binding):1- Ionotropic Receptors (Ion channel receptors)  They open ion
channels.
- Opening Na+ or Ca++ channels causes depolarization (influx of
ions) and hence EXCITATION. It approaches and overcomes the
threshold causing an action potential.
- Opening K+ or Cl- channels causes hyperpolarization (outflow of
ions) and hence INHIBITION. It becomes more negative becoming
distant from the threshold value.
2- Metatropic Receptors (Second messenger receptors)
- Can open specific ion channels (If Na+ excitation, if K+
inhibition), Activates cAMP or cGMP, Activation of one or more
intracellular enzymes, Activation of gene transcription.
- Once the neurotransmitter binds to the receptor it either
activates an excitatory G protein which increases cAMP
production or an inhibitory G protein which decrease the
production of cAMP.
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Physiology 2 - Sheet #6 - Dr.Loai Al-Zgoul - Done by: Yara Zreiqat
- Other second messenger such as PLC.
Differences Between Ionotropic and Metatropic Receptors
Ionotropic
Metatropic
Faster
Slower
Lasts longer
Signal Amplification is possible
Special to certain DNA to allow
transcription and synthesis of
the coded protein.
Drugs and the Synapse
As pharmacy students, it’s very important to learn the effects of drugs
on synaptic transmission. As said before, the post synaptic effect
depends mainly on the type of receptors present on the post synaptic
neuron. Therefore, drugs either work as AGONISTS, ANTAGONISTS or
ALLOSTERIC MODULATORS.
Agonist: a chemical that binds to a receptor and activates
the receptor to produce a biological response (activation). They mimic
(copy) the effect of the neurotransmitter. * The neurotransmitter is
the most potent (effective) agonist.
Antagonist: drugs that block the effects of neurotransmitters (no
activation). (It does not oppose the receptor’s action, it just block the
receptor)
When both are present, the activation and effect are less. E.g. we have
20 receptors, 20 agonists and antagonists with the same binding power.
10 agonists will bind to 10 receptors and the same for the other 10
antagonists. So, a lower effect is produced (in this case half the effect).
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Physiology 2 - Sheet #6 - Dr.Loai Al-Zgoul - Done by: Yara Zreiqat
Potency (efficacy): The efficacy of the drug is its tendency to activate
the receptor. E.g. antagonists display no efficacy (potency) to activate
the receptors they bind. Neurotransmitters have a high potency
(efficacy) that’s why they are most potent agonists.
Affinity: A drug has an affinity for a particular type of receptor if it binds
to that receptor. This affinity varies from strong to weak.
Allosteric Modulation:
a substance which indirectly influences
(modulates) the effects of a chemical
(neurotransmitter, drug, agonist…) on a
specific receptor. As you can see in the
picture the presence of alcohol
(ethanol) increased the effect of the
neurotransmitter GABA by increasing
the size of the passage way (allowing
the entrance of more Cl- ions) and makes it last for a longer period of
time. The allosteric modulator binds to a site different than that of the
neurotransmitter increasing the effect (whether it’s excitatory or
inhibitory).
When making the drug it’s important to know the following about the
neurotransmitter:
-
Rate limiting step
Clearance and inactivation
Location and pathway (which part of the brain it will affect?)
Dysfunction and CNS pathology
The synthesized drug will work by doing one or more of the following to
the neurotransmitter:
- Increasing the synthesis
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Physiology 2 - Sheet #6 - Dr.Loai Al-Zgoul - Done by: Yara Zreiqat
-
Causing vesicles to leak
Increasing release
Decreasing uptake
Blocking the breakdown into inactive chemical
Directly stimulating or blocking postsynaptic receptors
Neurotransmitters:
- Are chemicals found in the human’s cells that transmit signals
across a synapse from a presynaptic neuron to a postsynaptic
neuron.
- There are many ways to classify neurotransmitters.
- We will classify them as fast and slow neurotransmitters. Fast are
those that have ion channels mainly as their receptors and slow
are the ones that have mainly metatropic receptors. Metatropic
receptors involve second messengers which are called
‘modulators’ since they alter protein synthesis.
- Glutamate (L-glutamic acid) is an example of a fast
neurotransmitter that we shall discuss shortly.
Glutamate:
-
Fast neurotransmitter
Main excitatory neurotransmitter in the mammalian CNS.
95% of excitatory synapses in the brain are glutamatergic
Precursor for the neurotransmitter GABA which is the major
inhibitory neurotransmitter
- Its enzymatic pathway (refer to slides) shows that glutamate is
made from the amino acid glutamine and that glutamate is the
precursor for the production of GABA.
- Glutamate receptors may be ionotropic (majority) or metatropic
(minority)
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Physiology 2 - Sheet #6 - Dr.Loai Al-Zgoul - Done by: Yara Zreiqat
Ionotropic Receptors of Glutamate:
There are three types:
1- NMDA receptor
2- AMPA receptor
3- KAINATE receptor
All three are channels for Na+ and Ca++ ions (excitatory) and are
present of the postsynaptic neuron. However, NMDA allows the
passage of calcium ions more than sodium ions. AMPA allows the
passage of sodium ions more than calcium ions.
KAINATE receptors, on the other hand, are the only ones that are
present on the presynaptic neuron. The reason is to self-regulate the
neurotransmitter realease.
In most cases, presynaptic receptors (not KAINATE and Glutamate’s
case) allow the binding of the neurotransmitter when its
concentration increases in the synaptic cleft. Consequently, it
prevents the release more of the neurotransmitter. It gives it a
break-like period.
In the case of KAINATE receptors on the presynaptic neuron and
glutamate, the KAINATE allows the entry of Ca++ ions into the
PREsynaptic neuron. As we know, the entry of Calcium ions into the
PREsynaptic neuron releases more of the neurotransmitter.
Termination of signal:
Glutamate neurotransmitter’s effect is terminated (ended) by glial cells
(mainly astrocytes) which convert it back to its precursor, the amino
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Physiology 2 - Sheet #6 - Dr.Loai Al-Zgoul - Done by: Yara Zreiqat
acid glutamine. Glutamine is then transferred to the presynaptic
neuron which uses it again to synthesize glutamate and so on.
Glutamate and CNS disorders:
Stroke
Ischemia: is a restriction in blood supply to tissues, causing a shortage
of oxygen and glucose supply to the cells which in turn stops the
production of ATP. Glial cells have transporters which use ATP to
reuptake the glutamate. When there is no ATP, glutamate molecules
accumulate in the synaptic cleft which continue binding to the
receptors (NMDA and AMPA receptors) and allowing the entry of Na+
and mainly Ca++ ions causing excitation. This is known as excitotoxicity.
This leads to the death (apoptosis) of that area of the brain.
There is a certain drug that is given in the early 20-30 minutes to
decrease defect neurons in stroke patients. This drug blocks the
receptors (NMDA and AMPA) so it’s NMDA and AMPA antagonist.
However, it blocks mainly NMDA receptors since they allow the entry of
Ca++ ions more than AMPA. Calcium ions are a main cause of
apoptosis so that’s why this drug is mainly a NMDA antagonists.
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