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18/10/2012
THE NERVOUS SYSTEM
Dr Sarah Harney
Department of Physiology
[email protected]
• How is the Nervous System Organised?
• What are the functions of different brain regions?
• How does the nervous system transmit information?
• What happens in neurodegenerative diseases?
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The Human Nervous System
Central Nervous System (CNS)
Brain
Spinal Cord
Peripheral Nervous System
(PNS)
Peripheral Nervous System
Afferent
Efferent
Information from periphery
to CNS
Information from CNS to periphery
Sensory neurons
Somatic Nervous System
Autonomic Nervous System
Skeletal muscle
Sympathetic Nervous
System
Smooth muscle – gut, blood
vessels, bladder
Parasympathetic Nervous
System
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Sympathetic and Parasympathetic divisions
of the Autonomic Nervous System
• Opposing effects on many systems
• Use different neurotransmitters
A Few Facts about the Brain
• The adult human brain weighs 1300-1400 g
• The brain weighs 2% of total body weight
• Brain volume is 1400 ml
(80% of total cranial volume, blood 10% and CSF 10%)
• 78 % brain volume is water, ~12% lipid, 8% protein
• There are 100 billion neurons in the brain
• The brain uses 20% of total resting oxygen
From: http://faculty.washington.edu/chudler/facts.html
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Brain - protection
• Protected by:
– cranial bones
– meninges
• pia mater
• arachnoid
• dura mater
– Cerebrospinal fluid
Blood Supply to the Brain
Blood brain barrier
• The brain receives 20% of blood flow from the heart
• Blood flow through whole brain is 750-1000 ml/min
•The blood brain barrier has tight junctions between the blood vessel
endothelial cells that limit the flow of substances into the brain
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The Brain can be Divided into Lobes
Reading, writing,
Spatial judgement
Personality,
Motor activity
Vision
Memory
Brain component
Cerebral cortex
Cerebral cortex
Basal nuclei
(lateral to thalamus)
Basal nuclei
Thalamus
(medial)
Thalamus
Hypothalamus
Hypothalamus
Cerebellum
Cerebellum
Midbrain
Brain stem
Brain stem
(midbrain, pons,
and medulla)
Pons
Medulla
Spinal cord
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The Brain Stem
•
Brain stem consists
of:
– medulla oblongata
– pons
– midbrain
•
Brain stem produces
automatic behaviours
essential for survival
•
Respiration, heart
rate
•
vomiting
The Cerebellum
•
Approximately 10% of brain
mass but contains nearly
half of all brain neurons
•
Coordinates skeletal muscle
contraction
•
Regulates posture and
balance
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The Diencephalon
• Thalamus
– edits all sensory
inputs (except
smell) to cerebral
cortex
– functions in
cognition and
awareness
• allows crude
recognition of
pain, temp and
pressure
– relays information
from cerebellum to
primary motor
cortex
The Diencephalon
Hypothalamus
•
•
•
•
•
•
Major regulator of homeostasis
Produces hormones , regulates pituitary
hormones
Regulates emotional responses and
behaviours related to sexual arousal
Regulates eating and drinking
Controls body temperature
Regulates circadian rhythms and
consciousness
Pituitary gland
• Secretes growth hormone
• Secretes a number of hormones that act on the
thyroid, adrenals and gonads
Pineal gland
• Secretes melatonin, regulates circadian rhythm
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The Cerebral Cortex
• outer part of brain
•
•
allows ‘consciousness’
The human cortex makes up
77% of total brain volume
Different regions of cortex are
specialized for specific functions
Motor cortex
Somatosensory cortex
Sensory associative
cortex
Pars
opercularis
Visual associative
cortex
Broca’s
area
Visual
cortex
Primary
Auditory cortex
Wernicke’s
area
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Major Functions
1. Sensory perception
2. Voluntary control of movement
3. Language
4. Personality traits
5. Sophisticated mental events, such as thinking memory,
decision making, creativity, and self-consciousness
1. Inhibition of muscle tone
2. Coordination of slow, sustained movements
3. Suppression of useless patterns of movements
1. Relay station for all synaptic input
2. Crude awareness of sensation
3. Some degree of consciousness
4. Role in motor control
1. Regulation of many homeostatic functions, such as temperature
control, thirst, urine output, and food intake
2. Important link between nervous and endocrine systems
3. Extensive involvement with emotion and basic behavioral patterns
1. Maintenance of balance
2. Enhancement of muscle tone
3. Coordination and planning of skilled voluntary muscle activity
1. Origin of majority of peripheral cranial nerves
2. Cardiovascular, respiratory, and digestive control centers
3. Regulation of muscle reflexes involved with equilibrium and posture
4. Reception and integration of all synaptic input from spinal cord;
arousal and activation of cerebral cortex
5. Role in sleep-wake cycle
Brain component
Cerebral cortex
Basal nuclei
Thalamus
Hypothalamus
Cerebellum
Brain stem
(midbrain, pons,
and medulla)
Table 5-2, p. 141
fMRI Activity in Cortex during Movement
Foot Action
Hand Action
Mouth Action
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Electroencephalogram (EEG)
• Record of electrical activity in cortical
neurons
• “Brain waves”
• Major uses
– Clinical tool in diagnosis of cerebral
dysfunction
– Used in legal determination of brain
death
– Used to distinguish various stages of
sleep
– Used to diagnose abnormal brain
activity in epilepsy
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Electroencephalogram (EEG)
EEG waves have characteristic frequencies:
Delta
Theta
Alpha
Beta
Gamma
0.5 - 4 Hz
4 - 7 Hz
8 - 13 Hz
13-30 Hz
40 Hz
EEG Activity Correlates with different Sleep Stages
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EPILEPSY
Partial Seizure
•Localised electrical discharge
•Involuntary muscle contraction
•Abnormal sensory experiences
Generalized Seizure
•Frequent
•Synchronous discharge
throughout seizure
Spinal Cord
• Extends from brain stem through vertebral canal
• 31 pairs of spinal nerves emerge from spinal cord
through spaces formed between arches of adjacent
vertebrae
– Named for region of vertebral column from which
they emerge
• 8 pairs cervical (neck) nerves
• 12 pairs thoracic (chest) nerves
• 5 pairs lumbar (abdominal) nerves
• 5 pairs sacral (pelvic) nerves
• 1 pair coccygeal (tailbone) nerves
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Spinal Nerves
Length of human spinal
cord = 45 cm (male); 43
cm (female)
Length of human
vertebral column (male) =
71 cm
Length of human
vertebral column (female)
= 61 cm
The spinal cord
•
Spinal cord protected
by:
– vertebrae
– meninges
• pia mater
• arachnoid
• dura mater
– cerebrospinal fluid
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Cerebrospinal fluid
•
Total volume 125-150 ml
•
Mechanical protection
•
Chemical protection
•
Medium for exchange between blood and
nervous tissue
•
CSF is removed in a lumbar puncture (spinal
tap) to test for infection
Functional Classes of Neurons
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Spinal reflexes
• Spinal cord acts as integrating centre for spinal
reflexes
– Reflex - rapid, predictable, involuntary sequence of actions
that occur in response to a particular stimulus.
Components of a reflex arc
Reflex arc has five components:
– receptor
– sensory neuron
– integration centre
– motor neuron
– Effector
• Somatic reflex – skeletal muscle
• Autonomic reflex – smooth muscle, cardiac
muscle or gland
Pain, temperature, pH, changes in internal environment
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Afferent neurons have specialized sensory receptors
Taste buds
Rods and cones of the retina
Inner ear hair cell cilia
Olfactory receptors
Types of Receptors
• Photoreceptors
– Responsive to visible wavelengths of light
• Mechanoreceptors
– Sensitive to mechanical energy
• Thermoreceptors
– Sensitive to heat and cold
• Osmoreceptors
– Detect changes in concentration of solutes in body fluids
and resultant changes in osmotic activity
• Chemoreceptors
– Sensitive to specific chemicals
– Include receptors for smell and taste and receptors that
detect O2 and CO2 concentrations in blood and chemical
content of digestive tract
• Nociceptors
– Pain receptors that are sensitive to tissue damage or
distortion of tissue
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How do neurons function?
Basic Anatomy of a Neuron
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Neuronal cell types are many and varied
Cellular neuroanatomy was described in detail by Santiago Ramon y Cajal
(Nobel Prize 1906)
Cerebellum
Prefrontal cortex
Hippocampus
The Brain also contains Glial Cells
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Glia – comes from Greek word for glue
Astrocytes – are responsive to change in extracellular Ca2+, have a role in cell
signalling
Provide nutrients to neurons
Can become reactive astrocytes in stress and are involved in degeneration and
scarring
Oligodendrocytes – produce myelin
Microglia – the immune cells of the brain.
Release immune signalling molecules and mediate
degeneration during chronic inflammation
Neural Communication – Synaptic Transmission
• Nerve and muscle are excitable tissues
• Can undergo rapid changes in their membrane
potentials
• Can change their resting potentials into electrical
signals
– Electrical signals are critical to the function of the
nervous system and all muscles
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Neurons use electrical and chemical signalling
1. electrical
2. Chemical
synapse
3. electrical
The Resting Membrane Potential
High Na+
+ + +
- - K+ , + High
++
Cl-, various
anions
- - -
• The cell membrane maintains different ion concentrations inside the neuron
compared to the extracellular fluid
• K+ is high inside the cell, Na+ is high outside the cell
•The cell also contains Cl- and other anions (e.g. HCO3-, PO3-), making it more negatively
charged with respect to the outside
• Separation of positive and negative charges forms an electrical potential difference,
or voltage -this known as the membrane potential (Vm)
• Neurons have a membrane potential of ~-60 to -70 mV
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The Action Potential
• Rapid changes in membrane potential are a critical property of excitable cells
i.e. nerves and muscle
• Channels in the cell membrane permeability selectively allow the flow of ions into or
out of the cell
• Channels can be opened by changes in membrane potential or by binding of
neurotransmitters
• They are selective for specific ions e..g voltage-gated Na+ channels, voltage-gated K+
channels
• The Action Potential is a brief (1-2 ms) reversal in membrane potential which is
propagated along an axon
60
+ 30 mV
•An action potential, or spike, is
fired if Vm crosses a threshold (~ 40 mV)
40
20
Vm (mV)
0
-20
-40
- 70 mV
-60
0
10
Time (ms)
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Voltage-gated channels mediate the Action Potential
Na+
Closed channel
----
K+
K+
Cl-
Na+
Open channel
outside
+++
Cl-
Na+
Na+ +
Na
K+
Cl-
---K+ inside
+ + + ++
-K+
Cl-
-Cl-
Na+
Cl-
+
Na+ Na
Cl• Depolarization to a threshold (~-40 mV) opens voltage-gated Na+ channels
• Na+ enters the cell, making the membrane potential more positive e.g from -70 to + 30 mV
(Depolarization)
• K+ channels open to allow K+ to flow out of the cell, returning the cell to the resting
potential (Repolarization)
• The resting distribution of ions across the cell membrane is restored by the activity of
ion pumps
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Action Potentials
Permeability Changes and Ion Fluxes During an Action Potential
Types of Changes in Membrane
Potential
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Action Potentials propagate along the axon and trigger
neurotransmitter release at the axon terminals
Conduction velocity of action potential = 0.6-120 m/s
(2-400 km/h)
Myelination
• Most mammalian axons are myelinated.
• The myelin sheath is provided by oligodendrocytes
(CNS) and Schwann cells (PNS).
• Myelin is insulating, preventing passage of ions over
the membrane.
• Myelinated axons make up the white matter of the brain,
the neuronal cell bodies are the grey matter
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Saltatory Conduction
•
•
•
Myelinated regions of axon are electrically insulated.
Electrical charge moves along the axon rather than across the
membrane.
Action potentials occur only at unmyelinated regions: nodes of
Ranvier.
Myelin sheath
Node of Ranvier
Multiple Sclerosis is caused by Demyelination of Axons
• Autoimmune disease – immune system attacks myelin
• Leads to loss of nerve conduction
• Chronic inflammation leads to nerve degeneration
Red = Myelin
Green = Axon
Demyelination leads to
degeneration and
retraction of the affected
axon
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Action potential propagation results in transmitter
release from the axon terminal
Chemical Synapses
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Synapses
•
•
•
Junction between two neurons
Primary means by which one neuron directly interacts with another
neuron
Anatomy of a synapse:
Presynaptic neuron – conducts action potential toward synapse
– Axon terminal– contains synaptic vesicles
– Synaptic vesicles – stores neurotransmitter (carries signal across
a synapse)
– Postsynaptic neuron – neuron receiving the signal
– Synaptic cleft – space between the presynaptic
and postsynaptic neurons
Neurons have 1000-10000 synapses
From: Synapse Web, Kristen M Harris
http://synapses.clm.utexas.edu/
Neurotransmitters
• Vary from synapse to synapse
• Same neurotransmitter is always released at a particular
synapse
• Quickly removed from the synaptic cleft
• Some common neurotransmitters
– Acetylcholine
– Dopamine
– Norepinephrine
– Epinephrine
– Serotonin
– Histamine
– Glycine
– Glutamate
– Aspartate
– Gamma-aminobutyric acid (GABA)
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Long-term Potentiation is a model of learning and memory
Synaptic strengthening is induced by high frequency stimulation (e.g. 100 Hz), resulting in a
sustained increase in synaptic current amplitude
Synaptic current
HFS
Before HFS
After HFS
500 pA
10 ms
From Kopec and Malinow, 2006
Dendritic spines are larger after
LTP and have more
neurotransmitter receptors
Amplitude
HFS
Time
Neurogenesis and
Degeneration
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New neurons are made in specific areas in the adult brain
Dentate gyrus -new neurons shown in green
Tashiro et al.
• Generation of new neurons- neurogenesis – in adult brain was first described in 1998,
Eriksson et al., Nat. Med. 4: 1313-17
• New neurons are generated throughout adult life in only 2 brain areas in humans, the the
dentate gyrus region of the hippocampus and the subventricular zone near the lateral
ventricle
• Neurogenesis is stimulated by exercise and by drugs used to treat depression such as
tricyclic antidepressants and selective serotonin reuptake inhibitors e.g. Prozac
Migration and maturation of new neurons in dentate gyrus
Lie et al., Annu Rev
Pharmacol Toxicol 2004.
• New neurons migrate from the border of the granule cell layer
• New cells become integrated in the existing network of cells however, many die off
• Functional significance of neurogenesis still not well understood
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Brain disease
The brain is composed of 1011 neurons
Neurons are dying everyday: at least 0.5% a year after age 50
ALZHEIMER’S DISEASE
Estimated that 4,000,000 people in U.S. have Alzheimer's disease.
Estimated that 25-35% of people over age 85 have dementia.
Caring for patient with Alzheimer's disease can cost $47,000 per
year (NIH).
40,000 patients with AD in Ireland
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Alzheimer’s is associated with Amyloid plaque deposition
and Neurofibrillary Tangles
Brain section
NFT = neurofibrillary tangle i.e abnormal tau protein
• Alzheimer’s disease (AD) is recognised post-mortem by plaques and tangles in
brain tissue
• Plaques - abnormal deposition of b-amyloid protein, neurotoxic, causes
neurodegeneration
• Tangles – abnormal deposition of Tau protein, normally a structural protein
within cells
Synaptic inputs to neurons are lost in Alzheimer’s disease
Synaptic inputs on synaptic spines are
dramatically reduced
Shankar et al.
(2007)
J. Neurosci. 27:
2866-2875
AD animal model
Normal neuron
Normal
dendrite
with
spines
AD model
Walsh and Selkoe review Neuron (2004)
AD begins with a loss of dendrites in Alzheimer’s animal model
- Dendrites are where neurons receive inputs
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AD progression leads to severe degeneration
PET normal brain
NORMAL
PET AD brain
AD
Parkinson’s Disease
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Parkinson’s Disease is Due to a Loss of Dopamine Neurons
Loss of pigmentation in substantia nigra due to
loss of dopaminergic neurons
Mattson (2000) Nat. Rev. Mol. Biol.
1:120-129
Treatment
• Drugs (L-DOPA, precursor for dopamine synthesis), associated with side effects
including impulsive behaviour and compulsive gambling
• Deep brain stimulation (neurostimulator) –stimulation via implanted electrode
inhibits abnormal brain activity, relieving symptoms
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Protein misfolding and aggregation is a common
feature of a number of neurodegenerative
diseases
Alzheimer’s disease
Protein: b-Amyloid, tau
Brain region:
hippocampus and
cortex
Huntington’s disease
Protein: Huntingtin
Brain region: Striatum,
cortex
Parkinson’s disease
Protein: a-Synuclein
Brain region: Substantia
nigra
Prion disease e.g. CJD
Protein: b-amyloid
Different brain regions
ALS (Motor neuron disease)
Protein: Superoxide dismutase
(SOD1)
Brain region: Motor cortex,
brainstem
From Soto (2003) Nat. Rev. Neurosci. 4, 49-60
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