Neurophysiology, Neurotransmitters and the Nervous System

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Neurophysiology, Neurotransmitters and the
Nervous System
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The Neuron
The nervous system is made of nerve cells or
neurons and glial cells. Glial cells are not
excitable and provide metabolic and physical
support for the neurons. 90 of the cells are
glial cells. Neurons are excitable and control
behavior
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Neuron
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Resting potential
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Resting potential
There is a potential difference between the
inside and outside of as membrane. The inside is
about -70 mv relative to the outside.
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Resting Potential
The resting potential is caused by an uneven
distribution of ions (electrically charged
molecules) of potassium (K) and sodium (Na) and
chloride (Cl-). This is caused by Na/K ion
pumps that move 3 Na ions out of the cell for
every 2 K ions it moves in.
Therefore there are more ions outside the cell
than inside and the inside is negatively charged
with respect to the outside
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Ion pump
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Resting potential
An ion channel is a combination of large protein
molecules that cross the membrane and allow
specific ions to pass through at a specific rate,
These allow enough leakage of ions to mostly
neutralize the effect of the ion pump, but
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Ion channels
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Resting potential

• Forces maintaining the resting potential
• Diffusion pressure molecules want to move from
  areas of high concentration to areas of low
  concentration.
• Electrostatic charge ions with like charge are
  repelled and ions with a different charge are
  attracted.
• Operation of ion pumps and ion channels.

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Action potential

• Anything that alters the functioning of the ion
  channels can change the resting potential.
• If changes cause the resting potential to be
  reduced, this is called depolarization.
• If the change causes an increase in the resting
  potential, this is caused hyperpolarization.

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Action Potential

• We can insert an electrode across a membrane and
  cause depolarization, i.e., we can depolarize the
  cell.
• If we reduce the resting potential past a
  threshold, the resting potential breaks down.

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Action potential

• Voltage gated ion channels open and let Na into
  the cell. They are driven into the cell because
  of diffusion gradient and electrostatic charge.
• This causes the resting potential to reverse,
  i.e., the inside the cell becomes positive.
• Now the Na ion channels close and the K
  channels open and the K ions are driven out of
  the cell because of their concentration gradient
  and electrostatic charge.
• Finally the K channels close and the ion pumps
  kick in and the resting potential returns to
  normal.

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Action potential
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All or None Law

• Action potentials when they occur are always the
  same.
• Once the process is initiated, it must run its
  course and nothing can stop it or change it

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Transmission of action potentials along a membrane

• When an action potential occurs at one place on
  the membrane of an axon, the surrounding membrane
  is depolarized past threshold causing an action
  potential. This depolarizes the neighboring
  membrane, etc.
• Action potentials sweep across a membrane as fast
  as 100m/sec

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Transmission of action potentials along a membrane
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Postsynaptic potentials

• The membranes of dendrites and cell bodies do not
  have action potentials. Instead, any depolarizing
  stimulus causes a post synaptic potential (PSP)
  which spreads out across the membrane. The
  depolarization is weaker the further it gets
  from the stimulus. When the stimulus is turned
  off, the PSP disappears.

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Postsynaptic potentials

• Postsynaptic potentials can either be excitatory
  (depolarization) or inhibitory.
• Excitatory and inhibitory potentials can summate
  both in time (temporal summation) and across the
  membrane (spatial summation) .
• The net effect of summation is reflected at the
  axon hillock where action potentials are
  generated.

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The synapse

• Normally, cell bodies are stimulated by either by
• stimuli in the environment, e.g. sensory cells
  like the rods and cones in the eye, or
• Connections from other nerve cells, i.e.,
  synapses

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The Synapse
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The Synapse
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Synapse
Any neuron can have thousands of synapses on it
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Synapse

• When an action potential arrives at the terminal
  bouton, it causes Ca channels to open.
• This causes the vesicles to move to the membrane
  and release a chemical called a neurotransmitter
  to be released into the synaptic cleft.
• The neurotransmitter diffuses across the cleft
  and activates receptors on the postsynaptic
  membrane which cause changes on the resting
  potential by altering the functioning of ion
  channels.

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Proteins

• Ion pumps, ion channels, etc., are large
  molecules of protein.
• Proteins are long strings of amino acids that can
  fold into many three dimensional shapes. The same
  protein can have different configurations, i.e.,
  they can change shape.
• Receptors are protein molecules that change shape
  (are activated) by neurotransmitter molecules
  with a particular shape.

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Receptors

• Receptor sites can be part of an ion channel and
  when the receptor site is occupied by a
  neurotransmitter, the ion channel opens

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Post synaptic potential

• The change in the resting potential caused by the
  activation of a receptor site is called the post
  synaptic potential (PSP).
• IPSP when the change causes hyperpolarization
  or makes the cell harder to fire, this is called
  an inhibitory post synaptic potential.
• EPSP when the change causes depolarization,
  this is called an excitatory post synaptic
  potential.

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Post synaptic potential

• The excitation and inhibition caused by all the
  active synapses on the dendrites and cell body
  are summed and the net effect is reflected in the
  rate at which the axon hillock generates action
  potentials

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Summation
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Terminating synaptic action

• Once the neurotransmitter is released into the
  cleft, there must be a means by which its
  activity is terminated. This can be accomplished
  two ways
• The neurotransmitter can be destroyed by an
  enzyme in the cleft
• The neurotransmitter can be reabsorbed back into
  the bouton (reuptake).

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Second messenger
The neurotransmitter causes the release of a
molecule inside the cell which activates an ion
channel and causes it to open
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Second messenger cascade
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Second messenger cascade

• Second messenger molecules can activate a kinase
  which lasts for minutes and hours.
• Kinases can activate transcription factors (CREB
  and c-fos) which alter the expression of genes.
• Genes carry the codes for the creation of
  proteins including ion channels and receptor
  sites and this can cause permanent changes in
  synaptic function.

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autoreceptors

• The membrane of the presynaptic cell has many
  receptor sites which detect the neurotransmitter.
  This is a feedback system which regulated the
  amount of neurotransmitter released into the
  cleft

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Other signaling between neurons

• Neuromodulators are chemicals that can alter the
  effect of a neurotransmitter.
• Sometimes the postsynaptic membrane releases
  molecules that affect the presynaptic membrane.
• DSE- depolarization-induced suppression of
  excitation
• DSI depolarization-induced suppression of
  inhibition.
• Axo-axonal synapses axons may also have synapses

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Neurotransmitters
Acetylcholine (Ach) Biogenic amines
(monoamines) catecholamines Norepinephrine
(NE) Dopamine (DA) Epinephrine (E)
(adrenaline) indoleamine Serotonin (5-HT,
5-hydroxytryptamine)
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Amino acids GABA Glycine Glutamate Proline
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Peptides Substance P Somatostatin Vasopressin
Growth hormone Prolactin Insulin Opiate-like
transmitters Enkephalins Endorphins
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carbon monoxide nitric oxide
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Many hormones are neurotransmitters. Both have
the same function chemical signalling over
distances.
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Neurohormones

• Substances that act at neuron receptor sites,
  but are not specific to an individual synapse.
• May be released far from the synapse.
• Act as a neuromodulator (modify the activity of
  a neurotransmitter)

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Dales Law
A single neuron always produces the same
transmitter at every one of its synapses. It is
now known that the law is not always right.
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Drugs mostly act on the nervous system by
interacting with neurotransmission, They may act
on receptor sites and cause the same effect as a
transmitter agonism block a receptor site
antagonism decreasing activity of enzymes that
destroy a transmitter block reuptake
mechanisms blocking ion channels altering release
of transmitter altering the action of
neurohormones
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Synapses that use NE are nor adrenergic
(remember, adrenaline is another word for
epinephrine) DA are dopaminergic
5-HT are serotonergic ACh are
cholinergic etc
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Acetylcholine Broken down by AchE
(acetylcholinesterase) Receptors nicotinic and
muscarinic Stimulated Blocked
Function nicotinic nicotine curare
Voluntary muscle control (neuromuscular
junctions) muscarinic muscarine atropine
Involuntary muscle control botox and nerve
gasses
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Biogenic amines Serotonin, Dopamine
Norepinephrine and Epinephrine Broken down by MAO
and COMT Reabsorbed by transporter
mechanisms Influenced by amphetamines and
cocaine and SSRIs and SNRIs E and NE receptor
sites alpha (a)and Beta (ß) with subtypes 1 and
2 DA has 6 receptor subtypes D1 and D2....D6 with
sub sub types a b c, etc Serotonin has 4 main
receptor subtypes with sub sub types a b c etc.
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GABA

• Universally inhibitory transmitter
• Opens a Chloride ion channel which stabilizes the
  membrane and makes it harder to depolarize
• Drugs like benzodiazepines enhance the ability of
  GABA to open the ion channel.
• There are two types of GABA receptors GABAA and
  GABAB.
• There are many different subtypes of GABAA
  receptors which control different functions.
• GABAB receptors are less common and use a second
  messenger

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GABA
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Glutamate excitatory transmitter NMDA receptor
open ion channel and lets ions into the
cell the channels can be blocked by alcohol,
solvents and some hallucinogens Peptides opioid
type peptides enkephalins (5 amino
acids) endorphines (16 to 30 amino acids)
Receptor subtypes mu, kappa and delta
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The Nervous System
Central Nervous System (CNS) brain and spinal
cord Peripheral Nervous system (PNS) everything
else
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somatic NS conscious senses and voluntary
muscles transmitter is Ach and uses nicotinic
receptors autonomic NS unconscious
senses and involuntary muscles transmitter
is Ach with muscarinic receptors.
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Autonomic NS sympathetic and parasympathetic
divisions Parasympathetic always
active, controls daily vegetative functions
Ach major transmitter some drugs have
anticholinergic side effects, e.g dry mouth and
blurry vision Sympathetic active at times
of fear and anger fight - flight
response epinephrine (E) major transmitter
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CNS spinal cord Brain 100 billion neurons.
each has 100 synapses on other neurons and
receives 10,000 synapses from other neurons
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Spinal cord
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Brain
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Medulla Autonomic control centre Respiratory
centre controls breathing Vomiting
centre Cardiac functions Very sensitive to
depressant drugs like alcohol, opioids and
barbiturates Brain damage caused by drug overdose
is a result of lack of oxygen
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RAS and Raphé System RAS - arousal - many
interconnected centres - diffuse projection to
cortex and higher centres Raphé System -
many independent centres - serotonin - medial
forebrain bundle projects forward - sleep
- mood
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Locus Coeruleus mood fear, panic,
anger primarily NE, (50 to 75 NE neurons in the
brain) stimulated by monoamines inhibited by
GABA active during panic attack
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Cerebellum Coordination of motor
control Receives input from the motor areas of
the cortex and the muscles and coordinates smooth
muscle movement. Coordinates eye movements.
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Basal Ganglia Input side striatum caudate
nucleus and putamen - input from thalamus
and cortex Output side globus palladus - output
side with feedback to thalamus Motor
loop coordination of motor control - DA input
from substantia nigra - DA receptors - DA
deficiency - Parkinsons Disease - extrapyramidal
motor system
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Periaquiductal gray pain control - mu
receptors and morphine-like transmitters
punishment system
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Limbic system hypothalamus - eating and
drinking control medial forebrain bundle ---
reinforcement (pleasure?) centres mesolimbic
system (DA) ventral tegmental area (VTA, mu
receptors) nucleus accumbens hippocampus -
learning and memory amygdala and septum -
serotonergic input from the Raphé system
Aggression and emotion Inhibited by GABA
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Cortex
Cortex sensory input areas motor control output
areas language memory and thinking glutamate -
excitatory transmitter GABA - inhibitory
transmitter
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Frontal and prefrontal cortex
Frontal and prefrontal cortex monitors
relationship between cues and reinforces
(outcomes of behavior), inhibition of behavior
and the expression of emotion. Orbitofrontal
cortex learning and behavior control Prefrontal
cortex working memory, attention, decision
making, reasoning, planning and
judgment. Dorsolateral prefrontal cortex
maintenance of attention and manipulation Anderior
cingulate cortex attention, response selection,
response suppression, drug seeking and craving.
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Development
Formation of neurons Migration Attachment and
axon projection
Growth cone
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Development and teratology
Extension of axons is controlled by trophic
factors, chemical signals that guide it to its
target. These signals can be easily disrupted by
drugs and cause incorrect wiring of the CNS Eg
fetal alcohol syndrome only 4 layers rather
than the normal 6 in the cortex. Teratology
disruption of normal anatomical development, e.g
thalidomide Functional teratology a disruption
of normal behavioral development.
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