Transcript Lecture -1 Fall 2012

Saquiba Yesmine, PhD
1
Somatic Parts
Cranial nerves and their distributions
2
Visceral Motor Neurons
 Visceral motor neurons arise from cells in lateral regions of spinal
cord and send processes out anteriorly.
These processes synapse with other cells, usually other visceral
motor neurons
 The visceral motor neurons located in the spinal cord are referred to
as preganglionic motor neurons and their axons are called
preganglionic fibers;
the visceral motor neurons located outside the CNS are referred to as
postganglionic motor neurons and their axons are called
postganglionic fibers.
3
Classification of Visceral Motor Nerves

Visceral motor components associated
with spinal levels T1 to L2 are termed
sympathetic.

the
sympathetic
system
innervates
structures in peripheral regions of the
body and viscera;

Visceral motor components in cranial and
sacral regions, on either side of the
sympathetic
region,
are
termed
parasympathetic:

the parasympathetic system is more
restricted to innervation of the viscera
only.
4
Divisions of the Peripheral Autonomic System
On the efferent side, the autonomic nervous system
consists of two large divisions: (1) the sympathetic
or thoracolumbar outflow and (2) the
parasympathetic or craniosacral outflow.
The neurotransmitter of all preganglionic autonomic
fibers, most postganglionic parasympathetic fibers,
and a few postganglionic sympathetic fibers is
acetylcholine (ACh). Some postganglionic
parasympathetic nerves use nitric oxide (NO) as a
neurotransmitter; nerves that release NO are
referred to as nitrergic.
5
Divisions of the Peripheral Autonomic System
The adrenergic fibers comprise the majority of
the postganglionic sympathetic fibers; here the
primary transmitter is norepinephrine (NE,
noradrenaline, levarterenol).
Not all the transmitter(s) of the primary afferent
fibers, such as those from the mechano- and
chemoreceptors of the carotid body and aortic
arch, have been identified conclusively.
Substance P and glutamate are thought to
mediate many afferent impulses; both are
present in high concentrations in the dorsal
spinal cord
6
Sympathetic Nerves
7
Parasympathetic Nerves
8
9
Parasympathetic Nervous system
• The tenth (vagus) cranial nerve arises in the medulla and
contains preganglionic fibers, most of which do not
synapse until they reach the many small ganglia lying
directly on or in the viscera of the thorax and abdomen.
• In the intestinal wall, the vagal fibers terminate around
ganglion cells in the myenteric and submucosal plexuses.
Thus, in the parasympathetic branch of the autonomic
nervous system, preganglionic fibers are very long,
whereas postganglionic fibers are very short.
• The vagus nerve also carries a far greater number of
afferent fibers (but apparently no pain fibers) from the
viscera into the medulla; the cell bodies of these fibers lie
mainly in the nodose ganglion
10
Enteric Nervous System
• Mixing, propulsion, and absorption of nutrients in the GI
tract are controlled locally through a restricted part of the
peripheral nervous system called the enteric nervous
system (ENS).
• The ENS is involved in sensorimotor control. Thus
contains both afferent sensory neurons and motor nerves
and interneurons organized principally into two nerve
plexuses: the myenteric (Auerbach's) plexus and the
submucosal (Meissner's) plexus.
• The myenteric plexus, located between the longitudinal
and circular muscle layers, plays an important role in the
contraction and relaxation of GI smooth muscle.
• The submucosal plexus is involved with secretory and
absorptive functions of the GI epithelium, local blood flow,
and neuroimmune activities
11
Differences between Autonomic and Somatic Nerves
• The efferent nerves of the involuntary system supply all innervated
structures of the body.
•Voluntary system such as, skeletal muscle is served by somatic
nerves.
• Synaptic junctions in the autonomic nerves occur in ganglia that
are entirely outside the cerebrospinal axis. These ganglia are small
but complex structures that contain axodendritic synapses between
preganglionic and postganglionic neurons.
• Somatic nerves contain no peripheral ganglia, and the synapses
are located entirely within the cerebrospinal axis.
12
Differences between Autonomic and Somatic Nerves
• Many autonomic nerves form extensive peripheral plexuses.
• Such networks are absent from the somatic system.
• motor nerves to skeletal muscles are myelinated.
• Postganglionic autonomic nerves generally are nonmyelinated.
• When the spinal efferent nerves are interrupted, the denervated
skeletal muscles lack myogenic tone, are paralyzed, and atrophy,
• Smooth muscles and glands generally retain some level of
spontaneous activity independent of intact innervation.
13
Differences between Autonomic and Somatic Nerves
• The parasympathetic distribution is much more limited.
Furthermore, the sympathetic fibers ramify to a much
greater extent.
• A preganglionic sympathetic fiber may traverse a
considerable distance of the sympathetic chain and pass
through several ganglia before it finally synapses with a
postganglionic neuron.
• Terminals make contact with a large number of
postganglionic neurons. In some ganglia, the ratio of
preganglionic axons to ganglion cells may be 1:20 or more.
14
Differences between Autonomic and Somatic Nerves
The parasympathetic system, in contrast, has terminal
ganglia very near or within the organs innervated.
In some organs, a 1:1 relationship between the number of
preganglionic and postganglionic fibers has been
suggested, but the ratio of preganglionic vagal fibers to
ganglion cells in the myenteric plexus has been estimated
as 1:8000.
Exception: The cell bodies of somatic motor neurons reside
in the ventral horn of the spinal cord; the axon divides into
many branches, each of which innervates a single muscle
fiber, so more than 100 muscle fibers may be supplied by
one motor neuron to form a motor unit.
15
Neurotransmitter the compound which is synthesized and released presynaptically
and mimic the action of the endogenous compound that is released
on nerve stimulation.
Neuromodulator
The compound which has no intrinsic activity but is active only in
the face of ongoing synaptic activity, where it can modulate
transmission either pre- or postsynaptically (e.g. changes in
conductance or membrane potential). Substances such as CO and
ammonia, arising from active neurons or glia, are potential
modulators acting through non-synaptic actions.
Neurohormone
The compound which has intrinsic activity and can be released from
both neuronal and nonneuronal cells and travels in the circulation
to act at a site distant from its release site.
16
dopamine
• Neurotransmitter?
• Neurohormone?
Dopamine is released in the synapses at striatum of brain and
stimulate post synaptic neuron
Dopamine is released from the hypothalamus and travels through
the hypophyseal circulation to the pituitary, where it inhibits the
release of prolactin.
Serotonin is a neurotransmitter in the raphe nuclei, but at the facial
motor nucleus it acts primarily as a neuromodulator and secondarily as
a transmitter.
Most peptides, with their multiple activities in the brain and gut, are
generally considered to be neuromodulators, but substance P fulfills
the criteria of a neurotransmitter at sensory afferents to the dorsal
horn of the spinal cord.
17
It is difficult to classify neuroactive compounds as
neuro-transmitter, neuromodulator or
neurohormone until the site of action and the
activity of the agent were specified.
It is better to describe the activity of a
neuroactive agent at a specified site rather
than attempt to give a profitless definition.
18
Differences between Autonomic and Somatic Nerves
19
Ganglion and Nucleus
• Neurons exhibit the cytological characteristics of highly active
secretory cells.
• Large nuclei, large amounts of smooth and rough endoplasmic
reticulum; and frequent clusters of specialized smooth endoplasmic
reticulum and Golgi complex, in which secretory products of the cell are
packaged into membrane-bound organelles for transport from the
perikaryon to the axon or dendrites.
• Neurons and their cellular extensions are rich in microtubules, which
support the complex cellular structure and assist in the reciprocal
transport of essential macromolecules and organelles between the cell
body and distant axon or dendrites.
20
Synapse
21
Ganglion and Nucleus
A ganglion is simply a swelling.
In a nerve, ganglion means a swelling on the nerve.
It is used to mean the swelling caused by a collection of nerve cell bodies
on a peripheral nerve: cell bodies take up more space than fibres, so a
collection of cell bodies will cause a swelling.
A nucleus is an aggregation of cell
bodies in the CNS
(exception: basal ganglia of the brain)
Ganglia are peripheral;
Nuclei are central.
22
Ganglion and Nucleus
• Ganglia (singular ganglion), or neural ganglia, are structures located outside the
central nervous system made of concentration of neuron bodies.
• Examples of neural ganglia are the ganglia that concentrate cell bodies of
sensory neurons in the dorsal roots of the spinal cord and the ganglia of the
myenteric plexus responsible for the peristaltic movements of the digestive tube.
In the central nervous system (CNS) the concentrations of neuron bodies are
called nuclei and not ganglia.
Ganglia are peripheral;
Nuclei are central.
23
Synapses

A junction that mediates information transfer from
one neuron:
◦ To another neuron
 Called neuro-synapses or just synapse
◦ To an effector cell
 Neuromuscular synapse if muscle involved
 Neuroglandular synapse if gland involve
24
Synapses

Presynaptic neuron – conducts impulses
toward the synapse

Postsynaptic neuron – transmits impulses
away from the synapse

Two major types:
◦ Electrical synapses
◦ Chemical synapses
25
Synapses
1. Axodendritic synapse
2. Axosomatic synapse
3. Axoaxonic synapse
Figure 11.1726
Electrical Synapses

Pre- and postsynaptic
neurons joined by
gap junctions
◦ allow local current to
flow between
adjacent cells.
Connexons: protein
tubes in cell
membrane.

Rare in CNS or PNS
27
Electrical Synapses


Found in cardiac
muscle and many
types of smooth
muscle. Action
potential of one cell
causes action
potential in next
cell, almost as if the
tissue were one cell.
Important where
contractile activity
among a group of
cells important.
28
Chemical Synapses

Most common type

Cells not directly coupled as in electrical synapses

Components
◦ Presynaptic terminal
◦ Synaptic cleft
◦ Postsynaptic membrane (PSM)

Chemical neurotransmitters (NT’s) released by
presynaptic neuron

NT binds to receptor on PSM
29
Chemical Synapse
At rest, the interior of the typical mammalian axon is 70 mV
negative to the exterior.
The resting potential is essentially a diffusion potential based
chiefly on the 40 times higher concentration of K+ in the
axoplasm as compared with the extracellular fluid and the
relatively high permeability of the resting axonal membrane
to K+.
Na+ and Cl– are present in higher concentrations in the
extracellular fluid than in the axoplasm, but the axonal
membrane at rest is considerably less permeable to these
ions.
These ionic gradients are maintained by an energy-dependent
active transport mechanism, the Na+, K+-ATPase
30
Chemical Synapse
31
Chemical Synapse
1. In response to depolarization to a threshold level, an
action potential or nerve impulse is initiated.
2. The action potential consists of two phases. Following a
small gating current resulting from depolarization
inducing an open conformation of the channel, the initial
phase is caused by a rapid increase in the permeability
of Na+ through voltage- sensitive Na+ channels.
3. The result is inward movement of Na+ and a rapid
depolarization from the resting potential, which continues
to a positive overshoot.
4. The second phase results from the rapid inactivation of
the Na+ channel and the delayed opening of a K+
channel, which permits outward movement of K+ to
terminate the depolarization.
32
Chemical Synapse
Events at a chemical synapse
1. Arrival of action potential on
presynaptic neuron opens volagegated Ca++ channels.
2. Ca++ influx into presynaptic term.
3. Ca++ acts as intracellular messenger
stimulating synaptic vesicles to fuse
with membrane and release NT via
exocytosis.
4. Ca++ removed from synaptic knob by
mitochondria or calcium-pumps.
33
Chemical Synapse
Events at a chemical synapse
5. NT diffuses across synaptic cleft
and binds to receptor on
postsynaptic membrane
6. Receptor changes shape of ion
channel opening it and
changing membrane potential
7. NT is quickly destroyed by
enzymes or taken back up by
astrocytes or presynaptic
membrane.
34
Chemical Synapse
Events at a chemical synapse
Note:
For each nerve impulse
reaching the presynaptic
terminal, about 300
vesicles are emptied
into the cleft. Each
vesicle contains about
3000 molecules.
35
Removal of Neurotransmitter from Synaptic Cleft
• Method depends on neurotransmitter
• ACh: acetylcholinesterase splits
ACh into acetic acid and choline.
Choline recycled within
presynaptic neuron.
• Norepinephrine: recycled within
presynaptic neuron or diffuses
away from synapse.
Enzyme is monoamine oxidase
(MAO). Absorbed into circulation,
broken down in liver.
36
Synaptic Delay

0.2-0.5 msec delay between arrival of AP at synaptic
knob and effect on PSM
◦ Reflects time involved in Ca++ influx and NT release
◦ While not a long time, its cumulative synaptic delay
along a chain of neurons may become important.
◦ Thus, reflexes important for survival have only a few
synapses
Synaptic Fatigue
•
Under intensive stimulation, resynthesis and transport of
recycled NT my be unable to keep pace with demand for
NT
•
Synapse remains inactive until NT has been replenished
37
Receptor Molecules and Neurotransmitters

Neurotransmitter only "fits" in one receptor.

Not all cells have receptors.

Neurotransmitters are commonly classified as excitatory or
inhibitory.

Classification is useful but not precise. For example:
◦ ACh is stimulatory at neuromuscular junctions (skeletal)
◦ ACh is inhibitory at neuromuscular junction of the heart

Therefore, effect of NT on PSM depends on the type of receptor,
and not nature of the neurotransmitter

Some neurotransmitters (norepinephrine) attach to the presynaptic
terminal as well as postsynaptic and then inhibit the release of
more neurotransmitter.
38
Postsynaptic Potentials



NT affects the postsynaptic membrane potential
Effect depends on:
◦ The amount of neurotransmitter released
◦ The amount of time the neurotransmitter is bound to
receptors
The two types of postsynaptic potentials are:
◦ EPSP – excitatory postsynaptic potentials
◦ IPSP – inhibitory postsynaptic potentials
39
Excitatory Postsynaptic Potentials

EPSPs are graded potentials that can initiate an action
potential in an axon
◦ Use only chemically gated channels

Postsynaptic membranes do not generate action
potentials

But, EPSPs bring the RMP closer to threshold and
therefore closer to an action potential
40
Inhibitory Synapses and IPSPs

Neurotransmitter binding to a receptor at inhibitory
synapses:
◦ Causes the membrane to become more permeable
to potassium and chloride ions
◦ Leaves the charge on the inner surface more
negative (flow of K+ out of the cytosol makes the
interior more negative relative to the exterior of the
membrane
◦ Reduces the postsynaptic neuron’s ability to produce
an action potential
41
Summation

A single EPSP cannot induce an action potential

EPSPs must summate temporally or spatially to induce an
action potential

Temporal summation – one presynaptic neuron transmits
impulses in rapid-fire order

Spatial summation – postsynaptic neuron is stimulated by a
large number of presynaptic neurons at the same time

IPSPs can also summate with EPSPs, canceling each other
out
42
Summation
Figure 11.21
43
Major Neurotransmitters in the
Body
Neurotransmitter
Role in the Body
Acetylcholine
A neurotransmitter used by the spinal cord neurons to control muscles and
by many neurons in the brain to regulate memory. In most instances,
acetylcholine is excitatory.
Dopamine
The neurotransmitter that produces feelings of pleasure when released by
the brain reward system. Dopamine has multiple functions depending on
where in the brain it acts. It is usually inhibitory.
GABA
(gamma-aminobutyric acid)
The major inhibitory neurotransmitter in the brain.
Glutamate
The most common excitatory neurotransmitter in the brain.
Glycine
A neurotransmitter used mainly by neurons in the spinal cord. It probably
always acts as an inhibitory neurotransmitter.
Norepinephrine
Norepinephrine acts as a neurotransmitter and a hormone. In the
peripheral nervous system, it is part of the flight-or-flight response. In the
brain, it acts as a neurotransmitter regulating normal brain processes.
Norepinephrine is usually excitatory, but is inhibitory in a few brain areas.
Serotonin
A neurotransmitter involved in many functions including mood, appetite,
and sensory perception. In the spinal cord, serotonin is inhibitory in pain
pathways.
NIH Publication No. 00-4871
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45
Cholinergic Transmission
Cell Signaling and Synaptic Transmission
Most cell-to-cell communication in the CNS involves chemical transmission.
Chemical transmission requires several discreet specializations:
• Transmitter synthesis. Small molecules like ACh and NE are synthesized in
nerve terminals; peptides are synthesized in cell bodies and transported to nerve
terminals.
• Transmitter storage. Synaptic vesicles store transmitters, often in association
with various proteins and frequently with ATP.
• Transmitter release. Release of transmitter occurs by exocytosis. Depolarization
results in an influx of Ca2+, which in turn appears to bind to proteins called
synaptotagmins. An active zone is established to which vesicles dock and then
fuse with scaffolding proteins on the presynaptic membrane. After fusing with the
membrane and exocytotic release of their contents, synaptic vesicle proteins are
recycled through endocytosis.
46
Cell Signaling and Synaptic Transmission
•Transmitter recognition. Receptors exist on postsynaptic cells, which recognize
the transmitter. Binding of a neurotransmitter to its receptor initiates a signal
transduction event, as previously described.
•Termination of action. A variety of mechanisms terminate the action of
synaptically released transmitter, including hydrolysis (for acetylcholine and
peptides) and reuptake into neurons by specific transporters such as NET, SERT,
and DAT (for NE, 5-HT, DA). Inhibitors of NET, SERT, and DAT increase the dwell
time and thus the effect of those transmitters in the synaptic cleft. Inhibitors of the
uptake of NE and/or 5-HT are used to treat depression and other behavioral
disorders
47
Cholinergic Transmission
Choline is transported into the presynaptic nerve terminal by
a sodium-dependent carrier (A).
This transport can be inhibited by hemicholinium drugs.
ACh is transported into the storage vesicle by a second
carrier (B) that can be inhibited by vesamicol.
Release of transmitter occurs when voltage-sensitive
calcium channels in the terminal membrane are opened,
allowing an influx of calcium.
The resulting increase in intracellular calcium causes fusion of vesicles with the surface
membrane and exocytotic expulsion of ACh into the junctional cleft. This step is blocked by
botulinum toxin.
Acetylcholine's action is terminated by metabolism by the enzyme acetylcholinesterase.
Receptors on the presynaptic nerve ending regulate transmitter release.
48
Cholinergic Transmission
The terminals of cholinergic neurons contain large numbers of small membrane-bound
vesicles concentrated near the synaptic portion of the cell membrane as well as a smaller
number of large dense-cored vesicles located farther from the synaptic membrane.
The large vesicles contain a high concentration of peptide cotransmitters, while the smaller
clear vesicles contain most of the acetylcholine. Vesicles are initially synthesized in the neuron
soma and transported to the terminal. They may also be recycled several times within the
terminal.
Acetylcholine is synthesized in the cytoplasm from acetyl-CoA and choline through the
catalytic action of the enzyme choline acetyltransferase (ChAT). Acetyl-CoA is synthesized in
mitochondria, which are present in large numbers in the nerve ending.
Choline is transported from the extracellular fluid into the neuron terminal by a sodiumdependent membrane carrier (carrier A). This carrier can be blocked by a group of drugs
called hemicholiniums. Once synthesized, acetylcholine is transported from the cytoplasm
into the vesicles by an antiporter that removes protons (carrier B). This transporter can be
blocked by vesamicol.
Acetylcholine synthesis is a rapid process capable of supporting a very high rate of
transmitter release. Storage of acetylcholine is accomplished by the packaging of "quanta" of
acetylcholine molecules (usually 1000–50,000 molecules in each vesicle).
49
Continuation of Cholinergic Transmission
Release of transmitter is dependent on extracellular calcium and occurs when an action
potential reaches the terminal and triggers sufficient influx of calcium ions.
The increased Ca2+ concentration "destabilizes" the storage vesicles by interacting with
special proteins associated with the vesicular membrane. Fusion of the vesicular membranes
with the terminal membrane occurs through the interaction of vesicular proteins (vesicleassociated membrane proteins, VAMPs), eg,
synaptotagmin and synaptobrevin, with several proteins of the terminal membrane
(synaptosomeassociated proteins, SNAPs), eg, SNAP-25 and syntaxin.
Fusion of the membranes results in exocytotic expulsion of — in the case of somatic motor
nerves—several hundred quanta of acetylcholine into the synaptic cleft.
The amount of transmitter released by one depolarization of an autonomic postganglionic
nerve terminal is probably smaller. In addition to acetylcholine, several cotransmitters will be
released at the same time.
The ACh vesicle release process is blocked by botulinum toxin through the enzymatic
removal of two amino acids from one or more of the fusion proteins.
50
Continuation of Cholinergic Transmission
After release from the presynaptic terminal, acetylcholine molecules may
bind to and activate an acetylcholine receptor (cholinoceptor). Eventually
(and usually very rapidly), all of the acetylcholine released will diffuse within
range of an acetylcholinesterase (AChE) molecule.
AChE very efficiently splits acetylcholine into choline and acetate and
terminates the action of the transmitter. Most cholinergic synapses are richly
supplied with acetylcholinesterase; the half-life of acetylcholine in the
synapse is therefore very short.
51
52
Adrenergic Transmission
Adrenergic Transmission
Tyrosine is transported into the noradrenergic
ending by a sodium-dependent carrier (A).
Tyrosine is converted to dopamine, which is
transported into the vesicle by a
carrier (B) that can be blocked by reserpine.
The same carrier transports norepinephrine
(NE) and several other amines into these
granules.
Dopamine is converted to NE in the vesicle by
dopamine-hydroxylase.
Release of transmitter occurs when an action
potential opens voltage-sensitive
calcium channels and increases intracellular
calcium. Fusion of vesicles with the surface
membrane results in expulsion of
norepinephrine, cotransmitters, and
dopamine-hydroxylase.
53
Adrenergic Transmission
Adrenergic neurons transport a precursor molecule into the nerve
ending, then
synthesize the catecholamine transmitter, and finally store it in
membrane bound vesicles.
In most sympathetic postganglionic neurons, norepinephrine is the
final product.
In the adrenal medulla and certain areas of the brain, norepinephrine
is further converted to epinephrine.
Synthesis terminates with dopamine in the dopaminergic neurons of
the central nervous system.
Several important processes in these nerve terminals are potential
sites of drug action.
54
One of these, the conversion of tyrosine to dopa, is the ratelimiting step in
catecholamine transmitter synthesis. It can be inhibited by
the tyrosine analog metyrosine. A high-affinity carrier for
catecholamines located in the wall of the storage vesicle can
be inhibited by the reserpine alkaloids.
Another carrier transports norepinephrine and similar
molecules into the cell cytoplasm (reuptake 1). It can be
inhibited by cocaine and tricyclic antidepressant drugs,
resulting in an increase of transmitter activity in the synaptic
cleft.
55
Continuation of Adrenergic Transmission
Release of the vesicular transmitter store from noradrenergic nerve endings is
similar to the calcium-dependent process described above for cholinergic
terminals.
In addition to the primary transmitter (norepinephrine), ATP, dopamine- hydroxylase, and peptide cotransmitters are also released into the synaptic
cleft.
Indirectly acting sympathomimetics—eg, tyramine and amphetamines—are
capable of releasing stored transmitter from noradrenergic nerve endings.
These drugs are taken up into noradrenergic nerve endings by uptake 1.
In the nerve ending, they may displace norepinephrine from storage vesicles,
inhibit monoamine oxidase, and have other effects that result in increased
norepinephrine activity in the synapse.
56
Biosynthesis of catecholamines
The rate-limiting step, conversion
of tyrosine to dopa,
It can be inhibited by metyrosine
(a-methyltyrosine).
The alternative pathways shown by
the dashed arrows have not been
found to be of physiologic
significance in humans.
However, tyramine and octopamine
may accumulate in patients treated
with monoamine oxidase inhibitors.
57
58
Metabolism of catecholamines by catechol-Omethyltransferase (COMT) and monoamine oxidase (MAO).
Norepinephrine and
epinephrine
metabolized by -
MAO and COMT
59