PERIPHERAL NERVOUS SYSTEM
NEURONS AND ACTION POTENTIAL
Anatomy of a neuron
Several types of cells support an action potential, such as plant cells, muscle cells, and the
specialized cells of the heart (in which occurs the cardiac action potential). However, the main
excitable cell is the neuron, which also has the simplest mechanism for the action potential.
Neurons are electrically excitable cells composed, in general, of one or more dendrites, a single
soma, a single axon and one or more axon terminals. The dendrite is one of the two types of
synapses, the other being the axon terminal boutons. Dendrites form protrusions in response to
the axon terminal boutons. These protrusions, or spines, are designed to capture the
neurotransmitters released by the pre-synaptic neuron. It is here, where synapses from two
neurons communicate with one another. These spines have a thin neck connecting a bulbous
protrusion to the main dendrite. This ensures that changes occurring inside the spine are less
likely to affect the neighboring spines.
The dendrites then connect onto the soma. The soma houses the nucleus, which acts as the
regulator for the neuron. The soma surface is populated with voltage activated ion channels.
These channels help transmit the signals generated by the dendrites.
Emerging out from the soma is the axon hillock. This region is characterized by having an
incredibly high concentration of voltage activated sodium channels. In general, it is considered to
be the spike initiation zone for action potentials. Multiple signals generated at the spines, and
transmitted by the soma all converge here.
Immediately after the axon hillock is the axon. This is a thin tubular protrusion traveling away
from the soma. The axon is insulated by a myelin sheath. Myelin is composed of Schwann cells
that wrap themselves multiple times around the axonal segment. It forms a thick fatty layer that
prevents ions from entering or escaping the axon. This insulation both prevents significant signal
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decay as well as ensuring faster signal speed. This insulation, however, has the restriction that no
channels can be present on the surface of the axon. There are, therefore, regularly spaced patches
of membrane, which have no insulation. These Nodes of Ranvier can be considered to be 'mini
axon hillocks' as their purpose is to boost the signal in order to prevent significant signal decay.
At the furthest end, the axon loses its insulation and begins to branch into several axon terminals.
These axon terminals then end in the form the second class of synapses, axon terminal buttons.
These buttons have voltage-activated calcium channels, which come into play when signaling
other neurons.
Mechanism
Because the cytoplasm of the axon is electrically conductive, and because the myelin inhibits
charge leakage through the membrane, depolarization at one Node of Ranvier is sufficient to
elevate the voltage at a neighboring node. Thus, the voltage at the first Node of Ranvier extends
spatially to the next node of Ranvier. At each successive node, the membrane potential of the
axon is thereby brought to the threshold potential to initiate an action potential. Ions need only to
cross the axon membrane to propagate the action potential at the nodes, but not anywhere under
the myelin along the axon. Thus in myelinated axons, action potentials do not propagate
continuously as waves, but instead recur at successive nodes, and in effect "hop" along the axon,
by which process they travel faster than they would otherwise. (The action potential only moves
in one direction, because the sodium channels at the previous Node of Ranvier are inactivated,
and cannot regenerate another action potential, even when depolarized.) In summary, the charge
will passively depolarize the adjacent Node of Ranvier to threshold, triggering an action potential
in this region and subsequently depolarizing the next node, and so on.
Energy efficiency
Apart from increasing the speed of the nerve impulse, the myelin sheath helps reduce energy
expenditure and hence the amount of sodium/potassium ions that need to be pumped to bring the
concentration back to normal, is decreased.
When an action potential arrives at the end of the pre-synaptic axon, it causes the release of
neurotransmitters that open ion channels in the post-synaptic neuron. The combined excitatory
and inhibitory postsynaptic potentials of such inputs can begin a new action potential in the postsynaptic neuron.
Dynamics
Action potentials are most commonly initiated by excitatory postsynaptic potentials from a
presynaptic neuron. Typically, neurotransmitters are released by the presynaptic neuron. These
neurotransmitters then bind to receptors on the postsynaptic cell. This binding opens various
types of ion channels. This opening has the further effect of changing the local permeability of
the cell membrane and thus the membrane potential. If the binding increases the voltage
(depolarizes the membrane), the synapse is excitatory. If, however, the binding decreases the
voltage (hyperpolarizes the membrane), it is inhibitory. Whether the voltage is decreased or
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increased, the change propagates passively to nearby regions of the. Typically, the voltage
stimulus decays exponentially with the distance from the synapse and with time from the binding
of the neurotransmitter. Some fraction of an excitatory voltage may reach the axon hillock and
may (in rare cases) depolarize the membrane enough to provoke a new action potential. More
typically, the excitatory potentials from several synapses must work together at nearly the same
time to provoke a new action potential.
"All-or-None" Principle
The amplitude of an action potential is independent of the amount of current that produced it. In
other words, larger currents do not create larger action potentials. Therefore action potentials are
said to be all-or-none, since they either occur fully or they do not occur at all. Instead, the
frequency of action potentials is what encodes for the intensity of a stimulus. This is in contrast
to receptor potentials, whose amplitudes are dependent on the intensity of a stimulus.
Propagation
In saltatory conduction, an action potential at one Node of Ranvier causes inwards currents that
depolarize the membrane at the next node, provoking a new action potential there; the action
potential appears to "hop" from node to node.
Myelin and Saltatory conduction
In order to enable fast and efficient transduction of electrical signals in the nervous system,
certain neuronal axons are covered with myelin sheaths. Myelin is a membrane that wraps the
axon in segments separated by intervals known as nodes of Ranvier, is produced by specialized
cells, Schwann cells exclusively in the peripheral nervous system, and by oligodendrocytes
exclusively in the central nervous system. Myelin sheath reduces membrane capacitance and
increases membrane resistance in the inter-node intervals, allowing a fast, saltatory movement of
action potentials from node to node.
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Myelin prevents ions from entering or leaving the axon along myelinated segments. As a general
rule, myelination increases the conduction velocity of action potentials and makes them more
energy-efficient. The mean conduction velocity of an action potential ranges from 1 m/s to over
100 m/s, and, in general, increases with axonal diameter.
Action potentials cannot propagate through the membrane in myelinated segments of the axon.
However, the current is carried by the cytoplasm, which is sufficient to depolarize the first or
second subsequent Node of Ranvier. Instead, the ionic current from an action potential at one
Node of Ranvier provokes another action potential at the next node; this "hopping" of the action
potential from node to node is known as saltatory conduction. By contrast, in unmyelinated
axons, the action potential provokes another in the membrane immediately adjacent, and moves
continuously down the axon like a wave.
Myelin has two important advantages: fast conduction speed and energy efficiency. For axons
larger than a minimum diameter (roughly 1 micrometre), myelination increases the conduction
velocity of an action potential, typically tenfold. Conversely, for a given conduction velocity,
myelinated fibers are smaller than their unmyelinated counterparts. The ionic currents are
confined to the nodes of Ranvier, far fewer ions "leak" across the membrane, saving metabolic
energy. This saving is a significant selective advantage, since the human nervous system uses
approximately 20% of the body's metabolic energy.
The length of axons' myelinated segments is important to the success of saltatory conduction.
They should be as long as possible to maximize the speed of conduction, but not so long that the
arriving signal is too weak to provoke an action potential at the next node of Ranvier. In nature,
myelinated segments are generally long enough for the passively propagated signal to travel for
at least two nodes while retaining enough amplitude to fire an action potential at the second or
third node. Thus, the safety factor of saltatory conduction is high, allowing transmission to
bypass nodes in case of injury. However, action potentials may end prematurely in certain places
where the safety factor is low, even in unmyelinated neurons; a common example is the branch
point of an axon, where it divides into two axons.
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Some diseases degrade myelin and impair saltatory conduction, reducing the conduction velocity
of action potentials. The most well known demyelinating disease is multiple sclerosis, in which
the breakdown of myelin impairs coordinated movement.
Chemical synapses
In general, action potentials that reach the synaptic knobs cause a neurotransmitter to be released
into the synaptic cleft. Neurotransmitters are small molecules that may open ion channels in the
postsynaptic cell; most axons have the same neurotransmitter at all of their termini. The arrival
of the action potential opens voltage-sensitive calcium channels in the presynaptic membrane;
the influx of calcium causes vesicles filled with neurotransmitter to migrate to the cell's surface
and release their contents into the synaptic cleft. This complex process is inhibited by the
neurotoxins tetanospasmin and botulinum toxin, which are responsible for tetanus and botulism,
respectively.
Neuromuscular junctions
A special case of a chemical synapse is the neuromuscular junction, in which the axon of a motor
neuron terminates on a muscle fiber. In such cases, the released neurotransmitter is acetylcholine,
which binds to the acetylcholine receptor, an integral membrane protein in the membrane (the
sarcolemma) of the muscle fiber. However, the acetylcholine does not remain bound; rather, it
dissociates and is hydrolyzed by the enzyme, acetylcholinesterase, located in the synapse. This
enzyme quickly reduces the stimulus to the muscle, which allows the degree and timing of
muscular contraction to be regulated delicately. Some poisons inactivate acetylcholinesterase to
prevent this control, such as the nerve agents sarin and tabun, and the insecticides diazinon and
malathion.
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NEUROTRANSMITTERS
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell
across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the
membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where
they bind to receptors in the membrane on the postsynaptic side of the synapse. Release of
neurotransmitters usually follows arrival of an action potential at the synapse, but may also
follow graded electrical potentials. Low level "baseline" release also occurs without electrical
stimulation. Neurotransmitters are synthesized from plentiful and simple precursors, such as
amino acids, which are readily available from the diet and which require only a small number of
biosynthetic steps to convert.
Types of neurotransmitters
There are many different ways to classify neurotransmitters. Dividing them into amino acids,
peptides, and monoamines is sufficient for some classification purposes.
Major neurotransmitters:
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Amino acids: glutamate, aspartate, D-serine, γ-aminobutyric acid (GABA), glycine
Monoamines and other biogenic amines: dopamine (DA), norepinephrine (noradrenaline;
NE, NA), epinephrine (adrenaline), histamine, serotonin (SE, 5-HT)
Others: acetylcholine (ACh), adenosine, anandamide, nitric oxide, etc.
In addition, over 50 neuroactive peptides have been found, and new ones are discovered
regularly. Many of these are "co-released" along with a small-molecule transmitter, but in some
cases a peptide is the primary transmitter at a synapse. β-endorphin is a relatively well known
example of a peptide neurotransmitter; it engages in highly specific interactions with opioid
receptors in the central nervous system.
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By far the most prevalent transmitter is glutamate, which is excitatory at well over 90% of the
synapses in the human brain. The next most prevalent is GABA, which is inhibitory at more than
90% of the synapses that do not use glutamate. Even though other transmitters are used in far
fewer synapses, they may be very important functionally—the great majority of psychoactive
drugs exert their effects by altering the actions of some neurotransmitter systems, often acting
through transmitters other than glutamate or GABA.
Addictive drugs such as cocaine and amphetamine exert their effects primarily on the dopamine
system. The addictive opiate drugs exert their effects primarily as functional analogs of opioid
peptides, which, in turn, regulate dopamine levels.
Actions
As explained above, the only direct action of a neurotransmitter is to activate a receptor.
Therefore, the effects of a neurotransmitter system depend on the connections of the neurons that
use the transmitter, and the chemical properties of the receptors that the transmitter binds to.
Here are a few examples of important neurotransmitter actions:
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Glutamate is used at the great majority of fast excitatory synapses in the brain and spinal
cord. It is also used at most synapses that are "modifiable", i.e. capable of increasing or
decreasing in strength. Modifiable synapses are thought to be the main memory-storage
elements in the brain. Excessive glutamate release can lead to excitotoxicity causing cell
death.
GABA is used at the great majority of fast inhibitory synapses in virtually every part of the
brain. Many sedative/tranquilizing drugs act by enhancing the effects of GABA.
Correspondingly glycine is the inhibitory transmitter in the spinal cord.
Acetylcholine is distinguished as the transmitter at the neuromuscular junction connecting
motor nerves to muscles. The paralytic arrow-poison curare acts by blocking transmission at
these synapses.
Dopamine has a number of important functions in the brain. It plays a critical role in the
reward system, but dysfunction of the dopamine system is also implicated in Parkinson's
disease and schizophrenia.
Serotonin is produced by and found in the intestine (approximately 90%), and the remainder
in central nervous system neurons. It functions to regulate appetite, sleep, memory and
learning, temperature, mood, behavior, muscle contraction, and function of the
cardiovascular system and endocrine system. It is speculated to have a role in depression, as
some depressed patients are seen to have lower concentrations of metabolites of serotonin in
their cerebrospinal fluid and brain tissue.
Substance P is responsible for transmission of pain from certain sensory neurons to the
central nervous system.
Neurons expressing certain types of neurotransmitters sometimes form distinct systems, where
activation of the system affects large volumes of the brain, called volume transmission. Major
neurotransmitter systems include the noradrenaline (norepinephrine) system, the dopamine
system, the serotonin system and the cholinergic system.
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A brief comparison of the major neurotransmitter systems follows:
NEUROTRANSMITTER SYSTEMS
System
Effects
Noradrenaline System Arousal
Reward
Motor System
Reward
Dopamine System
Cognition
Endocrine
Nausea
Introversion
Mood
Serotonin System
Satiety
Body Temperatuer
Sleep
Decreased Nocicption
Cholinergic System
Lerning
Short Term Memory
Arousal
Reward
Drugs targeting the neurotransmitter of such systems affect the whole system; this fact explains
the complexity of action of some drugs. Cocaine, for example, blocks the reuptake of dopamine
back into the presynaptic neuron, leaving the neurotransmitter molecules in the synaptic gap
longer. Since the dopamine remains in the synapse longer, the neurotransmitter continues to bind
to the receptors on the postsynaptic neuron, eliciting a pleasurable emotional response.
Physical addiction to cocaine may result from prolonged exposure to excess dopamine in the
synapses, which leads to the down regulation of some postsynaptic receptors. After the effects of
the drug wear off, one might feel depressed because of the decreased probability of the
neurotransmitter binding to a receptor.
Prozac blocks re-uptake of serotonin by the presynaptic cell. This increases the amount of
serotonin present at the synapse and allows it to remain there longer, hence potentiating the
effect of naturally released serotonin.
Diseases may affect specific neurotransmitter systems. For example, Parkinson's disease is at
least in part related to failure of dopaminergic cells in deep-brain nuclei, for example the
substantia nigra. Treatments potentiating the effect of dopamine precursors have been proposed
and effected, with moderate success.
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Understanding the Transmission of Nerve Impulses
Nerve impulses have a domino effect. Each neuron receives an impulse and must pass it on to the
next neuron and make sure the correct impulse continues on its path. Through a chain of
chemical events, the dendrites (part of a neuron) pick up an impulse that's shuttled through the
axon and transmitted to the next neuron. The entire impulse passes through a neuron in about
seven milliseconds — faster than a lightning strike. Here's what happens in just five easy steps:
Polarization of the neuron's membrane: Sodium is on the outside, and potassium is on the
inside.
Cell membranes surround neurons just as any other cell in the body has a membrane. When a
neuron is not stimulated — it's just sitting with no impulse to carry or transmit — its
membrane is polarized. Not paralyzed. Polarized. Being polarized means that the electrical
charge on the outside of the membrane is positive while the electrical charge on the inside of
the membrane is negative. The outside of the cell contains excess sodium ions (Na+); the
inside of the cell contains excess potassium ions (K+). (Ions are atoms of an element with a
positive or negative charge.)
You're probably wondering: How can the charge inside the cell be negative if the cell
contains positive ions? Good question. The answer is that in addition to the K+, negatively
charged protein and nucleic acid molecules also inhabit the cell; therefore, the inside is
negative as compared to the outside.
Then, if cell membranes allow ions to cross, how does the Na+ stay outside and the K+ stay
inside? If this thought crossed your mind, you deserve a huge gold star! The answer is that
the Na+ and K+ do, in fact, move back and forth across the membrane. However, Mother
Nature thought of everything. There are Na+/K+ pumps on the membrane that pump the Na+
back outside and the K+ back inside. The charge of an ion inhibits membrane permeability
(that is, makes it difficult for other things to cross the membrane).
1. Resting potential gives the neuron a break.
When the neuron is inactive and polarized, it's said to be at its resting potential. It remains
this way until a stimulus comes along.
2. Depolarization - Action potential: Sodium ions move inside the membrane.
When a stimulus reaches a resting neuron, the gated ion channels on the resting neuron's
membrane open suddenly and allow the Na+ that was on the outside of the membrane to go
rushing into the cell. As this happens, the neuron goes from being polarized to being
depolarized.
Remember that when the neuron was polarized, the outside of the membrane was positive,
and the inside of the membrane was negative. Well, after more positive ions go charging
inside the membrane, the inside becomes positive, as well; polarization is removed and the
threshold is reached.
Each neuron has a threshold level — the point at which there's no holding back. After the
stimulus goes above the threshold level, more gated ion channels open and allow more Na+
inside the cell. This causes complete depolarization of the neuron and an action potential is
created. In this state, the neuron continues to open Na+ channels all along the membrane.
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When this occurs, it's an all-or-none phenomenon. "All-or-none" means that if a stimulus
doesn't exceed the threshold level and cause all the gates to open, no action potential results;
however, after the threshold is crossed, there's no turning back: Complete depolarization
occurs and the stimulus will be transmitted.
When an impulse travels down an axon covered by a myelin sheath, the impulse must move
between the uninsulated gaps called nodes of Ranvier that exist between each Schwann cell.
3. Repolarization: K+ ions move outside, and Na++ ions stay inside the membrane.
After the inside of the cell becomes flooded with Na+, the gated ion channels on the inside
of the membrane open to allow the K+ to move to the outside of the membrane. With K+
moving to the outside, the membrane's repolarization restores electrical balance, although it's
opposite of the initial polarized membrane that had Na+ on the outside and K+ on the inside.
Just after the K+ gates open, the Na+ gates close; otherwise, the membrane couldn't
repolarize.
4. Hyperpolarization: More K+ ions are on the outside than Na++ ions on the inside.
When the K+ gates finally close, the neuron has slightly more K+ on the outside than it has
Na+ on the inside. This causes the membrane potential to drop slightly lower than the resting
potential, and the membrane is said to be hyperpolarized because it has a greater potential.
(Because the membrane's potential is lower, it has more room to "grow."). This period
doesn't last long, though (well, none of these steps take long!). After the impulse has traveled
through the neuron, the action potential is over, and the cell membrane returns to normal
(that is, the resting potential).
5. Refractory period puts everything back to normal: K+ returns inside, Na++ returns
outside.
The refractory period is when the Na+ and K+ are returned to their original sides: Na+ on the outside
and K+ on the inside. While the neuron is busy returning everything to normal, it doesn't respond to
any incoming stimuli. It's kind of like letting your answering machine pick up the phone call that
makes your phone ring just as you walk in the door with your hands full. After the Na+/K+ pumps
return the ions to their rightful side of the neuron's cell membrane, the neuron is back to its normal
polarized state and stays in the resting potential until another impulse comes along.
The following figure shows transmission of an impulse.
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Transmission of a nerve impulse: Resting potential and action potential.
Like the gaps between the Schwann cells on an insulated axon, a gap called a synapse or synaptic
cleft separates the axon of one neuron and the dendrites of the next neuron. Neurons don't touch.
The signal must traverse the synapse to continue on its path through the nervous system.
Electrical conduction carries an impulse across synapses in the brain, but in other parts of the
body, impulses are carried across synapses as the following chemical changes occur:
1. Calcium gates open.
At the end of the axon from which the impulse is coming, the membrane depolarizes, gated
ion channels open, and calcium ions (Ca2+) are allowed to enter the cell.
2. Releasing a neurotransmitter.
When the calcium ions rush in, a chemical called a neurotransmitter is released into the
synapse.
3. The neurotransmitter binds with receptors on the neuron.
The chemical that serves as the neurotransmitter moves across the synapse and binds to
proteins on the neuron membrane that's about to receive the impulse. The proteins serve as
the receptors, and different proteins serve as receptors for different neurotransmitters — that
is, neurotransmitters have specific receptors.
4. Excitation or inhibition of the membrane occurs.
Whether excitation or inhibition occurs depends on what chemical served as the
neurotransmitter and the result that it had. For example, if the neurotransmitter causes the
Na+ channels to open, the neuron membrane becomes depolarized, and the impulse is
carried through that neuron. If the K+ channels open, the neuron membrane becomes
hyperpolarized, and inhibition occurs. The impulse is stopped dead if an action potential
cannot be generated.
If you're wondering what happens to the neurotransmitter after it binds to the receptor, you're
really getting good at this anatomy and physiology stuff. Here's the story: After the
neurotransmitter produces its effect, whether it's excitation or inhibition, the receptor
releases it and the neurotransmitter goes back into the synapse. In the synapse, the cell
"recycles" the degraded neurotransmitter. The chemicals go back into the membrane so that
during the next impulse, when the synaptic vesicles bind to the membrane, the complete
neurotransmitter can again be released.
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