Is the basic unit in the nervous system it is a specialized conductor cell that receives and transmits electrochemical nerve impulses?

2.2.1.7 Axon

Each neuron has only one axon. The initial segment of the axon is cone-shaped, called the axon hillock, which contains mainly neurofibrils but no Nissl bodies. The initial segment of the axon is about 15-25 μm long and is thinner than the dendrite, with the uniform thickness. Its smooth surface has few branches and no myelin sheath surrounding it. The portion of axon far from the cell body is wrapped by a myelin sheath, and that is the myelinated nerve fiber. Fine branches at the end of axon are called as axon terminals, which can make contact with other neurons or effector cells. The membrane covering the axon is axolemma, while the plasma in the axon is axoplasm, in which there are many neurofibils paralleling the long axis of the axon and slender mitochondria, but no Nissle bodies and Glogi complex. Thus there is no protein synthesis in the axon. The metabolic turnover of the axon’s components and the synthesis of neurotransmitters in the synaptic vesicles occurs in the cell body and then flow to axon terminal through the microtubules and neurofilaments in the axon. The main role of the axon is conducting nerve impulses from the cell body to other neurons or effector cells. Impulse conduction begins at the axon’s initial segment and then continues along the axolemma. Axon terminals formed by continuous branching constitute synapses with other neurons or effector cells.

During the long evolving process, neurons morph and form their own specialized functions. The neurons associated directly with receptors and conducting information to the center are called sensory neurons or afferent neurons. The neurons associated directly with effectors and conducting impulses from the center to the effector are called motor neurons or efferent neurons. Besides these neurons, all other neurons are interneurons forming neural networks.

The total number of efferent neurons in the human nervous system is several hundreds of thousands. The number of afferent neurons is more one to three times that of efferent neurons. The number of interneurons is the greatest; the number of interneurons just in the cerebral cortex is known as 14-15 billion.

2.3.1 Neurons and cognition

The “neuron” is a specialized “cell” known as the basic unit of the “nervous system.” A typical neuron consists of a “dendrite,” a cell body known as the “soma,” “axon hillock,” “axon,” and “axon terminals,” as shown at the top of Fig. 1.6A. A “type I synapse provides an excitatory connection” between one “axon terminal” of a neuron to the “dendrite” of another neuron. The other “type II inhibitory connection of synapses” is typically located on a cell body. The cell that sends out information is called a “presynaptic neuron,” and the cell that receives information is known as a “postsynaptic neuron” [3], as shown in Fig. 2.2A. It is important to mention that there are more specialized types and subtypes of “neurons” that form an extensive “neuron taxonomy”; a good resource is the digital database that can be found on the website “NeuroMorpho.org” [12]. One practical reason is that the differences between them could explain why certain diseases only harm a certain population of “neurons” [13]. The “neuron’s function” is based on two kinds of activities: “electrical” and “chemical.”

“Electrical activity is used to transmit signals within neurons.” “Neurons” employ electrical signals to relay information from one part of the neuron to another. “Within a single neuron, information is conducted via electrical signaling.” When a “neuron” is stimulated, an electrical impulse, called the “action potential,” moves along the “neuron axon,” which is a long threadlike part of a nerve. The “action potential” enables signals to travel very rapidly along the “neuron.”

“Chemical activity is used to transmit signals between neurons through a small gap that separates neurons, known as synapse,” as shown in Fig. 2.2A. These trigger the release of “neurotransmitters” which carry the impulse across the “synapse to the next neuron.” Once a nerve impulse has triggered the release of “neurotransmitters,” these “chemical messengers” cross the tiny “synaptic gap” and are taken up by specialized receptors on the surface of the next cell, as indicated at the bottom of Fig. 2.2A. This process converts the chemical signal back into an electrical signal. If the signal is strong enough, it will be propagated down to the next neuron by an “action potential” until once again it reaches a “synapse” and the process is repeated once more.

“Synapse”s are located throughout the “brain” and “nervous system” and refer to the junction between two neurons. They behave as a sort of “relay station” where a message in the form of a chemical “neurotransmitter” is passed from one “neuron or nerve fiber” to the next, or between the “neuron and the muscle or gland” the message is aimed at. On average, each “neuron has around 1000 synapses and depending on its type can have from just one to more than 1000 synapses.”

“Neurotransmitters” are chemicals that transmit signals from a “neuron” to a “target cell” across a “synapse.” There are different types of these small molecules manufactured in different kinds of “axon terminals.” The major classes of them include “amino acids,” “peptides,” and “monoamines.” Some important “neurotransmitters” are shown in Fig. 2.2A: “acetylcholine,” “dopamine,” “serotonin,” “gamma-aminobutyric acid,” “glutamate,” “epinephrine or adrenaline and norepinephrine,” “endorphins,” and others. The specific function of each “neurotransmitter” is as follows:

“Acetylcholine (Ach)” is used by the “CNS” and “PNS” to cause muscle contraction, and many “neurons in the brain to regulate memory.” In most instances, “Ach” has an “excitatory function,” and it is one of many “neurotransmitters” in the “autonomic nervous system,” and the only “neurotransmitter” used in the motor division of the “somatic nervous system.”

“Dopamine (DA)” is produced in few areas of the brain, including the “substantia nigra” and the “ventral tegmental area,” which is a group of “neurons” located close to the midline on the floor of the “midbrain” or “mesencephalon,” as indicated in Fig. 2.2B. “DA” is also a “neurohormone” released by the “hypothalamus,” and it has important roles in “behavior and cognition, voluntary movement, motivation, punishment and reward, sleep, mood, attention, working memory, and learning.”

“Serotonin (5-HT)” is a monoamine “neurotransmitter,” usually found in the “gastrointestinal tract,” “platelets,” and the “CNS.” This chemical is also known as the “happiness hormone,” because it arouses feelings of pleasure and well-being. “Low levels of serotonin are associated with increased carbohydrate cravings, depression or other mood symptoms, sensory perceptions, sleep deprivation, and hypersensitivity to pain.”

“Gamma-aminobutyric acid (GABA)” is the major inhibitory “neurotransmitter” in the brain. It is important in producing sleep, reducing anxiety, and forming memory. “The primary role of GABA is to slow down neuron activity.”

“Glutamate (Glu)” is the most abundant excitatory neurotransmitter in the vertebrate nervous system. “Glu is also the major excitatory transmitter in the brain, and the major mediator of excitatory signals in the mammalian central nervous system. It is involved in most aspects of normal brain function, including cognition, memory, and learning.”

“Epinephrine or adrenaline (Epi) and norepinephrine (NE),” these are separate but related hormones secreted by the medulla of the “adrenal glands.” These chemicals are also produced at the ends of sympathetic nerve fibers, where “they serve as chemical mediators for conveying the nerve impulses to effector organs. They are responsible for concentration, attention, mood, and both physical and mental arousal.”

“Endorphins” are produced by the “pituitary gland” and the “hypothalamus” in vertebrates during exercise, excitement, pain, consumption of spicy food, love, and orgasm. “Endorphins contribute to the feeling of well-being and act similarly to opiates. They are also known to reduce pain and anxiety.”

“We can deduce that any malfunction of synapses affects the creation and transition of neurotransmitters’ effects, as it can affect the order sent by the brain leading to many cognitive alterations. They are reflected as multiple symptoms in neurologic disorders” [14].

Publisher Summary

Motor neurons receive thousands of synaptic inputs—either on the soma or on the dendrites—from sensory cells, interneurons, and cells higher up in the central nervous system. Stimulation of excitatory connections depolarizes the motor neuron and this is an excitatory postsynaptic potential (EPSP). Other connections hyperpolarize the cell—inhibitory postsynaptic potential (IPSP). Both IPSPs and EPSPs decay with distance and time. If the axon hillock reaches threshold, it fires an action potential back over the soma and down the axon. Multiple simultaneous EPSPs and IPSPs can add by spatial summation. Repetitive EPSPs and IPSPs add by temporal summation. An action potential in the motor neuron propagates down the axon to the neuromuscular junction. The axon terminals are filled with thousands of tiny synaptic vesicles that contain acetylcholine. Muscle force on the outside of the muscle fiber lags behind the Ca2+ transient. The lag is due to a delay in troponin C binding of Ca2+ and a delay in the transmission of the force from the cross-bridges to the exterior of the muscle. The muscle behaves as if the force generators have a spring arranged in series with them. It is found that repetitive action potentials can cause additional Ca2+ release before the muscle relaxes from the first twitch.

1.3.1 Working mechanism of brain neural network

The brain is a collection of about 10 billion interconnected neurons. Neurons are electrically excitable cells in the nervous system that process and transmit information. A neuron’s dendritic tree is connected to a thousand neighboring neurons. When one of those neurons fire, a positive or negative charge is received by one of the dendrites. The strengths of all the received charges are added together through the processes of spatial and temporal summation. The aggregate input is then passed to the soma (cell body). The soma and the enclosed nucleus do not play a significant role in the processing of incoming and outgoing data. Their primary function is to perform the continuous maintenance required to keep the neuron functional. The output strength is unaffected by the many divisions in the axon; it reaches each terminal button with the same intensity it had at the axon hillock.

Each terminal button is connected to other neurons across a small gap called a synapse. The physical and neurochemical characteristics of each synapse determine the strength and polarity of the new input signal. This is where the brain is the most flexible—and the most vulnerable. At the molecular level, neuron signal generation and transmission and neurotransmitters are the basic problems attracting research scientists to engage in brain science investigation.

One of the greatest challenges in neuroscience is to determine how synaptic plasticity and learning and memory are linked. Two broad classes of models of synaptic plasticity are phenomenological models and biophysical models. Phenomenological models are characterized by treating the process governing synaptic plasticity as a black box. The black box takes in as input a set of variables and produces as output a change in synaptic efficacy. No explicit modeling of the biochemistry and physiology leading to synaptic plasticity is implemented. Two different classes of phenomenological models, rate based and spike based, have been proposed.

Biophysical models, in contrast to phenomenological models, concentrate on modeling the biochemical and physiological processes that lead to the induction and expression of synaptic plasticity. However, since it is not possible to implement precisely every portion of the physiological and biochemical networks leading to synaptic plasticity, even biophysical models rely on many simplifications and abstractions. Different cortical regions, such as the hippocampus and visual cortex, have somewhat different forms of synaptic plasticity.

3.15.4.1.2 Action potential

Young [16] and Alan Hodgkin and Andrew Huxley [73,74] made the earliest contributions to our understanding of electrophysiological behavior of the squid giant axon. The intracellular recordings in the mammalian nervous system demonstrated that mammalian action potential mechanism is similar to that of the squid giant axon [75–77]. Hodgkin and Huxley not only successfully achieved collecting the intracellular recordings, but also qualitatively and quantitatively explained the ionic mechanisms underlying the action potential. The initiation of action potential starts when an external stimulus comes to the initial segment of an axon, for example, to the axon hillock. Action potential establishes first a rapid, transient and increased membrane permeability to the Na+ ions (depolarization) and then becomes slower and then extend to the K+ ions (repolarization). In the 1940s, Hodgkin and Huxley started doing experiments on the permeability of the squid giant axon membrane to Na+ and K+ ions during action potential to determine the rise in the amplitude (depolarization) as a function of the external Na+ ion concentrations. These experiments showed that when a nerve cell has lower external Na+ ion concentration the rise of amplitude of the action potential decreases. Action potential propagates to long distances by the movement of the ions through voltage-gated ionic channels embedded in the plasma membrane of the neurons (Fig. 10). The voltage-gated ionic channels have three conformational states, for example, open, closed, and inactivation. The external stimulus command the voltage-gated Na+ channels to open and Na+ ions flux inside while depolarizing the neuron membrane. When depolarization reaches to a predetermined threshold, action potential begins. At the open state, the voltage-dependent Na+ channels make the intracellular membrane more positive than the extracellular surface of the membrane in the rising phase of the action potential and then the membrane becomes extraordinarily permeable to the Na+ ions and keep depolarizing. Eventually, the membrane potential becomes equal to the Na+ voltage (ENa=58 mV). This short-lived peak point voltage-dependent Na+ channels have enough voltage to prevent any further channel opening. As the cytoplasm becomes more positive, voltage-gated K+ channels open and K+ ions diffuse out of the neuron toward the extracellular space. K+ efflux causes repolarization stage of the action potential. Then, Na+/K+ ATPase is activated and this enzyme energizes the Na+/K+ pump. In this refractory phase, the Na+/K+ pump binds three Na+ ions from the inner side and two K+ ions from the exterior of the neuron and transports them to their original compartments by primary transport mechanism that consumes 1 ATP molecule. At the end, the membrane potential reaches to its normal resting state (−70 mV). All these events occur in a fraction of a second. Although, a signal is generated and transmitted in an axon in the form of action potential, the arrival of a signal to its destination relies on another mechanism which involves a specialized synapse. The transmission between synapses and target organs or tissues is a nerve-to-nerve signaling and all known nerve-to-muscle or gland signaling rely on the synaptic transmissions.

Summary

Motor neurons receive thousands of synaptic inputs, either on the soma or on the dendrites, from sensory cells, interneurons, and cells higher up in the CNS. Stimulation of excitatory connections depolarizes the motor neuron; this is an EPSP. Other connections hyperpolarize the cell (IPSP). Both IPSPs and EPSPs decay with distance and time. If the axon hillock reaches threshold, it fires an action potential back over the soma and down the axon. Multiple simultaneous EPSPs and IPSPs can add by spatial summation. Repetitive EPSPs and IPSPs add by temporal summation.

An action potential in the motor neuron propagates down the axon to the neuromuscular junction. There, axon terminals are filled with thousands of tiny synaptic vesicles that contain acetylcholine (ACh). The action potential activates voltage-gated Ca2+ channels in the membrane that open briefly to let in Ca2+, which then binds to special proteins that activate fusion of the synaptic vesicles with the active zone of the nerve terminal. The acetylcholine is released into a gap between muscle and nerve, and diffuses to the muscle membrane where it binds to the AChR, causing it to increase gNa on the muscle membrane. Influx of Na+ produces an end-plate potential which is conveyed electrotonically to nearby patches of muscle membrane, where an action potential begins and propagates in both directions away from the neuromuscular junction. The ACh signal is shut off by removal of Ca2+ from the nerve terminal cytoplasm and by destruction of ACh by acetylcholinesterase.

The muscle membrane action potential propagates along the muscle membrane and penetrates deep into the muscle along transverse tubules (T-tubules). Depolarization of the T-tubule is sensed by DHPRs on the T-tubule membrane. The DHPRs are mechanically linked to RyR located on the SR membrane immediately adjacent to the SR. RyR1 is a large tetramer that forms a gated Ca2+ channel across the SR membrane. These RyRs briefly open in response to depolarization of the T-tubules that is sensed by the DHPR. The terminal cisternae contain Ca2+ free in solution and bound to calsequestrin. Opening of the RyR1 channel releases the stored Ca2+, which increases cytosolic [Ca2+].

The released Ca2+ diffuses throughout the myofibril and binds to troponin C (TnC). Ca2+ binding alters the conformation of TnC, which in turn alters the disposition of TnI, TnT, and tropomyosin. At rest, tropomyosin inhibits the interaction of actin and myosin so that cross-bridge cycling cannot occur. Ca2+ binding to TnC removes the inhibition of tropomyosin so that cross-bridge cycling occurs. The result is actomyosin ATPase activity and force development or shortening of the muscle. Reuptake of the released Ca2+ by the SR Ca pump causes relaxation of the muscle because Ca2+ dissociates from TnC by mass action. Removal of Ca2+ from TnC causes tropomyosin to move back to its inhibitory position, cross-bridge cycling stops, and the muscle relaxes.

Muscle force on the outside of the muscle fiber lags behind the Ca2+ transient. The lag is due to a delay in TnC binding of Ca2+ and a delay in the transmission of the force from the cross-bridges to the exterior of the muscle. The muscle behaves as if the force generators have a spring arranged in series with them. Force is transmitted through the spring only to the extent that the spring is stretched. This takes time, so the force transient (the twitch) is both delayed and prolonged compared to the Ca2+ transient. At least some of the spring characteristics are in the myofilaments themselves.

Repetitive action potentials can cause additional Ca2+ release before the muscle relaxes from the first twitch. The prolonged elevation of cytosolic [Ca2+] gives the myofilaments more time to completely stretch the series elastic elements to fully transmit their force to the exterior of the muscle. Force increases with increasing frequency of stimulation until tetany is reached, in which there is maximum force and no waviness in the force.

19.7 Nervous system

Nervous system coordinates and controls the activities of the animals. Together, with the endocrine system, nervous system maintains the homeostasis [12]. Besides maintaining homeostasis it also functions for our perception, behavior and memories and controls all voluntary movements.

There are two sub main division of nervous system:

Central nervous system (CNS): includes brain and the spinal cord

Peripheral nervous system (PNS): includes cranial and spinal nerves

The nerve fiber of the PNS comprises afferent fibers that transmit impulses from tissues/organs to the CNS and efferent fibers that transmit regulatory impulses from the CNS to the concerned peripheral tissues/organs. The PNS is divided as somatic neural system (transmit impulses from CNS to skeletal muscles) and autonomic neural system somatic (transmits impulses from the CNS to the involuntary organs and smooth muscles of the body). The autonomic neural system is further classified into sympathetic neural system and parasympathetic neural system [12,13].

12.7 Model of a Whole Neuron

This section brings together the entire neuron, combing the dendrite, soma, axon, and presynaptic terminal. Dendrites and axons can be modeled as a series of cylindrical compartments, each connected together with an axial resistance, as described in Section 12.5.3. Both the axon and dendrites are connected to the soma. Of course, real neurons have many different arrangements, such as the dendrite connected to the axon, which then connects to the soma. The basic neuron consists of many dendrites, one axon, and one soma. Note that the dendrite and axon do not have to have constant diameter cylinders but may narrow toward the periphery.

As described previously, Figure 12.17 illustrates a generic electrical dendrite compartment model with passive channels, and Figure 12.28 illustrates the axon compartment with active channels at the axon hillock and the node of Ranvier. To model the myelinated portion of the axon, a set of passive compartments, like the dendrite compartment, can be used with capacitance, passive ion channels, and axial resistance. Shown in Figure 12.33 is a portion of the axon with myelin sheath, with three passive channels, and an active component for the node of Ranvier. The structure in Figure 12.33 can be modified for any number of compartments as appropriate. The soma can be modeled as an active or passive compartment depending on the type of neuron.

To model the neuron in Figure 12.33, Kirchhoff's current law is applied for each compartment (i.e., each line in Eq. (12.49) is for a compartment), giving

(12.49)…+CmdVmdt+ (Vm-VTH)RTH+(Vm-V′m)Ra+Cm dV′mdt+(V′m-V TH)RTH+(V′m- V″m)Ra+CmdV″mdt+(V″m-VTH) RTH+(V″m-Vm″′)Ra+GK(Vm″′-EK)+GNa(Vm″′-ENa)+(Vm″′-El)Rl+CmdVm″′dt+…

Because neurons usually have other channels in addition to the three of the squid giant axon, a model of the neuron should have the capability of including other channels, such as a fast sodium channel, delayed potassium conductance, high threshold calcium conductance, and so forth. Additional ion channels can be added for each compartment in Eq. (12.49) by adding

∑i=1nGi(Vm−Ei)

for each compartment for channels i=1,n. The values of Cm,RTH,Ra,andGi are dependent on the size of the compartment and the type of neuron modeled.

A complete model of the neuron can be constructed by including as many dendritic branches as needed, each described using Figure 12.17 and each modeled by

(12.50)…+CmdVmdt+(Vm−VTH)RTH+(Vm−V′m)Ra+ CmdV′mdt+(V′m−VTH)RTH+(V′m −V″m)Ra+…

a soma with passive or active properties using either

(12.51)Cm dVmdt+(Vm−VTH)RTH+(Vm−V′m) Ra

or

(12.52)GK(V″′m-EK )+GNa(V″′m-ENa )+(V″′m-El)R l+CmdV″′mdt

and an axon using Eq. (12.49) as described in Rodriguez and Enderle [3]. Except for the terminal compartment, two inputs are needed for the dendrite compartment: the input defined by the previous compartment's membrane potential and the next compartment's membrane potential. Additional neurons can be added using the same basic neuron, interacting with each other using the current from the adjacent neuron (presynaptic terminal) to stimulate the next neuron.

For illustration purposes, the interaction between two adjacent neurons is modeled using SIMULINK, shown in Figure 12.34, and the results shown in Figure 12.35. Three voltage-dependent channels for Na+, K+, and Ca+2, and also a leakage channel are used for the axon. We use a myelinated axon with four passive compartments between each node of Ranvier. The total axon consists of three active compartments and two myelinated passive segments. The dendrite consists of five passive compartments, and the soma is a passive spherical compartment. The stimulus is applied at the terminal end of the dendrite of the first neuron. It is modeled as an active electrode compartment. The size of each axon compartment is the same but different than the dendrite compartment. The input to the first neuron is shown in Figure 12.36.

11.7 MODEL OF THE WHOLE NEURON

This section brings together the entire neuron, combing the dendrite, soma, axon, and presynaptic terminal. Dendrites and axons can be modeled as a series of cylindrical compartments, each connected together with an axial resistance as described in Section 11.5.3. Both the axon and dendrites are connected to the soma. Of course, real neurons have many different arrangements, such as the dendrite connected to the axon, which then connects to the soma. The basic neuron consists of many dendrites, one axon, and one soma. Note that the dendrite and axon do not have to have constant-diameter cylinders, but may narrow toward the periphery.

As described previously, Figure 11.17 illustrates a generic electrical dendrite compartment model with passive channels, and Figure 11.28 illustrates the axon compartment with active channels at the axon hillock and the node of Ranvier. To model the myelinated portion of the axon, a set of passive compartments, like the dendrite compartment, can be used with capacitance, passive ion channels, and axial resistance. Shown in Figure 11.33 is a portion of the axon with myelin sheath, with three passive channels, and an active component for the node of Ranvier. The structure in Figure 11.33 can be modified for any number of compartments as appropriate. The soma can be modeled as an active or passive compartment depending on the type of neuron.

To model the neuron in Figure 11.33, Kirchhoff's current law is applied, giving

(11.49)…+CmdVmdt+(Vm-VTH)RTH+ (Vm-V′m)Ra+ CmdV′mdt+(V′m -VTH)RTH+(V′m-V″m)Ra+CmdV″mdt+(V″m-VTH)RTH+(V′m-V′″m)Ra+GK( V″′m-EK)+GNa(V″′m-ENa)+(V′″m-El)Rl+CmdV′″m dt+…

Because neurons usually have other channels in addition to the three of the squid giant axon, a model of the neuron should have the capability of including other channels, such as a fast sodium channel, delayed potassium conductance, or high-threshold calcium conductance. Additional ion channels can be added for each compartment in Equation 11.49, by adding

∑i=1nGi(Vm- Ei)

for each compartment for channels i = 1, n. The values of Cm, RTH, Ra, and?Gi are dependent on the size of the compartment and the type of neuron modeled.

A complete model of the neuron can be constructed by including as many dendritic branches as needed, each described using Figure 11.17, each modeled by

(11.50)…+CmdVmdt+(Vm-VTH)RTH+(Vm-V′m)Ra+CmdV′mdt+(V′m-VTH )RTH+(V′m-V″m)Ra+…

a soma with passive or active properties using either

(11.51)CmdVm dt+(Vm-VTH)RTH+(Vm-V′m)Ra

or

(11.52)GK(V′″m-EK)+ GNa(V′″m-ENa)+(V′″m-El)Rl+Cm dV′″mdt

and an axon using Equation 11.49 as described in Rodriguez and Enderle (2004). Except for the terminal compartment, two inputs are needed for the dendrite compartment; the input defined by the previous compartment's membrane potential and the next compartment's membrane potential. Additional neurons can be added using the same basic neuron, interacting with each other using the current from the adjacent neuron (presynaptic terminal) to stimulate the next neuron.

For illustration purposes, the interaction between two adjacent neurons is modeled using SIMULINK, shown in Figure 11.34, and the results shown in Figure 11.35. Three voltage-dependent channels for Na+, K+, and Ca2+, and also a leakage channel are used for the axon. We use a myelinated axon with four passive compartments between each node of Ranvier. The total axon consists of three active compartments and two myelinated passive segments. The dendrite consists of five passive compartments, and the soma is a passive spherical compartment. The stimulus is applied at the terminal end of the dendrite of the first neuron. It is modeled as an active electrode compartment. The size of each axon compartment is the same but different from the dendrite compartment. The input to the first neuron is shown in Figure 11.36.

Although this chapter has focused on the neuron, it is important to note that numerous other cells have action potentials that involve signaling or triggering. Many of the principles discussed in this chapter also apply to these other cells but the action potential defining equations are different. For example, the cardiac action potential can be defined with a DiFranceso–Noble, Luo–Rudy, or other models rather than a Hodgkin–Huxley model of the neuron.

Myelinating Schwann Cells and the Myelin Sheath

At the promyelinating stage, as SCs start to wrap around the axon, the distance between two consecutive spirals (the extracellular gap) is 12–14 nm. At the myelinating stage, exclusion of the cytoplasm and compaction of the cytoplasmic surfaces results in the formation of compact myelin (Figure 2). Then the extracellular space is reduced from 12–14 to 2 nm, which is characteristic of compact myelin. Each SC is surrounded by the basal lamina it has secreted, which is approximately 20–30 nm thick and does not extend into the mesaxon. Myelination takes place during the first 2 or 3 weeks after birth in the rat. The mechanism by which SCs ensheathe the axon has been a subject of intense speculation in the past. In the PNS, the myelin spiral around a single axon may consist of up to 100 layers, a fact that has rendered the old ‘jelly-roll’ hypothesis, proposing that myelin is laid down by a simple rotation of the Schwann cell nucleus around the axon, rather improbable (Figure 5(a)). In the CNS, such a hypothesis is precluded by the mere fact that a single glial cell can invest several axons with myelin. The prevailing hypothesis today is that ensheathment of the axon occurs by active progression of the inner (axonal) lip of the myelin lamella as it forms the myelin spiral (Figure 5(b)). As this movement progresses, the SC membrane on one side of the groove (in which the axon lies) comes into contact with the cell membrane on the other side of the groove. These parts of the membrane approximate and stay together and thus are seen, as the cell membrane lamella continues to wind around the axon, as a spiral of rings each made of double lines. Between adjacent double rings there is at first a layer of cytoplasm, but as the winding continues, the cytoplasm is squeezed back into the cell body.

The wrapping of the SCs around a short segment of the axon produces the myelin sheath, a lipid-rich layer formed by a greatly extended and modified plasma membrane (Figure 2). This membrane, since it is highly enriched in nonconductive ingredients and poor in conductive water-based media (cytoplasm), serves ideally as an effective insulant for the nerve fiber. The lipid component of the myelin sheath gives nerves a vacuolated appearance in histological stains. In myelinated axons, only the axon hillock and the terminal arborizations where the axon synapses with its target cells are completely devoid of the myelin sheath. Myelin and many of its morphological specializations such as the nodes of Ranvier and the Schmidt–Lantermann incisures, can be detected readily under the light microscope; however, much of our understanding of its organization is derived from studies carried out by other techniques offering higher resolution: polarized light, X-ray diffraction, and electron microscopy.

Large quantities of specialized myelin lipids and proteins are synthesized and trafficked during myelination, and it is believed that most of them reach the growing sheath in transport vesicles via the exocytic pathway. The molecular mechanism involved in synpatic vesicle release (utilizing the SNARE complex) seems to also be involved in the process of myelin lipid trafficking.

Along the myelinated fibers of the PNS, each internode of myelin is invested by one Schwann cell and each Schwann cell surrounds one internode (Figure 1). As discussed previously, this ratio of one internode of myelin to one Schwann cell represents a fundamental distinction between the SC and the oligodendrocyte, which is able to produce internodes at a ratio of 1:30 or greater. Another distinction is that the Schwann cell body always remains in close contact with its myelin internode, whereas the oligodendrocyte is not on an internode but extends processes toward them.

Under the electron microscope, myelin is visualized as a series of alternating dark and less-dark lines (protein layers) separated by unstained zones (the lipid hydrocarbon chains). This distinctive pattern of staining results from the way the myelin sheath is generated from the cell plasma membrane. The lighter (intraperiod) line represents the closely apposed protein coats of the outer aspect of the cell membrane; the darker (major dense) line corresponds to the fused inner protein coats of the membrane, formed as the cytoplasm has been squeezed out (Figure 6). Examination of PNS myelin swollen in hypotonic solutions confirms this interpretation. Electron microscopy observation of such preparations reveals splitting at the intraperiod line, showing the continuity of its membrane junction with the extracellular space. With good perfusion fixation and tissue staining the intraperiod line is always visualized as a double line, indicating that the extracellular sides of the unit membranes are closely apposed but not fused, as was thought in the past. When studied in fixed preparations, PNS myelin has an average repeat distance of 11.9 nm (approximately 30% less than in the unfixed state), in contrast to 10.6 nm for central myelin. External to the myelin lies the greater part of the SC cytoplasm, bounded at its outer surface by the cell membrane and basal lamina of the Schwann cell (Figure 2).

The myelin sheath can be divided, by virtue of its composition and morphology, into two distinct domains – compact myelin and noncompact myelin – each containing distinct proteins. Compact myelin contains P0, the 22 kDa peripheral myelin protein PMP-22, and myelin basic protein (MBP). MBP which is positively charged is considered important in linking the two cytoplasmic surfaces, whereas P0 is crucial for stabilizing the intraperiod line by keeping a 2-nm distance between the apposing extracellular faces of two adjacent compacted myelin membranes. Noncompact myelin, found at the paranodal regions flanking the nodes of Ranvier and in periodic interruptions of the compact myelin called Schmidt–Lantermann incisures, contains myelin-associated glycoprotein (MAG), the gap junction protein connexin32 (Cx32), and E-cadherin. E-cadherin is localized to adherens junctions, whereas the localization of Cx32 coincides with the location of gap junction-like structures. Adherens junctions and gap junctions are usually found between neighboring cells and their presence in the myelin sheath is atypical, and in this case they join adjacent layers of the same cell. Specific neuron–SC interactions that play an important role in the organization and function of peripheral nerves take place in the regions of noncompact myelin.