The Nerve

Cell body

The cell body of a neuron is also called the soma or perikaryon and may be round, stellate, pyramidal or fusiform in shape. Like any other cell it consists of a mass of cytoplasm with all its principal constituents surrounded by a cell membrane. The cell body contains a large nucleus with one or two nucleoli but there is no centrosome. The absence of centrosome indicates that the neuron has lost its ability for division. Thus, neurons once destroyed are replaced by neuroglia only. In addition to the general features of a typical cell (page 8), the cytoplasm of a neuron has following distinctive characteristics (Fig. 2.1-1):

Nissl granules/bodies. These are basophilic granules that seem to be composed of rough surfaced endoplasmic reticulum. The Nissl bodies are present in the dendrites as well but are usually absent from the axon hillock and the axon.

Neurofibrillae. These consist of microfilaments and microtubules. In certain degenerative diseases like Alzheimer's disease, the neurofilament protein gets altered, resulting in the formation of neurofibrillary tangles.

Pigment granules are seen in some neurons. For example, neuromelanin is present in the neurons of substantia nigra. Aging neurons contain a pigment lipofuscin.

Dendrites

The dendrites are multiple, small branched processes. Dendrites contain Nissl bodies and neurofibrillae.

Dendrites are the receptive processes of the neuron receiving signals from other neurons via their synapses with axon terminals.

Axon

The axon is the single long process of the nerve cell. It varies in length from a few microns to a metre. It arises from the conical extension of the cell body called axon hillock, which is devoid of the Nissl bodies. The part of the axon between the axon hillock and the beginning of myelin sheath is called the initial segment. In the axon, the cell membrane continues as axolemma and the cytoplasm as axoplasm. The axon terminates by dividing into a number of branches, each ending in a number of synaptic knobs that are also known as terminal buttons or axon telodendria. Synaptic knobs contain microvesicles in which chemical neurotransmitters are stored. Myelin sheath is present around the axon in the so-called myelinated nerve fibres (Fig. 2.1-2).

Myelin sheath which consists of protein–lipid complex is produced by glial cells called Schwann cells which encircle the axons forming around it a thin sleeve. Each Schwann cell provides the myelin sheath for a short segment of the axon. At the junction of any two such segments there is a short gap, i.e. periodic 1 μm constrictions at about 1 mm distance. These gaps are the nodes of Ranvier. There are some axons which are devoid of myelin sheath.

Myelination of axons increases the speed of conduction, but greatly increases their diameter.

Axons perform the specialized function of conducting impulses away from the cell body. They transmit propagated impulses (all-or-none transmission).

Depending upon the functions

Depending upon the functions the neurons are of two types: motor and sensory.

Depending on myelination

Depending on myelination of the axons, the neurons are of two types: myelinated and non-myelinated.

1 Macroglia

Macroglia or large glial cells are ectodermal in origin. These are of two types:

2 Microglia

Microglia or the small glial cells are mesodermal in origin. These are the smallest neuroglial cells having flattened cell body and short processes. They are more numerous in grey matter than in white matter. These act as phagocytes and become active after damage to nervous tissue by trauma or disease.

1 Anterograde transport

Anterograde transport, i.e. transport of materials away from the cell body. Some materials travel 100–400 mm a day along the axoplasm. Microtubules play an important role in this form of transport.

2 Retrograde transport

Retrograde transport, i.e. axoplasmic flow towards the cell body, may also carry tetanus toxin and neurotropic viruses (e.g. polio, herpes simplex and rabies) along the axon into the neuronal cell bodies in the CNS. It has also been employed by the neuroanatomists for charting out neural pathways.

1. Resting membrane potential is recorded as a straight baseline at −70 mV.

2. Stimulus artefact is recorded as a mild deflection of the baseline as soon as the stimulus is applied. The stimulus artefact occurs due to leakage of current from the stimulating electrode to the recording electrode.

3. Latent period is recorded as a short isoelectric period (0.5–1 ms) following the stimulus artefact. It represents the interval between the application of stimulus and the onset of action potential. It depends upon the distance between the site of stimulation, and the point of recording and the velocity of action potential along the particular axon.

4. Firing level. After the latent period, phase of depolarization starts. To begin with, depolarization proceeds relatively slow up to a level called the firing level (−55 mV), at which depolarization occurs very rapidly.

5. Overshoot. From the firing level, the curve reaches the zero potential rapidly and then overshoots the zero line up to +35 mV.

6. Spike potential. After reaching the peak (+35 mV), the phase of depolarization is completed and the phase of repolarization starts and the potential descends quickly near the firing level. The phase of rapid rise of potential in depolarization and a rapid fall in repolarization phase, combinedly constitute the so-called spike potential. Its duration is approximately 1 ms in an axon.

7. After depolarization is the slow repolarization phase which follows a rapid fall in spike potential and extends up to attainment of the RMP level. It is called phase of negative after potential and lasts for about 4 ms.

8. After hyperpolarization. After reaching the resting level (−70 mV) the potential further falls and becomes more negative (−72 mV). This phase is called after hyperpolarization or phase of positive after potential. It lasts for a prolonged period (35–40 ms). Finally, the RMP is restored.

Role of voltage-gated Na⁺ and K⁺ channels

1. Polarization phase. Resting membrane potential (−70 mV) is due to distribution of more cations outside the cell membrane and more anions inside the cell membrane. At this point though Na⁺ are more in ECF, they cannot enter the cell due to the impermeability of the membrane.

2. Depolarization phase. When threshold stimulus is applied to the cell membrane, at the point of stimulation (Fig. 2.1-7), the permeability of the membrane for Na⁺ ions increases. At first the rise of permeability for Na⁺ is slow till it reaches the firing level. When the membrane depolarizes, the Na⁺ channels start opening up. The opening of the Na⁺ channels depolarizes the membrane further, leading to the opening of greater number of Na⁺ channels. As the concentration gradient and electrical gradient of this ion are directed inwards, there occurs a rapid influx of Na⁺ ions into the cell. This rapid entry of Na⁺ is sufficient to overwhelm the repolarizing forces.

3. Repolarization phase. Repolarization occurs due to decrease in further Na⁺ influx and K⁺ efflux through the voltage-gated K⁺ channels which open later than Na⁺ channels but remain activated for prolonged period.

4. After depolarization. This is due to the fact that the rate of K⁺ efflux slows down as the electrical gradient responsible for initial rapid diffusion declines. This last phase of slow repolarization due to slow efflux of K⁺ is called after depolarization.

5. After hyperpolarization. The slow efflux of K⁺ con tinues even after the resting membrane potential is reached, resulting in a prolonged phase of hyperpolarization, during which the membrane potential falls up to −72 mV. However, little after, the voltage-gated K⁺ channels also shut down. The final ionic distribution is brought to the resting state by the action of Na⁺–K⁺ pump and the leak channels (K⁺, Cl⁻).

• Rheobase (R) refers to the minimum intensity of stimulus which if applied for adequate time (utilization time) produces a response.

• Chronaxie (C) refers to the minimum duration for which the stimulus of double the rheobase intensity must be applied to produce a response. Within limits, chronaxie of a given excitable tissue is constant. In other words, the chronaxie is an index of the excitability of a tissue and can be used to compare the excitability of various tissues. For example, a nerve fibre has far shorter chronaxie value than a muscle fibre indicating greater excitability of the former.

• When a stimulus of weaker intensity than the rheobase is applied, it will not produce a response, no matter how long the stimulus is applied.

• Stimulus of extremely short duration will not produce any response, no matter how intense that may be.

• When a stimulus of subthreshold intensity is applied to the axon then no action potential is produced (none response).

• A response in the form of spike of action potential is observed when the stimulus is of threshold intensity.

• There occurs no increase in the magnitude of action potential when the strength of stimulus is more than the threshold level (all response).

(i) Refractory period

Refractory period refers to the period following action potential (produced by a threshold stimulus) during which a nerve fibre either does not respond or responds subnormally to a stimulus of threshold intensity or greater than threshold intensity. It is of two types:

(a) Absolute refractory period (ARP). It is a short period following action potential during which second stimulus, no matter how strong it may be, cannot evoke any response (another action potential). In other words, during absolute refractory period the nerve fibre completely loses its excitability. The absolute refractory period corresponds to the period of action potential from the firing level until repolarization is almost one-third complete (spike potential). During this period neither a fresh impulse can be generated, nor can an impulse generated elsewhere pass through this area.

Ionic basis of absolute refractory period. The Na⁺ channels are closed and slow potassium channels are not yet opened. Sodium channels do not open unless potential comes back to resting level. Therefore, during this period (absolute refractory period) the nerve fibre is not stimulated at all.

(b) Relative refractory period (RRP). It is a short period during which the nerve fibre shows response, if the strength of stimulus is more than normal. It extends from the end of absolute refractory period to the start of after depolarization of the action potential.

Ionic basis of relative refractory period. During this stage the Na⁺ channels are coming out of inactivated stage and voltage-gated potassium channels are still opened. The stronger stimulus (suprathreshold) at this stage is able to open more Na⁺ channels and thus excite a response. The action potential elicited during this period, however, has a lower upstroke.

(ii) Supernormal period

During supernormal period, the membrane is hyperexcitable, i.e. the threshold of stimulus is decreased. This period corresponds with the after depolarization phase of the action potential.

(iii) Subnormal period

During this period the membrane excitability is low, i.e. the threshold of stimulus is increased. This period corresponds with the after hyperpolarization stage of the action potential.

Types of electrotonic potentials

Depending upon the nature (negative or positive) of subthreshold level current used to stimulate (Fig. 2.1-11), the electrotonic potentials are of two types:

1. Catelectrotonic potential. Catelectrotonic potentials are localized depolarizing potential changes in the membrane potential produced when the stimulus of subthreshold strength is applied with cathode. This potential change rises sharply and then decays exponentially with time.

2. Anelectrotonic potential. Anelectrotonic potentials are the localized hyperpolarizing potential changes in the membrane potential when anodal subthreshold current is applied.

Graded potentials

As shown in Fig. 2.1-11, the electrotonic potentials produced by varying intensities of stimuli are proportionate to the magnitude of stimulation. Therefore, these are also known as graded potentials. The graded response is achieved both at cathode and anode up to 7 mV of depolarization or hyperpolarization.

Differences between graded potentials and action potential are summarized in Table 2.1-1.

• In the resting phase (polarized state), the axonal membrane is outside positive and inside negative (Fig. 2.1-12A).

• When an unmyelinated axon is stimulated at one site by a threshold stimulus, there occurs action potential at that site, i.e. that site is depolarized. In other words, at that site outside becomes negative and inside positive (reversal of polarity) but the neighbouring areas until now remain in polarized state (Fig. 2.1-12C).

• As ECF and ICF are both conductive to electricity, a current will flow from positive polarized area to negative activated area through the ECF and in the reverse direction in the ICF (Fig. 2.1-12C). Thus, a local circuit current flows between the resting polarized site to the depolarized site of the membrane (current sink).

• This circular current flow depolarizes the neighbouring area of the membrane up to the firing level, and a new action potential is produced which in turn depolarizes the neighbouring area ahead. Thus, due to successive depolarization of the neighbouring area, the action potential is propagated along the entire length of the axon (Fig. 2.1-12D). This type of conduction is known as electrotonic conduction. Once initiated, the moving impulse cannot spread to reverse direction because the proximal site is in refractory state and thus the distal sites being in polarized state keep on getting depolarized. Thus, the direction of propagation of impulse is that of current flow inside the nerve fibre (Fig. 2.1-12E).

• The depolarization remains at any site for some length of time; therefore, portion which depolarizes first also repolarizes first. Thus, the repolarization is also propagated following the depolarization (Fig. 2.1-12F).

1. Temperature. A decrease in temperature delays conduction, i.e. slows down the conduction velocity.

2. Axon diameter affects the conduction velocity through the resistance offered by the axoplasm (Ri) to the flow of axoplasmic current. If the diameter of the axon is greater, the axoplasmic resistance (Ri) is lesser and hence the velocity of conduction is higher.

3. Myelination increases conduction velocity by its following effects:

1 Microelectrodes

The microelectrodes are usually very small pipette (micropipette) of tip size less than 1 μm diameter. The tip of micropipette electrode is impaled through the cell membrane of the nerve fibre. Another electrode called indifferent electrode is placed in the extracellular fluid (Fig. 2.1-14).

The microelectrode can be connected to the cathode ray oscilloscope through a suitable amplifier for recording rapid changes in membrane potential during nerve impulse transmission.

2 Electronic amplifier

This device can magnify the potential changes of the tissue to more than thousand times so that these can be recorded on the oscilloscope screen.

3 Cathode ray oscilloscope

Cathode ray oscilloscope (CRO) is almost an inertialess instrument which can record and measure the electrical events of living tissues instantaneously. The CRO primarily consists of a glass tube with a cathode, fluorescent surface (screen) and two sets of electrically charged plates (Fig. 2.1-14).

Cathode is in the form of an electronic gun. When connected to a suitable anode and electric current, the electronic gun emits electrons.

Fluorescent surface (the face of glass tube coated with fluorescent material) acts as a screen. The electrons emitted from the cathode are directed into a beam which hits this screen.

Electrically charged plates are arranged in two sets: vertical and horizontal

Monophasic recording of action potential

For monophasic recording of action potential, one microelectrode is placed inside the nerve fibre and the other electrode on the outside surface. These electrodes are then connected to the cathode ray oscilloscope (Fig. 2.1-14). When the nerve is stimulated a typical monophasic record of action potential obtained has the following components:

It has been described in detail on page 32.

Biphasic recording of action potential

For biphasic recording of action potential, both the exploring electrodes (x and y) are placed on the outside surface of nerve fibre and are connected to a CRO (Fig. 2.1-15). When nerve is stimulated, the excitation of one electrode causes deflection opposite to that of another during the passage of impulse. Record of this alternate deflection of one negative below the baseline and one positive above the baseline (called biphasic action potential) is depicted (Fig. 2.1-16).

Response of a mixed nerve to stimulus

Response of a mixed nerve to a stimulus will depend upon the thresholds of the individual axon in the nerve and their distance from the stimulating electrode (Fig. 2.1-17):

Features of a compound action potential.

1 Letter classification of Erlanger and Gasser

This is the best known classification based on the diameter and conduction velocity of the nerve fibres. The nerve fibres have been classified as follows:

‘Type A’ nerve fibres. The fastest conducting fibres are called type A fibres. Their diameter varies from 12–20 μm and conduction velocity from 70–120 m/s. They are myelinated fibres.

Type A fibres have been further subdivided into α, β, γ and δ. Type A fibres subserve both motor and sensory functions.

‘Type B’ nerve fibres. These fibres are myelinated, have a diameter of less than 3 μm and their conduction velocity varies from 4–30 m/s. They form preganglionic autonomic efferent fibres, afferent fibres from skin and viscera, and free nerve endings in connective tissue of muscle.

‘Type C’ nerve fibres. These are unmyelinated, have a diameter of 0.4–1.2 μm and their conduction velocity varies from 0.5–4 m/s. These form the postganglionic autonomic fibres, some sensory fibres carrying pain sensations, some fibres from thermoreceptors and some from viscera. The salient features of type A, B and C nerve fibres are summarized in Table 2.1-2.

2 Numerical classification

Some physiologists have classified sensory nerve fibres by a numerical system into type Ia, Ib, II, III and IV. A comparison of the numerical classification and the letter classification is shown in Table 2.1-3.

3 Susceptibility of nerve fibres to hypoxia, pressure and local anaesthetics

Hypoxia. As shown in Table 2.1-4, the type B fibres are most susceptible to hypoxia.

Pressure. Type A fibres are most susceptible to pressure and type C least.

Local anaesthetics. Type C fibres (conducting pain, touch and temperature sensations generated by cutaneous receptors) are most susceptible to local anaesthetics. This fact is useful for surgical interventions under local anaesthesia.

Axis cylinder

Axis cylinder becomes swollen and irregular in shape within a few hours of injury. After a few days it breaks up into small fragments, the neurofibrils within it break down into granular debris and are seen in the space occupied by axis cylinder.

Changes in the cell body of neuron

Changes in the cell body of injured neuron start within 48 h and continue up to 15–20 days. The changes are discussed below.

Nissl substances undergo disintegration and dissolution (chromatolysis).

Golgi apparatus, mitochondria and neurofibrils are fragmented and eventually disappear.

Cell body draws in more fluid, enlarges and becomes spherical.

Nucleus is displaced to the periphery (towards cell membrane). Sometimes the nucleus is extruded out of the cell, in which case the neuron atrophies and finally disappears completely.

Anatomical regeneration

Functional regeneration

The above described regenerative changes constitute the anatomical regeneration. The functional (physiological) recovery, however, occurs after a long period.