the excitable tissue

Physiology of Nerve & Muscle Cells

Excitable Tissue: Nerve

INTRODUCTION
د.فرح نبيل عباسLec:1,2,3,4
The human central nervous system (CNS) contains about 1011 (100 billion) neurons. It also contains 10-50 times this number of glial cells.
NERVECELLS
Morphology
Neurons in the mammalian central nervous system come in many different shapes and sizes. However, most have the same parts as the typical spinal motor neuron. This cell has five to seven processes called dendrites that extend outward from the cell body , the dendrites have small knobby projections called dendritic spines. A typical neuron also has a long fibrous axon that originates from a somewhat thickened area of the cell body, the axon hillock. The first portion of the axon is called the initial segment. The axon divides into terminal branches, each ending in a number of synaptic knobs. The knobs are also called terminal buttons. They contain granules or vesicles in which the synaptic transmitters secreted by the nerves are stored.
The axons of many neurons are myelinated, ie, they acquire a sheath of myelin, a protein-lipid complex that is wrapped around the axon. Outside the CNS, the myelin is produced by Schwann cells, glia-like cells found along the axon. Myelin forms when a Schwann cell wraps its membrane around an axon up to 100 times.
Not all mammalian neurons are myelinated; some are unmyelinated, ie, are simply surrounded by Schwann cells without the wrapping of the Schwann cell membrane around the axon that produces myelin. Most neurons in invertebrates are unmyelinated.



Motor neuron with myelinated axon.

Protein Synthesis & Axoplasmic Transport

Nerve cells are secretory cells, but they differ from other secretory cells in that the secretory zone is generally at the end of the axon, far removed from the cell body. There are few if any ribosomes in axons and nerve terminals, and all necessary proteins are synthesized in the endoplasmic reticulum and Golgi apparatus of the cell body and then transported along the axon to the synaptic knobs by the process of axoplasmic flow. Thus, the cell body maintains the functional and anatomic integrity of the axon; if the axon is cut, the part distal to the cut degenerates (wallerian degeneration). Anterograde transport occurs along microtubules.
EXCITATION & CONDUCTION
Nerve cells have a low threshold for excitation. The stimulus may be electrical, chemical, or mechanical. Two types of physicochemical disturbances are produced: non propagated potentials called, depending on their location, synaptic, generator, or electrotonic potentials; and propagated disturbances, the action potentials (or nerve impulses). These are the only electrical responses of neurons and other excitable tissues, and they are the main language of the nervous system. They are due to changes in the conduction of ions across the cell membrane that are produced by alterations in ion channels.


Resting Membrane Potential
The resting membrane potential is the potential difference that exists across the membrane of excitable cells, such as nerve and muscle, in the period between action potentials (i.e., at rest). it is conventional to refer the intracellular potential to the extracellular potential.

Action Potentials

The action potential is a phenomenon of excitable cells, such as nerve and muscle, and consists of a rapid depolarization (upstroke) followed by repolarization of the membrane potential. Action potentials are the basic mechanism for transmission of information in the nervous system and in all types of muscle.
• Depolarization is the process of making the membrane potential less negative. As noted, the usual resting membrane potential of excitable cells is oriented with the cell interior negative. Depolarization makes the interior of the cell less negative, or it may even cause the cell interior to become positive.
• Hyperpolarization is the process of making the membrane potential more negative. As with depolarization.
• Inward current is the flow of positive charge into the cell. Thus, inward currents depolarize the membrane potential. An example of an inward current is the flow of Na+ into the cell during the upstroke of the action potential.
• Outward current is the flow of positive charge out of the cell. Outward currents hyperpolarize the membrane potential. An example of an outward current is the flow of K+ out of the cell during the repolarization phase of the action potential.
• Threshold potential is the membrane potential at which occurrence of the action potential is inevitable. Because the threshold potential is less negative than the resting membrane potential, an inward current is required to depolarize the membrane potential to threshold. At threshold potential, net inward current (e.g., inward Na+ current) becomes larger than net outward current (e.g., outward K+ current), and the resulting depolarization becomes self-sustaining, giving rise to the upstroke of the action potential. If net inward current is less than net outward current, the membrane will not be depolarized to threshold, and no action potential will occur (see all-or-none response).
• Overshoot is that portion of the action potential where the membrane potential is positive (cell interior positive).
• Undershoot, or hyperpolarizing afterpotential, is that portion of the action potential, following repolarization, where the membrane potential is actually more negative than it is at rest.
• Refractory period is a period during which another normal action potential cannot be elicited in an excitable cell. Refractory periods can be absolute or relative.

CHARACTERISTICS OF ACTION POTENTIALS

• Stereotypical size and shape. Each normal action potential for a given cell type looks identical, depolarizes to the same potential, and repolarizes back to the same resting potential.
• Propagation. An action potential at one site causes depolarization at adjacent sites, bringing those adjacent sites to threshold. Propagation of action potentials from one site to the next is nondecremental.
• All-or-none response. An action potential either occurs or does not occur. If an excitable cell is depolarized to threshold in a normal manner, then the occurrence of an action potential is inevitable. On the other hand, if the membrane is not depolarized to threshold, no action potential can occur. Indeed, if the stimulus is applied during the refractory period, then either no action potential occurs, or the action potential will occur but not have the stereotypical size and shape.


IONIC BASIS OF THE ACTION POTENTIAL

The action potential is a fast depolarization (the upstroke), followed by repolarization back to the resting membrane potential , which occur in the following steps:
1. Resting membrane potential. At rest, the membrane potential is approximately -70 mV (cell interior negative). The K+ conductance or permeability is high and K+ channels are almost fully open, allowing K+ ions to diffuse out of the cell down the existing concentration gradient. This diffusion creates a K+ diffusion potential, which drives the membrane potential toward the K+ equilibrium potential. At rest, the Na+ conductance is low, and, thus, the resting membrane potential is far from the Na+ equilibrium potential.
2. Upstroke of the action potential. An inward current, usually the result of current spread from action potentials at neighboring sites, causes depolarization of the nerve cell membrane to threshold, which occurs at approximately -60 mV. This initial depolarization causes rapid opening of the activation gates of the Na+ channel, and the Na+ conductance promptly increases and becomes even higher than the K+ conductance The increase in Na+ conductance results in an inward Na+ current; the membrane potential is further depolarized toward, but does not quite reach, the Na+ equilibrium potential of +65 mV..
3. Repolarization of the action potential. The upstroke is terminated, and the membrane potential repolarizes to the resting level as a result of two events. First, the inactivation gates on the Na+ channels respond to depolarization by closing, but their response is slower than the opening of the activation gates. Thus, after a delay, the inactivation gates close the Na+ channels, terminating the upstroke. Second, depolarization opens K+ channels and increases K+ conductance to a value even higher than occurs at rest. The combined effect of closing of the Na+ channels and greater opening of the K+ channels makes the K+ conductance much higher than the Na+ conductance. Thus, an outward K+ current results, and the membrane is repolarized.
4. Hyperpolarizing after potential (undershoot). For a brief period following repolarization, the K+ conductance is higher than at rest, and the membrane potential is driven even closer to the K+ equilibrium potential (hyperpolarizing afterpotential). Eventually, the K+ conductance returns to the resting level, and the membrane potential depolarizes slightly, back to the resting membrane potential. The membrane is now ready, if stimulated, to generate another action potential.



Electrogenesis of the Action Potential
The nerve cell membrane is polarized at rest, with positive charges lined up along the outside of the membrane and negative charges along the inside. During the action potential, this polarity is abolished and for a brief period is actually reversed, Positive charges from the membrane ahead of and behind the action potential flow into the area of negativity represented by the action potential ("current sink"). By drawing off positive charges, this flow decreases the polarity of the membrane ahead of the action potential. Such electrotonic depolarization initiates a local response, and when the firing level is reached, a propagated response occurs that in turn electrotonically depolarizes the membrane in front of it.

Saltatory Conduction
Conduction in myelinated axons depends upon a similar pattern of circular current flow. However, myelin is an effective insulator, and current flow through it is negligible. Instead, depolarization in myelinated axons jumps from one node of Ranvier to the next, with the current sink at the active node serving to electrotonically depolarize to the firing level the node ahead of the action potential. This jumping of depolarization from node to node is called saltatory conduction. It is a rapid process, and myelinated axons conduct up to 50 times faster than the fastest unmyelinated fibers.

Orthodromic & Antidromic Conduction
An axon can conduct in either direction. When an action potential is initiated in the middle of it, two impulses traveling in opposite directions are set up by electrotonic depolarization on either side of the initial current sink.
In a living animal, impulses normally pass in one direction only, ie, from synaptic junctions or receptors along axons to their termination. Such conduction is called orthodromic. Conduction in the opposite direction is called antidromic. Since synapses, unlike axons, permit conduction in one direction only, any antidromic impulses that are set up fail to pass the first synapse they encounter (see Chapter 4) and die out at that point.

PROPERTIES OF MIXED NERVES
Peripheral nerves in mammals are made up of many axons bound together in a fibrous envelope called the epineurium. Potential changes recorded extracellularly from such nerves therefore represent an algebraic summation of the all-or-none action potentials of many axons. The thresholds of the individual axons in the nerve and their distance from the stimulating electrodes vary. With subthreshold stimuli, none of the axons are stimulated and no response occurs. When the stimuli are of threshold intensity, axons with low thresholds fire and a small potential change is observed. As the intensity of the stimulating current is increased, the axons with higher thresholds are also discharged. The electrical response increases proportionately until the stimulus is strong enough to excite all of the axons in the nerve. The stimulus that produces excitation of all the axons is the maximal stimulus, and application of greater, supramaximal stimuli produces no further increase in the size of the observed potential.

Compound Action Potentials
Another property of mixed nerves, as opposed to single axons, is the appearance of multiple peaks in the action potential. The multipeaked action potential is called a compound action potential. It has a unique shape because a mixed nerve is made up of families of fibers with various speeds of conduction. Therefore, when all the fibers are stimulated, the activity in fast-conducting fibers arrives at the recording electrodes sooner than the activity in slower fibers; and the farther away from the stimulating electrodes the action potential is recorded, the greater is the separation between the fast and slow fiber peaks. The number and size of the peaks vary with the types of fibers in the particular nerve being studied. If less than maximal stimuli are used, the shape of the compound action potential also depends upon the number and type of fibers stimulated.

NERVE FIBER TYPES & FUNCTION
Erlanger and Gasser divided mammalian nerve fibers into A, B, and C groups, further subdividing the A group into ?, ?, ?, and ? fibers. By comparing the neurologic deficits produced by careful dorsal root section and other nerve-cutting experiments with the histologic changes in the nerves, the functions and histologic characteristics of each of the families of axons responsible for the various peaks of the compound action potential have been established. In general, the greater the diameter of a given nerve fiber, the greater its speed of conduction. The large axons are concerned primarily with proprioceptive sensation, somatic motor function, conscious touch, and pressure, while the smaller axons subserve pain and temperature sensations and autonomic function. The dorsal root C fibers conduct some impulses generated by touch and other cutaneous receptors in addition to impulses generated by pain and temperature receptors.
Further research has shown that not all the classically described lettered components are homogeneous, and a numerical system (Ia, Ib, II, III, IV) has been used by some physiologists to classify sensory fibers. Unfortunately, this has led to confusion.
In addition to variations in speed of conduction and fiber diameter, the various classes of fibers in peripheral nerves differ in their sensitivity to hypoxia and anesthetics. This fact has clinical as well as physiologic significance. Local anesthetics depress transmission in the group C fibers before they affect the touch fibers in the A group. Conversely, pressure on a nerve can cause loss of conduction in large-diameter motor, touch, and pressure fibers while pain sensation remains relatively intact. Patterns of this type are sometimes seen in individuals who sleep with their arms under their heads for long periods, causing compression of the nerves in the arms. Because of the association of deep sleep with alcoholic intoxication, the syndrome is commonest on weekends and has acquired the interesting name Saturday night or Sunday morning paralysis.







Fiber Type

Function Fiber
Diameter
(?m) Conduction
Velocity
(m/s) Spike
Duration
(ms) Absolute
Refractory
Period (ms)
A
? Proprioception; somatic motor 12-20 70-120
? Touch, pressure 5-12 30-70 0.4-0.5 0.4-1
? Motor to muscle spindles 3-6 15-30
? Pain, cold, touch 2-5 12-30
B Preganglionic autonomic <3 3-15 1.2 1.2
C
Dorsal root Pain, temperature, some mechano-reception, reflex responses 0.4-1.2 0.5-2 2 2
Sympathetic Postganglionic sympathetics 0.3-1.3 0.7-2.3 2 2
1 A and B fibers are myelinated; C fibers are unmyelinated.

Nerve fiber types in mammalian nerve
NEUROTROPHINS
Trophic Support of Neurons
A number of proteins that are necessary for survival and growth of neurons have been isolated and studied. Some of these neurotrophins are products of the muscles or other structures that the neurons innervate, but others are produced by astrocytes. These proteins bind to receptors at the endings of a neuron. They are internalized and then transported by retrograde transport to the neuronal cell body, where they foster the production of proteins associated with neuronal development, growth, and survival. Other neurotrophins are produced in neurons and transported anterogradely to the nerve ending, where they maintain the integrity of the postsynaptic neuron.

Nerve Growth Factor
The first neurotrophin to be characterized was nerve growth factor (NGF), a protein growth factor that is necessary for the growth and maintenance of sympathetic neurons and some sensory neurons. It is present in a broad spectrum of animal species, including humans, and is found in many different tissues.

NEUROGLIA
In addition to neurons, the nervous system contains glial cells (neuroglia). Glial cells are very numerous; as noted above, there are 10-50 times as many glial cells as neurons. The Schwann cells that invest axons in peripheral nerves are classified as glia. In the CNS, there are three main types of neuroglia. Microglia consists of scavenger cells that resemble tissue macrophages. They probably come from the bone marrow and enter the nervous system from the circulating blood vessels. Oligodendrogliocytes are involved in myelin formation. Astrocytes, which are found throughout the brain, are of two subtypes. Fibrous astrocytes, which contain many intermediate filaments, are found primarily in white matter. Protoplasmic astrocytes are found in gray matter and have granular cytoplasm. Both types send processes to blood vessels, where they induce capillaries to form the tight junctions that form the blood-brain barrier. They also send processes that envelope synapses and the surface of nerve cells. They have a membrane potential that varies with the external K+ concentration but do not generate propagated potentials. They produce substances that are trophic to neurons, and they help maintain the appropriate concentration of ions and neurotransmitters by taking up K+ and the neurotransmitters glutamate and ?-aminobutyrate (GABA).