Neurobiology 104 - 2003 Dr Geoff Meyer

The Peripheral Nervous System

The human nervous system is by far the most complex system in the body, and is formed by a network of over 100 million nerve cells (neurons) assisted by many more supporting (glial) cells. Anatomically the nervous system is divided into the central nervous system, (CNS) consisting of the brain, spinal cord and retina, and the peripheral nervous system (PNS) composed of nerve fibers and small aggregates of nerve cells called nerve ganglia.

Structurally, nerve tissue consists of two cell types: nerve cells (neurons) and several types of glial cells, which support and protect neurons.

Neurons respond to environmental changes (stimuli) by altering electric potentials that exist between the inner and outer surfaces of their membranes, generating a nerve impulse. This impulse is capable of traveling long distances, and transmitting information to other neurons, muscles and glands.

Neurons.

Neurons are responsible for the reception, transmission and processing of stimuli;

triggering certain cell activities, and release of neurotransmitters/chemical messengers.

Most neurons consist of three parts: the dendrites, which are specialized for receiving stimuli from the environment, sensory epithelial cells or other neurons; the cell body or perikaryon which represents the trophic center for the whole nerve cell and is also receptive to stimuli; and the axon which is a single process specialized for generating or conducting nerve impulses to other cells (nerve, muscle or gland cells). Axons may also receive information from other neurons; this information mainly modifies the transmission of action potentials to other neurons. The distal portion of the axon is usually branched and constitutes the terminal arborisation. Each branch of this arborisation terminates on the next cell in end bulbs (boutons) which interact with other neurons or non-nerve cells, forming structures called synapses. Synapses transmit information to the next cell in the circuit.

Neurons and their processes are extremely variable in size and shape. According to the size and shape of their processes, most neurons can be classified as either: multipolar neurons which have more than two cell processes, one process being the axon and the others dendrites; bipolar neurons, with one dendrite and one axon; and pseudounipolar neurons which have a single process extending from the perikaryon which then divides into two branches. One branch (the dendrite) extends to a peripheral nerve ending and the other (the axon) towards the central nervous system.

Most neurons of the body are multipolar. Bipolar neurons are found in the ear, retina and olfactory mucosa, while pseudounipolar neurons are found in the spinal ganglia (dorsal root ganglia).

Neurons can be classified according to their functional roles. Motor (efferent) neurons control effector organs such as muscle fibers and exocrine and endocrine glands.
Sensory (afferent) neurons are involved in the reception of sensory stimuli from the environment and from within the body. Interneurons form a communicating and integrating network between the sensory and motor neurons. Highly developed functions of the nervous system cannot be ascribed to simple neuronal circuits; rather they depend on complex interactions established by the integrated functions of many neurons. It is estimated that 99.9% of the neurons in the body are interneurons.

In the CNS, nerve cell bodies are present only in the gray matter. White matter contains neuronal processes but no neuronal cell bodies. In the PNS, cell bodies are found in ganglia.

The cell body (perikaryon) is the part of the neuron that contains the nucleus and surrounding cytoplasm. Most nerve cells have a spherical, large, euchromatic nucleus with a prominent nucleolus. The cell body contains a highly developed rER organized into aggregates of parallel cisternae, and numerous free and bound ribosomes. Under the light microscope, the rER and free ribosomes appear as basophilic granular areas called Nissl bodies/substance.

Dendrites are usually short and divide like the branches of a tree. Most neurons have numerous dendrites which considerably increase the receptive area of a cell. The arborisation of dendrites makes it possible for one neuron to receive and integrate a great number of axon terminals from other nerve cells.

Most neurons have only one axon; a very few have no axon at all. Axons may be short, or very long; the axons of the motor cells of the spinal cord that innervate the foot muscles, may have a length of up to a meter. In neurons that give rise to a myelinated axon, the unmyelinated portion of the axon between the cell body and the first myelinated segment, is called the initial segment. This is the site where various inhibitory and excitatory stimuli impinging on the neuron are summed, resulting in a decision to propagate --or not to propagate--an action potential, or nerve impulse.

The synapse is responsible for the unidirectional transmission of nerve impulses. Synapses are the sites where contact occurs between neurons and other effector cells (muscles and glands). Most synapses transmit the impulse by releasing neurotransmitters at the axon terminal. The synapse is formed by an axon terminal (presynaptic terminal) that delivers the impulse; a part of another cell (this can be the dendrite, the cell body, or the axon) where a new impulse is generated (postsynaptic terminal); and a thin intercellular space called the synaptic cleft. Most synapses are chemical synapses and transmit nerve impulses through neurotransmitters. A few synapses transmit impulses through gap junctions, and are called electrical synapses.

I. The Peripheral Nervous System (PNS)

The PNS consists of nerve cell bodies and nerve fibers, and supporting cells (Schwann cells and satellite cells) that are distributed outside of the CNS. Aggregates of nerve cell bodies are known as ganglia, bundles or fascicles of nerve fibers (axons) are known as nerves. Large peripheral nerves may contain several fascicles. Ganglia serve as relay stations to transmit nerve impulses; one nerve enters and another exits from each ganglion. The direction of the nervous impulse determines whether the ganglion will be a sensory or a motor ganglion.

Neurocrest gives rise to peripheral neurons (cranial, sensory, sympathetic, parasympathetic and enteric ganglia), Schwann cells and satellite cells.

A. Peripheral Nerves and Schwann cells

1) The cell bodies and dendrites of peripheral nerves, are located in the CNS or in peripheral ganglia. Their axons pass to the periphery and innervate body tissues including muscles and glands. These nerves establish communication between brain and spinal cord centers and the sense organs and effectors (muscles, glands etc.). They possess afferent and efferent fibers to and from the CNS. Afferent fibers carry the information obtained from the interior of the body and the environment to the CNS. Efferent fibers carry impulses from the CNS to the effector organs commanded by these centers. Nerves possessing only sensory fibers are called sensory nerves; those composed only of fibers carrying impulses to the effectors are called motor nerves. Most nerves have both sensory and motor fibers and are called mixed nerves; these nerves have both myelinated and unmyelinated axons.

Peripheral nerves are made up of bundles (fascicles) of unmyelinated, myelinated or a mixture of myelinated and unmyelinated nerve fibers. Peripheral nerves also contain Schwann cells, blood vessels and a few fibroblasts.

The cell bodies from which the peripheral nerves originate include motor neurons of the CNS, neurons of the sensory ganglia and neurons of the sympathetic, parasympathetic, and enteric divisions of the autonomic nervous system (see below). The cell bodies of motor neurons are located in distinct regions, called nuclei , of the brainstem and spinal cord. The preganglionic neurons of the sympathetic and parasympathetic divisions are located in the spinal cord and brainstem.

2) Peripheral nerve sheaths consist of 3 layers of connective tissue which surround the nerves, fascicles and fibers.

a) Epineurium is a dense irregular connective tissue layer which surrounds the entire nerve and fills the space between the nerve fascicles. The epineurium is composed of collagen and elastic fibers with fibroblasts, macrophages and mast cells. This layer also contains numerous blood vessels, small lymphatics and a few small nerves, which innervate the blood vessels.

b) Perineurium consists of connective tissue and flattened epithelial cells which surround the nerve fascicle. The epithelial cells are connected at their edges by tight junctions (zonulae occludentes) that form an effective barrier to most substances. The thickness of the perineurium is dependent on the size of the nerve fascicle, with thicker nerve fascicles having multiple epithelial cell layers. The epithelial cell layer has a basal lamina on each of its sides.

c) Endoneurium consists of a thin layer of connective tissue, consisting of reticular fibers, which surrounds the Schwann cell sheath. A basal lamina, derived from the Schwann cells, separates the endoneurium from the Schwann cells. Endoneurial reticular fibers are produced by Schwann cells. Occasional fibroblasts and capillaries are found.

3) Schwann cells surround all of the axon except the initial segment and the axon terminal. The outer surface of a Schwann cells is always associated with a basal lamina.

a) A myelinated axon refers to the situation when an individual axon is surrounded by multiple layers of a single Schwann cell. The general rule is - the larger the axon, the thicker the myelin sheath.

The structure and relationship of the axon and myelin sheath can be illustrated by describing the development of the myelin sheath. The Schwann cell first surrounds the axon (the point where the Schwann cell membranes first meet is called the mesaxon) and then begins to wrap around the axon, forming several layers. The inner or cytoplasmic sides of the Schwann cell plasma membrane fuse, resulting in a tight wrapping around the axon. This fusion is seen as dark lines (major dense lines) in electron micrographs. The cytoplasm is squeezed out from between the membranes, except in some areas called Schmidt-Lantermann clefts. The extracellular space (light lines seen in electron micrographs; intraperiod lines) lies between the fused Schwann cell membranes.

Myelin consists of a lipid-protein complex that is characterized by myelin basic protein and phospholipids. Myelin can be demonstrated by staining with osmium tetroxide, which preserves the myelin and stains it black.

Many Schwann cells are distributed along a nerve and the points at which they meet are called nodes of Ranvier. Adjacent Schwann cells interdigitate at the node. When an axon potential passes along a nerve, it jumps from node to node, significantly increasing conduction rates. This is called saltatory conduction.

b) Unmyelinated axons lie in grooves of furrows formed by the Schwann cells - however no myelin sheath is formed. These axons are generally 1 mm in diameter or smaller. Where the Schwann cell membranes meet is also called the mesaxon. As is the case for myelinated axons, several Schwann cells aligned end-to-end surround these axons along their entire length. Unmyelinated axons conduct slowly.

A single Schwann cell can envelop a number of unmyelinated axons. There are two different arrangements of unmyelinated axons and Schwann cells. The first, which is more common, consists of single axons surrounded by a Schwann cell. The second consists of bundles of axons which are surrounded by a Schwann cell.

B. Organization of the Spinal Cord

The spinal cord is obviously not a part of the PNS. However, afferent nerves which enter the spinal cord from the periphery, and efferent nerves which leave the spinal cord on their way to the periphery, make up the bulk of the nerves of PNS. Thus a short description of the spinal cord may help to elucidate the structural relationships between the CNS and the PNS.

The spinal cord is continuous with the brain and is divided into a number of segments. Each segment is connected to a pair of spinal nerves and each spinal nerve is joined to its segment of the cord by a number of roots which are grouped either as posterior (dorsal) or anterior (ventral) roots. The dorsal roots contain afferent or sensory nerves, while the ventral roots contain efferent or motor nerves.

In cross section, the spinal cord exhibits a butterfly-shaped, gray inner substance, the gray matter surrounding the central canal, and a whitish peripheral substance, the white matter. The gray matter contains neuronal cell bodies and their dendrites, as well as axons and glial cells. The white matter contains only myelinated and unmyelinated axons traveling to and from other parts of the spinal cord and the brain, and axons traveling to and from the periphery.

C. Sensory Ganglia and Sensory (afferent) Fibers

Sensory ganglia receive afferent impulses that go to the CNS. Two types of sensory ganglia exist. Some are associated with cranial nerves (cranial ganglia); others are associated with the dorsal roots of the spinal nerves and are called spinal ganglia or dorsal root ganglia. They contain the cell bodies and fibers of pseudounipolar neurons transmitting information from the periphery to the CNS. Dorsal root ganglion cells synapse with interneurons in the dorsal horn of the spinal cord and may be associated with a variety of receptors in the periphery.

The cell bodies of neurons in the dorsal root ganglia have a round appearance and vary in size. They are surrounded by smaller, cuboidal shaped glial cells known as satellite cells. These help to maintain a controlled environment around the neuronal cell body, providing electrical insulation as well as a pathway for metabolic exchange.

Sensory ganglia are surrounded by a connective tissue layer that is continuous with the epineurium of the nerve.

Sensory fibers may innervate the periphery as free nerve endings or can be encapsulated by transducer cells and connective tissue. Examples of encapsulated receptors include Meissner’s and Pacinian corpuscles which are found in the skin.

In the sensory system, both the somatic and visceral afferent components, a single neuron connects the receptor through a sensory ganglion, to the spinal cord or brain stem.

D. Autonomic Nervous System (ANS)

The autonomic nervous system regulates visceral functions, and is especially important in the control of cardiac and smooth muscles , and glands.

Traditional textbook descriptions speak of the sympathetic and parasympathetic divisions of the autonomic nervous system. The modern concept is the division of the ANS into three anatomical divisions--sympathetic, parasympathetic and enteric. Neuronal cell bodies in the parasympathetic division of the ANS are round in appearance, while neurons in the sympathetic and enteric divisions are multipolar, usually with short, stubby dendrites. Satellite cells surround these neurons.

In the ANS, a chain of two neurons connects the CNS to smooth muscle, cardiac muscle and glands. These are called the visceral efferents. One neuron is preganglionic and the next is postganglionic. The preganglionic neurons of the ANS have their cell bodies in specific locations in the CNS, either in the brainstem, or in the spinal cord. The axons of these preganglionic neurons leave the CNS and travel in peripheral nerves to synapse with the postganglionic neurons in peripheral ganglia (i.e. ganglia which lie outside of the CNS). The axons of the postganglionic neurons then travel to the effector organs, innervating them directly. (The cell bodies of motor neurons that innervate skeletal muscle (somatic efferents) are also located in the brain, brain stem or spinal cord. However, a single neuron conveys impulses from the CNS, via peripheral nerves, to the effector organ; they do not synapse in a peripheral ganglion, as do the neurons of the ANS).

1) Sympathetic division. Preganglionic cell bodies are located in the lateral horn of the thoracic and lumbar divisions of the spinal cord. Postganglionic cell bodies are located in ganglia lying close to the spinal cord (paravertebral ganglia; sympathetic chain ganglia) or in the celiac and mesenteric ganglia. These ganglia contain multipolar neurons and numerous satellite cells that surround the cell bodies. Peripheral ganglia are surrounded by connective tissue which is continuous with the epineurium. Sympathetic neurons often innervate blood vessels. Their neurotransmitters include noradrenaline and peptide transmitters.

2) Parasympathetic division. Preganglionic cell bodies are located in the brainstem and sacral division of the spinal cord. Postganglionic cell bodies are located in the viscera near their target tissue. Their neurotransmitters include acetylcholine and peptide transmitters.

The sympathetic and parasympathetic divisions of the ANS often supply the same organs. In these cases the actions of the two are usually antagonistic. An example of this is the innervation of cardiac muscle; sympathetic stimulation increases its activity, while parasympathetic stimulation inhibits its activity. However they may also work together. Thus the parasympathetic system causes erection by increasing blood flow to the penis, while the sympathetic system causes ejaculation by stimulating contraction of smooth muscles surrounding the epididymis and accesory sex organs.

3) Enteric division. This division of the ANS integrates local gastrointestinal reflexes, co-ordinates smooth muscle activity and integrates sympathetic and parasympathetic inputs. Enteric ganglia are located between the longitudinal and circular smooth muscles (submucosal plexus or Auerbach’s plexus) and in the submucosa (submucosal plexus or Meissner’s plexus) of the gastrointestinal tract. These ganglia contain multipolar neurons and astrocyte like glial cells. Enteric neurons innervate smooth muscle, the mucosa and submucosa, and the blood vessels of the digestive system. Their neurotransmitters include acetylcholine and peptide transmitters.