Soma

The plasma membrane of the soma is unmyelinated and contacted by inhibitory and excitatory axosomatic synapses; very occasionally, somasomatic and dendrosomatic contacts may be made. The non-synaptic surface is covered by either astrocytic or satellite oligodendrocyte processes.

The cytoplasm of a typical soma (see Fig. 2.2) is rich in rough and smooth endoplasmic reticulum and free polyribosomes, which reveals a high level of protein synthetic activity. Free polyribosomes often congregate in large groups associated with the rough endoplasmic reticulum. These aggregates of RNA-rich structures are visible by light microscopy as basophilic Nissl (chromatin) bodies or granules (Fig. 2.4). They are more obvious in large, highly active cells such as spinal motor neurones, which contain large stacks of rough endoplasmic reticulum and polyribosome aggregates. Maintenance and turnover of cytoplasmic and membranous components are necessary in all cells; the huge total volume of cytoplasm within the soma and processes of many neurones requires a considerable commitment of protein synthetic machinery. Neurones synthesize other proteins (e.g., enzyme systems) involved in the production of neurotransmitters and in the reception and transduction of incoming stimuli. Various transmembrane channel proteins and enzymes are located at the surfaces of neurones, where they are associated with ion transport. The apparatus for protein synthesis (including RNA and ribosomes) occupies the soma and dendrites but is usually absent from axons.

Fig. 2.4 Large multipolar neuronal perikarya in the magnocellular part of the feline red nucleus, showing prominent Nissl granules, bases of dendrites and axon hillocks. The nuclei are euchromatic and vesicular, with prominent nucleoli. The small nuclei scattered in the surrounding neuropil are characteristic of the various categories of neuroglial cell.

(Photograph by Kevin Fitzpatrick on behalf of GKT School of Medicine, London.)

The nucleus is characteristically large, round and euchromatic, with one or more prominent nucleoli, as is typical of all cells engaged in substantial levels of protein synthesis. The cytoplasm contains many mitochondria and moderate numbers of lysosomes. Golgi complexes are typically seen close to the nucleus, near the bases of the main dendrites and opposite the axon hillock.

The neuronal cytoskeleton is a prominent feature of its cytoplasm, and it gives shape, strength and rigidity to the dendrites and axons. Neurofilaments (the intermediate filaments of neurones) and microtubules are abundant; they occur in the soma and extend along dendrites and axons, in proportions that vary with the type of neurone and cell process. Bundles of neurofilaments constitute neurofibrils, which can be seen by light microscopy in silver stained sections. Neurofilaments are heteropolymers of proteins assembled from three polypeptide subunits: NF-L (68 kDa), NF-M (160 kDa) and NF-H (200 kDa). NF-M and NF-H have long C-terminal domains that project as side arms from the assembled neurofilament and bind to neighbouring filaments. They can be heavily phosphorylated, particularly in the highly stable neurofilaments of mature axons, and are thought to give axons their tensile strength. Some axons are almost filled by neurofilaments. Dendrites usually have more microtubules than axons.

Microtubules are important in axonal transport. Centrioles persist in mature postmitotic neurones, where they are concerned with the generation of microtubules rather than cell division. Centrioles are associated with cilia on the surfaces of developing neuroblasts. Their significance, other than at some sensory endings (e.g., the olfactory mucosa), is not known.

Pigment granules appear in certain regions (e.g., neurones of the substantia nigra contain neuromelanin), probably a waste product of catecholamine synthesis. In the locus coeruleus a similar pigment, rich in copper, gives neurones a bluish colour. Some neurones are unusually rich in certain metals, which may form a component of enzyme systems, such as zinc in the hippocampus and iron in the oculomotor nucleus. Ageing neurones, especially in spinal ganglia, accumulate granules of lipofuscin (senility pigment). They represent residual bodies, which are lysosomes packed with partially degraded lipoprotein material (corpora amylacea).

Dendrites

Dendrites are highly branched, usually short processes that project from the soma (see Fig. 2.2). The branching patterns of many dendritic arrays are probably established by random adhesive interactions between dendritic growth cones and afferent axons that occur during development. There is an overproduction of dendrites in early development, which is pruned in response to functional demand as the individual matures and information is processed through the dendritic tree. There is evidence that dendritic trees may be plastic structures throughout adult life, expanding and contracting as the traffic of synaptic activity varies through afferent axodendritic contacts. Groups of neurones with similar functions have a similar stereotypical tree structure (Fig. 2.5), suggesting that the branching patterns of dendrites are important determinants of the integration of afferent inputs that converge on the tree.

Fig. 2.5 Purkinje neurone from the cerebellum of a rat stained by the Golgi–Cox method, showing the extensive two-dimensional array of dendrites.

(Courtesy of Martin Sadler and M. Berry, Division of Anatomy and Cell Biology, GKT School of Medicine, London.)

Dendrites differ from axons in many respects. They represent the afferent rather than the efferent system of the neurone, and they receive both excitatory and inhibitory axodendritic contacts. They may also make dendrodendritic and dendrosomatic connections (see Fig. 2.8), some of which are reciprocal. Synapses occur either on small projections called dendritic spines or on the smooth dendritic surface. Dendrites contain ribosomes, smooth endoplasmic reticulum, microtubules, neurofilaments, actin filaments and Golgi complexes. The neurofilament proteins of dendrites are poorly phosphorylated. Dendrite microtubules express the microtubule-associated protein (MAP-2) almost exclusively, in comparison with axons.

Dendritic spine shapes range from simple protrusions to structures with a slender stalk and expanded distal end. Most spines are no more than 2 µm long and have one or more terminal expansions, but they can also be short and stubby, branched or bulbous. Free ribosomes and polyribosomes are concentrated at the base of the spine. Ribosomal accumulations near synaptic sites provide a mechanism for activity-dependent synaptic plasticity through the local regulation of protein synthesis.

Axons

The axon originates either from the soma or from the proximal segment of a dendrite, at a specialized region called the axon hillock (see Fig. 2.2), which is free of Nissl granules. Action potentials are initiated here. The axonal plasma membrane (axolemma) is undercoated at the hillock by a concentration of cytoskeletal molecules, including spectrin and actin fibrils, which are thought to be important in anchoring numerous voltage-sensitive channels to the membrane. The axon hillock is unmyelinated and often participates in inhibitory axo-axonal synapses. This region of the axon is unique because it contains ribosomal aggregates immediately below the postsynaptic membrane.

When present, myelin begins at the distal end of the axon hillock. Myelin thickness and internodal segment lengths are positively correlated with axon diameter. In the PNS unmyelinated axons are embedded in Schwann cell cytoplasm; in the CNS they lie free in the neuropil. Nodes of Ranvier are specialized constricted regions of myelin-free axolemma where action potentials are generated and where an axon may branch. The density of sodium channels in the axolemma is highest at the nodes of Ranvier and very low along internodal membranes. In contrast, sodium channels are spread more evenly within the axolemma of unmyelinated axons. Fast potassium channels are also present in the paranodal regions of myelinated axons. Fine processes of glial cytoplasm (astrocyte in the CNS, Schwann cell in the PNS) surround the nodal axolemma. The terminals of an axon are unmyelinated. They expand into presynaptic boutons, which may form connections with axons, dendrites, neuronal somata or, in the periphery, muscle fibres, glands and lymphoid tissue. They may themselves be contacted by other axons, forming axo-axonal presynaptic inhibitory circuits. Further details of neuronal microcircuitry are given in Kandel and Schwartz (2000).

Axons contain microtubules, neurofilaments, mitochondria, membrane vesicles, cisternae and lysosomes; they do not usually contain ribosomes or Golgi complexes, except at the axon hillock. However, ribosomes are found in the neurosecretory fibres of hypothalamo-hypophysial neurones, which contain the mRNA of neuropeptides. Organelles are differentially distributed along axons; for instance, there is a greater density of mitochondria and membrane vesicles in the axon hillock, at nodes and in presynaptic endings. Axonal microtubules are interconnected by cross-linking microtubule-associated proteins (MAPs), of which tau is the most abundant. Microtubules have an intrinsic polarity: in axons, all microtubules are uniformly oriented with their rapidly growing ends directed away from the soma and toward the axon terminal. Neurofilament proteins ranging from high to low molecular weights are highly phosphorylated in mature axons, whereas growing and regenerating axons express a calmodulin-binding membrane-associated phosphoprotein and growth-associated protein-43 (GAP-43), as well as poorly phosphorylated neurofilaments.

Axons respond differently to injury, depending on whether the damage occurs in the CNS or PNS. The glial microenvironment of a damaged central axon does not facilitate regrowth, and reconnection with original synaptic targets does not normally occur. In the PNS the glial microenvironment is capable of facilitating axonal regrowth; however, the functional outcome of clinical repair of a large mixed peripheral nerve, especially if the injury occurs some distance from the target organ or produces a long defect in the damaged nerve, is frequently unsatisfactory.

Synapses

Transmission of impulses across specialized junctions (synapses) between two neurones is largely chemical. It depends on the release of neurotransmitters from the presynaptic side; this causes a change in the electrical state of the postsynaptic neuronal membrane, resulting in either its depolarization or its hyperpolarization.

The patterns of axonal termination vary considerably. A single axon may synapse with one neurone, such as climbing fibres ending on cerebellar Purkinje neurones; more often, it synapses with many, such as cerebellar parallel fibres, which provide an extreme example of this phenomenon. In synaptic glomeruli (e.g., in the olfactory bulb) and synaptic cartridges, groups of synapses between two or more neurones form interactive units encapsulated by neuroglia (Fig. 2.6).

Fig. 2.6 Arrangement of complex synaptic units. A, Synaptic glomerulus with excitatory (+) and inhibitory (–) synapses grouped around a central dendritic terminal expansion. The directions of transmission are shown by the arrows. B, Synaptic cartridge with a group of synapses surrounding a dendritic segment. Each complex unit is enclosed within a glial capsule (green).

Electrical synapses (direct communication via gap junctions) are rare in the human CNS and are confined largely to groups of neurones with tightly coupled activity, such as the inspiratory centre in the medulla. They are not discussed further here.

Classification of Chemical Synapses

Chemical synapses have an asymmetric structural organization (Figs 2.7, 2.8), in keeping with the unidirectional nature of their transmission. Typical chemical synapses share a number of important features. They all display an area of presynaptic membrane apposed to a corresponding postsynaptic membrane; the two are separated by a narrow (20 to 30 nm) gap, the synaptic cleft. Synaptic vesicles containing neurotransmitters lie on the presynaptic side, clustered near an area of dense material on the cytoplasmic aspect of the presynaptic membrane. A corresponding region of submembrane density is present on the postsynaptic side. Together these define the active zone, the area of the synapse where neurotransmission takes place.

Fig. 2.7 Electron micrographs demonstrating various types of synapses. A, Pale cross-section of a dendrite on which two synaptic boutons end. The upper bouton contains round vesicles, and the lower bouton contains flattened vesicles of the small type. A number of pre- and postsynaptic thickenings mark the specialized zones of contact. B, Type I synapse containing both small, round, clear vesicles and large, dense-core vesicles of the neurosecretory type. C, Large terminal bouton of an optic nerve afferent fibre, making contact with a number of postsynaptic processes, in the dorsal lateral geniculate nucleus of a rat. One of the postsynaptic processes (*) also receives a synaptic contact from a bouton containing flattened vesicles (right). D, Reciprocal synapses between two neuronal processes in the olfactory bulb.

(A and C, Courtesy of A.R. Lieberman, Department of Anatomy, University College, London.)

Fig. 2.8 Structural arrangements of different types of synaptic contact. A, The gap junction (B) and the desmosome (E) have no synaptic significance. Excitatory synaptic boutons are shown (C and G), containing small, spherical, translucent vesicles. Also depicted are a bouton with dense-core, catecholamine-containing vesicles (D); an inhibitory synapse containing small flattened vesicles (F); a reciprocal synaptic structure between two dendritic profiles, inhibitory toward the dendrite (A) and excitatory in the opposite direction (H); an inhibitory synapse containing large flattened vesicles (I); two serial synapses—one (J) excitatory to the dendrite and one (K) inhibitory to J; and a neurosecretory ending (L) adjacent to a vascular channel (M), surrounded by a fenestrated endothelium. All the boutons in this diagram are of the terminal type except for G, which is a bouton de passage. B, Axosomatic and axoinitial segment synapses. FS, symmetric synapses with flattened vesicles; RA, asymmetric synapses with rounded vesicles. C, Ribbon synapse: triad at the base of a retinal rod.

Chemical synapses can be classified according to a number of different parameters, including the neuronal regions forming the synapse, their ultrastructural characteristics, the chemical nature of their neurotransmitters and their effects on the electrical state of the postsynaptic neurone. The classification described here is limited to associations between neurones. Neuromuscular junctions share many (although not all) of these parameters and are often referred to as peripheral synapses. They are described separately in Chapter 22.

Synapses can occur between almost any surface regions of the participating neurones. The most common type occurs between an axon and either a dendrite or a soma, when the axon is expanded as a small bulb or bouton (see Figs. 2.7, 2.8). This may be a terminal of an axonal branch (terminal bouton) or one of a row of bead-like endings, with the axon making contact at several points and often with more than one neurone (bouton de passage). Boutons may synapse with dendrites, including dendritic spines or the flat surface of a dendritic shaft; a soma, usually on its flat surface, but occasionally on spines; the axon hillock and the terminal boutons of other axons.

The connection is classified according to the direction of transmission, with the incoming terminal region named first. Most common are axodendritic synapses, although axosomatic connections are frequent. All other possible combinations are found, but they are less common: axoaxonic, dendroaxonic, dendrodendritic, somatodendritic and somatosomatic. Axodendritic and axosomatic synapses occur in all regions of the CNS and in autonomic ganglia, including those of the ENS. The other types appear to be restricted to regions of complex interaction between larger sensory neurones and microneurones, such as in the thalamus.

Ultrastructurally, synaptic vesicles may be internally clear or dense and of different sizes (loosely categorized as small or large) and shape (round, flat or pleomorphic, i.e., irregularly shaped). The submembranous densities may be thicker on the postsynaptic than on the presynaptic side (asymmetric synapses) or equivalent in thickness (symmetric synapses). Synaptic ribbons are found at sites of neurotransmission in the retina and inner ear. They have a distinctive morphology, in that the synaptic vesicles are grouped around a ribbon- or rod-like density oriented perpendicular to the cell membrane (see Fig. 2.8).

Synaptic boutons make obvious close contacts with postsynaptic structures, but many other terminals lack specialized contact zones. Areas of transmitter release occur in the varicosities of unmyelinated axons, where the effects are sometimes diffuse (e.g., the aminergic pathways of the basal ganglia and in autonomic fibres in the periphery). In some instances, such axons may ramify widely throughout extensive areas of the brain and affect the behaviour of very large populations of neurones (e.g., the diffuse cholinergic innervation of the cerebral cortices). Pathological degeneration of these pathways can therefore cause widespread disturbances in neural function.

Neurones express a variety of neurotransmitters, either as one class of neurotransmitter per cell or, more often, as several. Good correlations exist between some types of transmitters and specialized structural features of synapses. In general, asymmetric synapses with relatively small spherical vesicles are associated with acetylcholine (ACh), glutamate, serotonin (5-hydroxytryptamine, or 5-HT) and some amines; those with dense-core vesicles include many peptidergic synapses and other amines (e.g., noradrenaline (norepinephrine), adrenaline (epinephrine), dopamine). Symmetric synapses with flattened or pleomorphic vesicles have been shown to contain either γ-aminobutyric acid (GABA) or glycine.

The neurosecretory endings found in various parts of the brain and in neuroendocrine glands have many features in common with presynaptic boutons. They all contain peptides or glycoproteins within dense-core vesicles of characteristic size and appearance. These are often ellipsoidal or irregular in shape and relatively large; for example, oxytocin and vasopressin vesicles in the neurohypophysis may be up to 200 nm across.

Synapses may cause depolarization or hyperpolarization of the postsynaptic membrane, depending on the neurotransmitter released and the classes of receptor molecule in the postsynaptic membrane. Depolarization of the postsynaptic membrane results in excitation of the postsynaptic neurone, whereas hyperpolarization has the effect of transiently inhibiting electrical activity. Subtle variations in these responses may also occur at synapses where mixtures of neuromediators are present and their effects are integrated.

Astrocytes

Astrocytes are star-shaped glia whose processes ramify through the entire central neuropil (see Fig. 2.9). Their processes are functionally coupled at gap junctions and form an interconnected network that ensheathes all neurones, except at synapses and along the myelinated segments of axons. Astrocyte processes terminate as end-feet at the basal lamina of blood vessels and where they form the glia limitans (glial-limiting membrane) at the pial surface (Fig. 2.10). Ultrastructurally, astrocytes typically have a pale nucleus with a narrow rim of heterochromatin, although this is variable. They have pale cytoplasm containing glycogen, lysosomes, Golgi complexes and bundles of glial intermediate filaments within their processes (the last are found particularly in fibrous astrocytes, which occur predominantly in white matter). Glial intermediate filaments are formed from glial fibrillary acidic protein (GFAP); its presence can be used clinically to identify tumour cells of glial origin. A second morphological type of astrocyte, the protoplasmic astrocyte, is found mainly in grey matter. The significance of these subtypes is unclear: there are few known functional differences between fibrous and protoplasmic astrocytes.

Fig. 2.10 Astrocytes. A, Immunofluorescent technique showing astrocytes immunopositive for glial fibrillary acidic protein (GFAP) in the human cerebral cortex. B, Classic heavy-metal impregnation technique (Cajal method). C, Immunoperoxidase technique, GFAP. Note perivascular end-feet embracing the capillary (C).

(A, Preparation by Jonathan Carlisle, Division of Anatomy and Cell Biology, GKT School of Medicine, London; B and C, by permission from Young, B., Heath, J.W., 2000. Wheater’s Functional Histology. Churchill Livingstone, Edinburgh.)

Astrocytes are thought to provide a network of communication in the brain via interconnecting low-resistance gap junctional complexes. They signal to one another using intracellular calcium wave propagation, triggered by synaptically released glutamate. Functionally, this may coordinate astrocyte activities, including ion (particularly potassium) buffering, neurotransmitter uptake and metabolism (e.g., of excess glutamate, which is excitotoxic), membrane transport and the secretion of peptides, amino acids, trophic factors, etc, essential for efficient neuronal activity.

Injury to the CNS induces astrogliosis, which is seen as local increases in the number and size of cells expressing GFAP and in the extent of their meshwork of processes, forming a glial scar. It is thought that the local glial scar environment, which may include oligodendrocytes and myelin debris, inhibits the regeneration of CNS axons or fails to provide the necessary stimuli for axonal regrowth.

Pituicytes are glial cells found in the neural parts of the pituitary gland, the infundibulum and neurohypophysis. They resemble astrocytes, but their processes end mostly on endothelial cells in the neurohypophysis and tuber cinereum.

Blood–Brain Barrier

Proteins circulating in the blood enter most tissues of the body except those of the brain, spinal cord or peripheral nerves. This concept of a blood–brain barrier (and blood–nerve barrier) covers many substances, some of which are actively transported across the blood–brain barrier, whereas others are actively excluded. The blood–brain barrier is located at the capillary endothelium within the brain. It depends on the presence of tight junctions between endothelial cells and a relative lack of transcytotic vesicular transport. The tightness of the barrier depends on the close apposition of astrocytes to blood capillaries (Figs. 2.10C, 2.11).

Fig. 2.11 Relationship among the glia limitans, perivascular cells and blood vessels in the brain, in longitudinal and transverse section. A sheath of astrocytic end-feet wraps around the vessel and, in vessels larger than capillaries, its investment of pial meninges. Vascular endothelial cells are joined by tight junctions and supported by pericytes; perivascular macrophages lie outside the endothelial basal lamina.

The blood–brain barrier develops during embryonic life but may not be fully completed by birth. Moreover, there are certain areas of the adult brain in which the endothelial cells do not have tight junctions, and a free exchange of molecules occurs between blood and adjacent brain. Most of these areas are situated close to the ventricles and are known as circumventricular organs. Otherwise, unrestricted diffusion through the blood–brain barrier is possible only for substances that can cross biological membranes because of their lipophilic character. Lipophilic molecules may be actively re-exported by the brain endothelium.

Breakdown of the blood–brain barrier occurs following brain damage caused by ischaemia or infection, and this permits an influx of fluid, ions, protein and other substances into the brain. It is also associated with primary and metastatic cerebral tumours. Computed tomography (CT) and magnetic resonance imaging (MRI) scans can demonstrate such breakdown of the blood–brain barrier clinically. A similar breakdown of the blood–brain barrier may be seen post mortem in patients who were jaundiced. Normally, the brain, spinal cord and peripheral nerves remain unstained by bile, except for the choroid plexus, which is often stained a deep yellow. However, areas of recent infarction (1 to 3 days) are stained by bile pigment as a result of localized breakdown of the blood–brain barrier.

Oligodendrocytes

Oligodendrocytes myelinate CNS axons and are most commonly seen as intrafascicular cells in myelinated tracts (Figs 2.12, 2.13). They usually have round nuclei, and their cytoplasm contains numerous mitochondria, microtubules and glycogen. They display a spectrum of morphological variation, from large euchromatic nuclei and pale cytoplasm to heterochromatic nuclei and dense cytoplasm. Oligodendrocytes may enclose up to 50 axons in separate myelin sheaths: the largest calibre axons are usually ensheathed on a 1 : 1 basis. Some oligodendrocytes are not associated with axons and are either precursor cells or perineuronal (satellite) oligodendrocytes whose processes ramify around neuronal somata.

Fig. 2.12 Ensheathment of a number of axons by the processes of an oligodendrocyte. The oligodendrocyte soma is shown in the centre, and its myelin sheaths are unfolded to varying degrees to show their extensive surface area.

(Modified from Morell and Norton 1980 by Raine 1984, by permission.)

Fig. 2.13 A, Oligodendrocyte enwrapping several axons with myelin, demonstrated in a whole-mounted rat anterior medullary velum, immunolabelled with antibody to an oligodendrocyte membrane antigen. B and C, Confocal micrographs of a mature myelin-forming oligodendrocyte (B) and astrocyte (C) iontophoretically filled in the adult rat optic nerve with an immunofluorescent dye by intracellular microinjection.

(A, Courtesy of Fiona Ruge; B and C, prepared by Dr. A. Butt and Kate Colquhoun, Division of Physiology, and photographed by Sarah-Jane Smith using the pseudocolour technique, Division of Anatomy and Cell Biology, GKT School of Medicine, London.)

Within tracts, interfascicular oligodendrocytes are arranged in long rows in which single astrocytes intervene at regular intervals. Groups of oligodendrocytes myelinate the surrounding axons: their processes are radially aligned to the axis of each row. Myelinated tracts therefore consist of cables of axons, which are predominantly myelinated by a row of oligodendrocytes running down the axis of each cable.

Oligodendrocytes originate from the ventricular neuroectoderm and the subependymal layer in the fetus and continue to be generated from the subependymal plate postnatally. Stem cells migrate and seed into white and grey matter to form a pool of adult progenitor cells that may later differentiate to replenish lost oligodendrocytes and possibly remyelinate pathologically demyelinated regions.

Myelin and Myelination

Myelin is secreted by oligodendrocytes (CNS) and Schwann cells (PNS). A single oligodendrocyte may ensheathe up to 50 separate axons, depending on their calibre, whereas myelinating Schwann cells ensheathe axons on a 1 : 1 basis.

In general, myelin is laid down around axons larger than 2 µm in diameter. However, the critical minimal axon diameter for myelination is smaller and more variable in the CNS than in the PNS and is approximately 0.2 µm (compared with 1 to 2 µm in the PNS). Because there is considerable overlap between the size of the smallest myelinated axons and the largest unmyelinated axons, axonal calibre is unlikely to be the only factor in determining myelination. Additionally, the first axons to become ensheathed ultimately reach larger diameters than do later ones. There is a reasonable linear relationship between axon diameter and internodal length and myelin sheath thickness. As the sheath thickens from a few lamellae to up to 200, the axon may also grow from 1 to 15 µm in diameter. Internodal lengths increase about 10-fold during the same time.

It is not known how myelin is formed in either the PNS or the CNS. The ultrastructural appearance of myelin (Fig. 2.14) is usually explained in terms of the spiral wrapping of a flat glial process around an axon and the subsequent extrusion of cytoplasm from the sheath at all points other than incisures and paranodes. In this way, it is thought that the compacted external surfaces of the plasma membrane of the ensheathing glial cell produce the minor dense lines, and the compacted inner cytoplasmic surfaces produce the major dense lines, of the mature myelin sheath (Fig. 2.15). These correspond to the intraperiod and period lines, respectively, defined in X-ray studies of myelin. The inner and outer zones of occlusion of the spiral process are continuous with the minor dense line and are called the inner and outer mesaxons.

Fig. 2.14 Transverse section of sciatic nerve showing a myelinated axon and several non-myelinated axons (A), ensheathed by Schwann cells (S).

(Courtesy of Professor Susan Standring, GKT School of Medicine, London.)

Fig. 2.15 Stages in myelination of a peripheral axon.

There are significant differences between central and peripheral myelin, reflecting the fact that oligodendrocytes and Schwann cells express different proteins during myelinogenesis. The basic dimensions of the myelin membrane are different. CNS myelin has a period repeat thickness of 15.7 nm, whereas PNS myelin has a period to period line thickness of 18.5 nm. The major dense line space is approximately 1.7 nm in CNS myelin, compared with 2.5 nm in PNS myelin.

Myelin membrane contains protein, lipid and water, which forms at least 20% of the wet weight. It is a relatively lipid-rich membrane and contains 70% to 80% lipid. All classes of lipid have been found, and the precise lipid composition of PNS and CNS myelin is different. The major lipid species are cholesterol (the most common single molecule), phospholipids and glycosphingolipids. Minor lipid species include galactosylglycerides, phosphoinositides and gangliosides. The major glycolipids are galactocerebroside and its sulphate ester sulphatide; these lipids are not unique to myelin but are present in characteristically high concentrations. CNS and PNS myelin also contains low concentrations of acidic glycolipids, which constitute important antigens in some inflammatory demyelinating states. Gangliosides, which are glycosphingolipids characterized by the presence of sialic acid (N-acetylneuraminic acid), account for less than 1% of the lipid.

A relatively small number of protein species accounts for the majority of myelin protein. Some of these proteins are common to both PNS and CNS myelin, but others are different. Proteolipid protein and its splice variant DM20 are found only in CNS myelin, whereas myelin basic protein and myelin-associated glycoprotein (MAG) occur in both. MAG is a member of the immunoglobulin supergene family and is localized specifically in those regions of the myelin segment where compaction starts, namely, the mesaxons and inner periaxonal membranes, paranodal loops and incisures in both CNS and PNS sheaths. It is thought to have a functional role in membrane adhesion.

In the developing CNS, axonal outgrowth precedes the migration of oligodendrocyte precursors, and oligodendrocytes associate with and myelinate axons after their phase of elongation: oligodendrocyte myelin gene expression is not dependent on axon association. In marked contrast, Schwann cells in the developing PNS are associated with axons during the entire phase of outgrowth from CNS to target organ.

Myelination does not occur simultaneously in all parts of the body in late fetal and early postnatal development. White matter tracts and nerves in the periphery have their own specific temporal patterns, related to their degree of functional maturity.

Mutations of the major myelin structural proteins have now been recognized in a number of inherited human neurological diseases. As would be expected, these mutations produce defects in myelination and in the stability of nodal and paranodal architecture, consistent with the suggested functional roles of the relevant proteins in maintaining the integrity of the myelin sheath. The molecular organization of myelinated axons is described in Scherer and Arroyo (2002).

Ependyma

Ependymal cells line the ventricles and central canal of the spinal cord (Fig. 2.16). They form a single-layered epithelium that varies from squamous to columnar in form. At the ventricular surface, cells are joined by gap junctions and occasional desmosomes. Their apical surfaces have numerous microvilli and cilia, which contribute to the flow of CSF. There is considerable regional variation in the ependymal lining of the ventricles, but four major types have been described: the general ependyma that overlies grey matter, the general ependyma that overlies white matter, specialized areas of ependyma in the third and fourth ventricles and the choroidal epithelium.

Fig. 2.16 Ciliated cuboidal ependymal cells lining the central canal of the spinal cord. Similar cells line most of the ventricular system of the brain.

(By permission from Kierszenbaum, A.L., 2002. Histology and Cell Biology. Mosby, St. Louis, and courtesy of Dr. Wan-hua Amy Yu.)

The ependymal cells overlying areas of grey matter are cuboidal; each cell bears approximately 20 central apical cilia, surrounded by short microvilli. The cells are joined by gap junctions and desmosomes and do not have a basal lamina. Beneath them there may be a subependymal zone, two to three cells deep, consisting of cells that generally resemble ependymal cells. The capillaries beneath them have no fenestrations and few transcytotic vesicles, which is typical of the CNS. Where the ependyma overlies myelinated tracts of white matter, the cells are much flatter, and few are ciliated. There are gap junctions and desmosomes between cells, but their lateral margins interdigitate, unlike those overlying grey matter. No subependymal zone is present.

Specialized areas of ependymal cells are found in four areas around the margins of the third ventricle. These areas, called the circumventricular organs, consist of the lining of the median eminence of the hypothalamus, the subcommissural organ, the subfornical organ and the vascular organ of the lamina terminalis (Ch. 15). The area postrema, at the inferoposterior limit of the fourth ventricle, has a similar structure. In all these sites the ependymal cells are only rarely ciliated, and their ventricular surfaces bear many microvilli and apical blebs. They have numerous mitochondria, well-formed Golgi complexes and a rather flattened basal nucleus. They are joined laterally by tight junctions that form a barrier to the passage of materials across the ependyma and by desmosomes. Many of the cells are tanycytes (ependymal astrocytes) and have basal processes that project into the perivascular space surrounding the underlying capillaries. Significantly, these capillaries are fenestrated and therefore do not form a blood–brain barrier. It is believed that neuropeptides can pass from nervous tissue into the CSF by active transport through the ependymal cells in these specialized areas, giving them access to a wide population of neurones via the permeable ependymal lining of the rest of the ventricle.

The ependyma is highly modified where it lies adjacent to the vascular layer of the choroid plexus.

Choroid Plexus

The ependymal cells in the choroid plexus resemble those of the circumventricular organs, except that they do not have basal processes; instead, they form a cuboidal epithelium that rests on a basal lamina adjacent to the enclosed fold of pia mater and its capillaries (Figs. 2.17, 2.18). Capillaries of the choroid plexus are lined by a fenestrated endothelium. Cells have numerous long microvilli, with only a few cilia interspersed between them. They also have many mitochondria, large Golgi complexes and basal nuclei, consistent with their secretory activity: they produce most components of the CSF. They are linked by tight junctions that form a transepithelial barrier (a component of the blood–CSF barrier) and by desmosomes. Their lateral margins are highly folded.

Fig. 2.17 Choroid plexus within a ventricle. Frond-like projections of vascular stroma derived from the pial meninges are covered with a low columnar epithelium that secretes cerebrospinal fluid.

(By permission from Stevens, A., Lowe, J.S., 1996. Human Histology, 2nd ed. Mosby, London.)

Fig. 2.18 Schematic representation of the arrangement of tissues forming the choroid plexus.

(By permission from Nolte, J., 2002. The Human Brain, 5th ed. Mosby, London.)

The choroid plexus has a villous structure where the stroma is composed of pial meningeal cells, and it contains fine bundles of collagen and blood vessels. During fetal life, erythropoiesis occurs in the stroma, which is then occupied by bone marrow–like cells. In adult life, the stroma contains phagocytic cells, and these, together with the cells of the choroid plexus epithelium, phagocytose particles and proteins from the ventricular lumen.

Age-related changes occur in the choroid plexus that can be detected on imaging of the brain. Calcification of the choroid plexus can be detected by X-ray or CT scan in 0.5% of individuals in the first decade of life and in 86% in the eighth decade. There is a sharp rise in the incidence of calcification with age, from 35% of CT scans in the fifth decade to 75% in the sixth decade. The visible calcification is usually restricted to the glomus region of the choroid plexus, the vascular bulge in the choroid plexus as it curves to follow the anterior wall of the lateral ventricle into the temporal horn.

Microglia

Microglia are small dendritic cells found throughout the CNS (Fig. 2.19), including the retina. Evidence largely supports the view that they are derived from fetal monocytes or their precursors, which invade the developing nervous system. An alternative hypothesis holds that microglia share a lineage with ependymal cells and are thus neural tube derivatives. According to the monocyte theory, haematogenous cells pass through the walls of neural blood vessels and invade CNS tissue prenatally as amoeboid cells. Later they lose their motility and transform into typical microglia, bearing branched processes that ramify in non-overlapping territories within the brain. All microglial domains, defined by their dendritic fields, are equivalent in size and form a regular mosaic throughout the brain. The expression of microglia-specific antigens changes with age: many are downregulated as microglia attain the mature dendritic form.

Fig. 2.19 Micrograph showing activated microglial cells in the CNS, in a biopsy from a patient with Rasmussen’s encephalitis, visualized using MHC class II antigen immunohistochemistry.

(Courtesy of Dr. Norman Gregson, Division of Neurology, GKT School of Medicine, London.)

Microglia have elongated nuclei with peripheral heterochromatin. The scant cytoplasm is pale staining and contains granules, scattered cisternae of rough endoplasmic reticulum and Golgi complexes at both poles. Two or three primary processes stem from opposite poles of the cell body and branch repeatedly to form short terminal processes. The function of microglia in the normal brain is obscure. Like astrocytes, microglia are activated by traumatic and ischaemic injury. In many diseases, including Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, acquired immunodeficiency syndrome (AIDS), amyotrophic lateral sclerosis (motor neurone disease) and paraneoplastic encephalitis, they become phagocytic and are actively involved in synaptic stripping and clearance of neuronal debris. Some transform into amoeboid, motile cells.

Entry of Inflammatory Cells into the Brain

Although the CNS has long been considered an immunologically privileged site, lymphocyte surveillance of the brain may be a normal, low-grade activity that is enhanced in disease. Lymphocytes are able to enter the brain in response to viral infections and as part of the autoimmune response in multiple sclerosis. Activated, but not resting, lymphocytes pass through the endothelium of small venules, a process that requires the expression of recognition and adhesion molecules, which are induced following cytokine activation. They subsequently migrate into the brain parenchyma. Within the CNS, microglia and astrocytes can be induced by T-cell cytokines to act as efficient antigen-presenting cells. Lymphocytes probably drain along lymphatic pathways to regional cervical lymph nodes.

Polymorphonuclear leukocyte entry into the CNS is less common than lymphocyte entry, but it is seen in the early stages of infarction and autoimmune disease and, in particular, in pyogenic infections. These cells probably enter the nervous system following the expression of adhesion molecules on endothelium and pass through the endothelial layer. In the later stages of inflammation, monocytes may follow similar pathways.

Within the subarachnoid space, polymorphonuclear leukocytes and lymphocytes pass through the endothelium of large veins into the CSF during the inflammatory phase of meningitis.

Peripheral Nerve Fibres

The classification of peripheral nerve fibres is based on various parameters, such as conduction velocity, function and fibre diameter. Of the two classifications in common use, the first divides fibres into three major classes designated A, B and C, corresponding to peaks in the distribution of their conduction velocities. In humans, group A fibres are subdivided into α, β, δ and γ subgroups; group B fibres are preganglionic autonomic efferents, and group C fibres are unmyelinated. Fibre diameter and conduction velocity are proportional in most fibres. Group Aα fibres are the largest and conduct most rapidly, and group C fibres are the smallest and slowest.

The largest afferent axons (Aα fibres) innervate encapsulated cutaneous, joint and muscle receptors and some large alimentary enteroceptors. Aδ fibres innervate thermoreceptors and nociceptors, including those in dental pulp, skin and connective tissue. C fibres have thermoreceptive, nociceptive and interoceptive functions. The largest somatic efferent fibres (Aα) are up to 20 µm in diameter. They innervate extrafusal muscle fibres exclusively and conduct at a maximum of 120 m/s. Fibres to fast twitch muscles are larger than those to slow twitch muscles. Aβ fibres are restricted to collaterals of Aα fibres and form plaque endings on some intrafusal muscle fibres. Aγ fibres are exclusively fusimotor to plate and trail endings on intrafusal muscle fibres. C fibres are postganglionic sympathetic and parasympathetic axons. This scheme can be applied to all fibres of spinal and cranial nerves, except perhaps those of the olfactory nerve, whose fibres form a uniquely small and slow group.

A second classification, used for afferent fibres of somatic muscles, divides myelinated fibres into groups I, II and III. Group I fibres are large (12 to 22 µm) and include primary sensory fibres of muscle spindles (group Ia) and smaller fibres of Golgi tendon organs (group Ib). Group II fibres are the secondary sensory terminals of muscle spindles, with diameters of 6 to 12 µm. Group III fibres, 1 to 6 µm in diameter, have free sensory endings in the connective tissue sheaths around and within muscles and are believed to be nociceptive, relaying pressure pain in externally stimulated muscles. Paciniform (encapsulated) endings of muscle sheaths may also contribute fibres to this class. Group IV fibres are unmyelinated, with diameters of less than 1.5 µm; they include free endings in muscles and are primarily nociceptive.

Connective Tissue Sheaths

Nerve trunks, whether uni- or multifascicular, are surrounded by an epineurium. Individual fasciculi are enclosed by a multilayered perineurium, which in turn surrounds the endoneurium or intrafascicular connective tissue (see Fig. 2.20).

Schwann Cells

Schwann cells are the major glial type in the PNS. In vitro they are fusiform in appearance. Both in vitro and in vivo they ensheathe peripheral axons and myelinate those greater than 2 µm in diameter. In a mature peripheral nerve fibre, they are distributed along the axons in longitudinal chains. The precise geometry of their association depends on whether the axon is myelinated or unmyelinated. In myelinated axons the territory of a Schwann cell defines an internode.

The molecular phenotype of mature myelin-forming Schwann cells is different from that of mature non-myelinating Schwann cells. Adult myelin-forming Schwann cells are characterized by the presence of several myelin proteins, some but not all of which are shared with oligodendrocytes and central myelin. In contrast, expression of the low-affinity neurotrophin receptor (p75^NTR) and GFAP intermediate filament protein (which differs from the CNS form in its post-translational modification) characterizes adult non-myelin-forming Schwann cells.

Schwann cells arise during development from multipotent cells of the very early migrating neural crest, which also give rise to peripheral neurones. Axon-associated signals are critical in controlling the proliferation of developing Schwann cells and their precursors. Neurones may also regulate the developmentally programmed death of Schwann cell precursors, as a mechanism for matching numbers of axons and glia within each peripheral nerve bundle. Neuronal signals appear to control the production of basal laminae by Schwann cells, the induction and maintenance of myelination and, in the mature nerve, Schwann cell survival (few Schwann cells persist in chronically denervated nerves). Schwann cell signals may influence axonal calibre, and they are crucial in the repair of damaged peripheral nerves. The acute Schwann cell response to axonal injury and degeneration involves mitotic division and the elaboration of signals that promote the regrowth of axons.

Myelinated Axons

Myelinated axons (see Fig. 2.14) have a 1 : 1 relationship with their ensheathing Schwann cells. The territory of an individual Schwann cell defines an internode (Fig. 2.21): internodal length varies directly with the diameter of the fibre, from 150 to 1500 µm. The interval between two internodes is a node of Ranvier. In the PNS the myelin sheaths on either side of a node terminate in asymmetrically swollen paranodal bulbs. Schwann cell cytoplasm forms a continuous layer only in the perinuclear (mid-internodal) and paranodal regions. Between these sites, internodal Schwann cytoplasm forms a delicate network over the inner (abaxonal) surface of the myelin sheath. The outer (adaxonal) layer of Schwann cell cytoplasm is frequently discontinuous, and axons are surrounded by a narrow periaxonal space (15 to 20 nm), which, although nominally part of the extracellular space, is functionally isolated from it at the paranodes. For further details, see Scherer and Arroyo (2002).

Fig. 2.21 General plan of a myelinated nerve fibre in longitudinal section, including one complete internodal segment and two adjacent paranodal bulbs, used as a key for the more detailed microarchitecture of specific subregions. A, Transverse section through the centre of a node of Ranvier, with numerous finger-like processes of adjacent Schwann cells converging toward the nodal axolemma. Many microtubules and neurofilaments are visible within the axoplasm. B, Arrangement of the axon, myelin sheath and Schwann cell cytoplasm at the node of Ranvier and in the paranodal bulbs.

(A, Courtesy of Professor Susan Standring, GKT School of Medicine, London; B, courtesy of P.L. Williams and D.N. Landon.)

Nodes of Ranvier (see Fig. 2.21)

PNS nodes of Ranvier are typically 0.8 to 1.1 µm long. The calibre of the nodal axon is characteristically reduced relative to that of the internodal axon; this is most marked in the largest calibre axons. Nodes are filled with an amorphous gap substance and processes of Schwann cell cytoplasm and are surrounded by a continuous basal lamina elaborated by the ensheathing Schwann cells. In large-calibre axons the surfaces of the paranodal bulbs and of the underlying axon are fluted as they approach the nodes. The grooves in the external surface of the myelin sheath produced by this fluting are filled by Schwann cell cytoplasm, characterized by large numbers of mitochondria. In smaller fibres this arrangement is less obvious, although the paranodal cytoplasm usually contains mitochondria. Fine processes arise from the paranodal collar of Schwann cell cytoplasm and extend into the nodal gap substance, where they interdigitate with their counterparts from the adjacent Schwann cell. In small-calibre axons the processes contact the nodal axolemma. In large-calibre axons, where the processes are more numerous, they form regular hexagonal arrays that fill the nodal gap. Expanded terminal loops of paranodal Schwann cell cytoplasm either abut the paranodal axolemma directly or, in the case of the largest calibre myelinated axons, abut each other to form stacks with a typical ‘ear of wheat’ configuration.

Schmidt–Lanterman incisures

Schmidt–Lanterman incisures are helical decompactions of internodal myelin. The major dense line of the myelin sheath is split to enclose a continuous spiral band of granular cytoplasm that passes between the abaxonal and adaxonal layers of Schwann cell cytoplasm. The minor dense line of the incisural myelin sheath separates to create a long channel that connects the periaxonal space with the extracellular fluid in the endoneurium. The function of incisures is not known, but their structure suggests that they may participate in the transport of molecules across the myelin sheath.

Satellite Cells

Many non-neuronal cells of the nervous system have been called satellite cells. The list includes small, round extracapsular cells in peripheral ganglia, ganglionic capsular cells and Schwann cells. The term is sometimes used to describe all non-neuronal cells, both central and peripheral, that are closely associated with neuronal somata. The name is also given to precursor cells associated with striated muscle fibres. Within the nervous system, the term is most commonly reserved for the flat, epithelioid satellite cells (ganglionic glial cells, capsular cells) that surround the neuronal somata of peripheral ganglia (Fig. 2.22). The cytoplasm of capsular cells resembles that of Schwann cells, and their deep surfaces interdigitate with reciprocal infoldings in the membranes of the enclosed neurones. The capsular layer is continuous with similar cells that enclose the initial part of the dendroaxonal process in unipolar sensory neurones of the dorsal spinal roots and, subsequently, with the Schwann cells surrounding their peripheral and central processes.

Fig. 2.22 Typical field in a dorsal root ganglion. Note the characteristic juxtaposition of large ovoid neuronal somata and the fascicles of myelinated and non-myelinated axons (top). Note also the nuclei of the capsular (satellite) cells that surround each neuronal soma (Grübler stain).

(By permission from Dr. J.B. Kerr, Monash University, from Kerr, J.B., 1999. Atlas of Functional Histology. Mosby, London.)

Blood Supply of Peripheral Nerves

The blood vessels supply a nerve end in a capillary plexus that pierces the perineurium. Its branches run parallel with the fibres, connected by short transverse vessels, forming narrow, oblong meshes similar to those found in muscle. The blood supply of peripheral nerves is unusual. Endoneurial capillaries have atypically large diameters, and intercapillary distances are greater than in many other tissues. Peripheral nerves have two separate, functionally independent vascular systems: an extrinsic system (regional nutritive vessels and epineurial vessels) and an intrinsic system (longitudinally running microvessels in the endoneurium). Anastomoses between the two systems produce considerable overlap in the territories of the segmental arteries. This unique pattern of vessels, together with a high basal nerve bloodflow relative to metabolic requirements, gives peripheral nerves a high degree of resistance to ischaemia.

Sensory Ganglia

The sensory ganglia of dorsal spinal roots (see Fig. 2.22) and the ganglia of the trigeminal, facial, glossopharyngeal and vagal cranial nerves are enclosed in periganglionic connective tissue, which resembles the perineurium. Ganglionic neurones are unipolar. They have spherical or oval somata of varying sizes, which are aggregated in groups between fasciculi of myelinated and unmyelinated nerve fibres. For each neurone, the single axodendritic process bifurcates into central and peripheral processes; in myelinated fibres the junction occurs at a node of Ranvier. The peripheral process reaches a sensory ending, and because it conducts impulses toward the soma, strictly speaking, it functions as an elongated dendrite. However, because it has the typical structural and other functional properties of a peripheral axon, it is conventionally described as an axon.

Each soma has a capsule of satellite glial cells. Outside this lie the axodendritic process and its peripheral and central divisions, which are ensheathed by Schwann cells. The cells lie within a delicate vascular connective tissue that is continuous with the endoneurium of the nerve root.

Sensory ganglionic neurones are not entirely confined to discrete craniospinal ganglia. They often occupy heterotopic positions, either singly or in small groups, distal or proximal to their ganglia.

Autonomic Ganglia

Neurones in autonomic ganglia are multipolar and have dendritic trees on which preganglionic autonomic motor fibres synapse. They are surrounded by a mixed neuropil of afferent and efferent fibres, dendrites, synapses and non-neural cells. Autonomic ganglia are largely relay stations. A small fraction of their fibres traverses one or more ganglia without synapsing: some are efferent fibres en route to another ganglion, and some are afferents from the viscera and glands. There is considerable variation in the ratio between pre- and postganglionic fibres. Preganglionic sympathetic axons may synapse with many postganglionic neurones for the wide dissemination and perhaps amplification of sympathetic activity, a feature not found to the same degree in parasympathetic ganglia. Dissemination may also be achieved by connections with ganglionic interneurones or by the diffusion within the ganglion of transmitter substances produced locally (paracrine effect) or elsewhere (endocrine effect).

Most neurones of autonomic ganglia have somata ranging from 25 to 50 µm; a less common type is smaller, 15 to 20 µm, and often clustered in groups. Dendritic fields of these multipolar neurones are complex, and dendritic glomeruli have been observed in many ganglia. Clusters of small granular adrenergic vesicles occupy the soma and dendrites, probably representing the storage of catecholamines. Ganglionic neurones receive many axodendritic synapses from preganglionic nerve fibres; axosomatic synapses are less numerous. Postganglionic fibres commonly arise from the initial stem of a large dendrite and produce few or no collateral processes.

Enteric Ganglia

The ENS is composed of ganglionic neurones and associated nerves (Fig. 2.23) serving different functions, including regulation of gut motility and mucosal transport. Extrinsic autonomic fibres supply the gut wall, and together with intrinsic enteric ganglionic neurones and the endocrine and cardiovascular systems, they integrate the activities of the digestive system as a result of either interaction with enteric neurones (e.g. via vagal fibres) or direct regulation of the local bloodflow (via postganglionic sympathetic fibres).

Fig. 2.23 Myenteric plexus of ganglia (G) and fibres that lies between the inner circular (IC) and outer longitudinal (OL) smooth muscle layers of the gut wall.

Enteric ganglionic neurones are predominantly peptidergic or monoaminergic and can be classified accordingly. Other neurones express nitric oxide synthase and release NO. There are regional differences in the numbers of ganglia and the classes of neurone they contain. For example, myenteric plexus ganglia are less frequent in oesophageal smooth muscle (1.5 per centimeter) than in the small and large intestines (approximately 10 per centimeter of bowel length). Oesophageal enteric neurones all coexpress VIP and neuropeptide Y (NPY), whereas gastrin- and somatostatin-containing fibres are rare. In contrast, gastrin- and somatostatin-containing neurones are abundant in the small and large intestines, and although both types are present, very few VIP neurones coexpress NPY.

Correlations can be made between some phenotypical classes of enteric neurones and their functional properties, although much remains undetermined. Cholinergic neurones are excitatory, cause muscular contraction and mainly project orally. NO-releasing neurones are generally larger and project for longer distances, mainly anally. They are inhibitory neurones, some of which also express VIP, and they promote muscular relaxation.

General Features of Sensory Receptors

There are three major forms of sensory receptor: neuroepithelial, epithelial and neuronal.

Fig. 2.24 Some major types of sensory endings of general afferent fibres (omitting neuromuscular, neurotendinous and hair-related types).

A neuroepithelial receptor is a neurone with a soma situated near a sensory surface and an axon that conveys sensory signals into the CNS to synapse on second-order neurones. This is an evolutionarily primitive arrangement, and the only example in humans is the sensory neurone of the olfactory epithelium.

An epithelial receptor is a cell that is modified from non-nervous sensory epithelium and innervated by a primary sensory neurone, whose soma lies near the CNS. Examples are epidermal Merkel cells, auditory receptors and taste buds. Activity in this type of receptor elicits the passage of excitation from the receptor by neurotransmission across a synaptic gap. In taste receptors, individual cells are constantly being renewed from the surrounding epithelium. In many ways, visual receptors in the retina are similar in their form and relations. These cells are derived from the ventricular lining of the fetal brain and are not replaced.

A neuronal receptor is a primary sensory neurone with a soma in a craniospinal ganglion and a peripheral axon, the end of which is a sensory terminal. All cutaneous sensors (with the exception of Merkel cells) and proprioceptors are of this type; their sensory terminals may be encapsulated or linked to special mesodermal or ectodermal structures to form part of the sensory apparatus. The extraneural cells are not necessarily excitable, but they create the environment for excitation of the neuronal process.

The receptor stimulus is transduced into a graded change of electrical potential at the receptor surface (receptor potential), which initiates an all-or-none action potential transmitted to the CNS. This may occur in the receptor, where this is a neurone, or partly in the receptor and partly in the neurone innervating it, in the case of epithelial receptors.

Transduction varies with the modality of stimulus, usually causing depolarization of the receptor membrane (or, in the retina, hyperpolarization). In mechanoreceptors it may involve deformation of the membrane structure, which results in strain- or voltage-sensitive transducing protein molecules opening ion channels. In chemoreceptors, receptor action may resemble that for ACh at neuromuscular junctions. Visual receptors share similarities with chemoreceptors: light causes changes in receptor proteins, which activate G-proteins, resulting in the release of second messengers, and this affects membrane permeability.

The quantitative responses of sensory endings to stimuli vary greatly and increase the flexibility of sensory systems’ functional design. Although increased excitation with an increasing stimulus level is a common pattern (‘on’ response), some receptors respond to decreased stimulation (‘off’ response). Even unstimulated receptors show varying degrees of spontaneous background activity against which an increase or decrease in activity occurs with changing levels of stimulus. In all receptors studied, when stimulation is maintained at a steady level, there is an initial burst (the dynamic phase), followed by gradual adaptation to a steady level (the static phase). Although all receptors show these two phases, one may predominate, providing a distinction between rapidly adapting endings, which accurately record the rate of stimulus onset, and slowly adapting endings, which signal the constant amplitude of a stimulus (e.g. position sense). Dynamic and static phases are reflected in the amplitude and duration of the receptor potential and also in the frequency of action potentials in the sensory fibres. The stimulus strength necessary to elicit a response in a receptor (i.e., its threshold level) varies greatly between receptors and provides an extra level of information about stimulus strength.

Functional Classification of Receptors

Receptors may be classified in several ways. They may be classified by the modalities to which they are sensitive, such as mechanoreceptors (which are responsive to deformation, e.g. touch, pressure, sound waves), chemoreceptors, photoreceptors and thermoreceptors. Some receptors respond selectively to more than one modality (polymodal receptors): they usually have high thresholds and respond to damaging stimuli associated with irritation or pain (nociceptors).

Another widely used classification divides receptors on the basis of their distribution in the body into exteroceptors, proprioceptors and interoceptors. Exteroceptors and proprioceptors are receptors of somatic afferent components of the nervous system, whereas interoceptors are receptors of the visceral afferent pathways.

Exteroceptors respond to external stimuli and are found at, or close to, body surfaces. They can be subdivided into the general or cutaneous sense organs and the special sensory organs. General sensory receptors include free and encapsulated terminals in skin and near hairs. Special sensory organs are the olfactory, visual, acoustic, vestibular and taste receptors.

Proprioceptors respond to stimuli to deeper tissues, especially of the locomotor system, and are concerned with detecting movement, mechanical stresses and position. They include Golgi tendon organs, neuromuscular spindles, Pacinian corpuscles, other endings in joints and vestibular receptors. Proprioceptors are stimulated by the contraction of muscles, the movement of joints and changes in the position of the body. They are essential for the coordination of muscles, the grading of muscular contraction and the maintenance of equilibrium.

Interoceptors are found in the walls of the viscera, glands and vessels, where their terminations include free nerve endings, encapsulated terminals and endings associated with specialized epithelial cells. Nerve terminals are found in the layers of visceral walls and the adventitia of blood vessels, but the detailed structure and function of many of these endings are not well established. Encapsulated (lamellated) endings occur in the heart, adventitia and mesenteries. Free terminal arborizations occur in the endocardium, loose connective tissue, the endomysium of all muscles and connective tissue generally.

Visceral nerve terminals are not usually responsive to stimuli that act on exteroceptors, and they do not respond to localized mechanical and thermal stimuli. Tension produced by excessive muscular contraction or by visceral distension often causes pain, particularly in pathological states; this pain is frequently poorly localized and of a deep-seated nature. Visceral pain is often referred to the corresponding dermatome.

Interoceptors include vascular chemoreceptors, such as the carotid body, and baroceptors, which are concerned with the regulation of bloodflow and pressure and with the control of respiration. Irritant receptors respond polymodally to noxious chemicals or damaging mechanical stimuli and are widely distributed in the epithelia of the alimentary and respiratory tracts; they may initiate protective reflexes.

Free Nerve Endings

Sensory endings that branch to form plexuses occur in many sites (see Fig. 2.24). They occur in all connective tissues, including those of the dermis, fasciae, capsules of organs, ligaments, tendons, adventitia of blood vessels, meninges, articular capsules, periosteum, perichondrium, Haversian systems in bone, parietal peritoneum, walls of viscera and endomysium of all types of muscle. They also innervate the epithelium of the skin, corneas, buccal cavity and alimentary and respiratory tracts and their glands. Within epithelia they lack Schwann cell ensheathment and are enveloped instead by epithelial cells. Afferent fibres from free terminals may be myelinated or unmyelinated but are always of small diameter and low conduction velocity. When afferent axons are myelinated, their terminal arborizations are not. These terminals serve several sensory modalities. In the dermis, they may be responsive to moderate cold or heat (thermoreceptors); light mechanical touch (mechanoreceptors); damaging heat, cold or deformation (unimodal nociceptors) and damaging stimuli of several kinds (polymodal nociceptors). Similar fibres in deeper tissues may also signal extreme conditions, and these are experienced, as with all nociceptors, as pain. Free endings in the corneas, dentine and periosteum may be exclusively nociceptive.

Special types of free endings are associated with epidermal structures in the skin. They include terminals associated with hair follicles (peritrichial receptors), which branch from myelinated fibres in the deep dermal cutaneous plexus; the number, size and form of the endings are related to the size and type of hair follicle innervated. These endings respond mainly to movement when hair is deformed and belong to the rapidly adapting mechanoreceptor group.

Merkel tactile endings lie at the base of the epidermis or around the apical ends of some hair follicles and are innervated by large myelinated axons. The axon expands into a disc, which is applied closely to the base of the Merkel cell in the basal layer of the epidermis. Merkel cells, which are believed to be derived from the neural crest, contain many large (50 to 100 nm) dense-core vesicles, presumably containing transmitters, which are concentrated near the junction with the axon. Merkel endings are slow-adapting mechanoreceptors and are responsive to sustained pressure and sensitive to the edges of applied objects.

Encapsulated Endings

Encapsulated endings are a major group of special endings, although they exhibit considerable variety in their size, shape and distribution. They all share a common feature, which is that the axon terminal is encapsulated by non-excitable cells. This category of ending includes lamellated corpuscles of various kinds (e.g. Meissner’s, Pacinian), Golgi tendon organs, neuromuscular spindles and Ruffini endings (see Fig. 2.24).

Meissner’s Corpuscles

Meissner’s corpuscles are found in the dermal papillae of all parts of the hands and feet, the fronts of the forearms, lips, palpebral conjunctiva and mucous membrane of the apical part of the tongue. They are most concentrated in thick, hairless skin, especially of the finger pads, where there may be up to 24 corpuscles/cm² in young adults. Mature corpuscles are cylindrical in shape, approximately 80 µm long and 30 µm across, with their long axes perpendicular to the skin surface. Each corpuscle has a connective tissue capsule and a central core (Fig. 2.25). Meissner’s corpuscles are rapidly adapting mechanoreceptors, sensitive to shape and textural changes in exploratory and discriminatory touch; their acute sensitivity provides the neural basis for reading Braille text.

Fig. 2.25 Tactile Meissner’s corpuscle in a dermal papilla in the skin, demonstrated using the Gros–Bielschowsky technique.

(Courtesy of N. Cauna, University of Pittsburgh.)

Pacinian Corpuscles

Pacinian corpuscles are situated subcutaneously in the palmar and plantar aspects of the hands and feet and their digits; in the external genitalia, arms, neck, nipple, periosteum, and interosseous membranes; near joints and in the mesentries. They are oval, spherical or irregularly coiled and are up to 2 mm long and 100 to 500 µm or more across; the larger ones are visible to the naked eye. Each corpuscle has a capsule, an intermediate growth zone and a central core that contains an axon terminal. The capsule is formed by approximately 30 concentrically arranged lamellae of flat cells approximately 0.2 µm thick (Fig. 2.26). Adjacent cells overlap, and successive lamellae are separated by an amorphous proteoglycan matrix that contains circularly oriented collagen fibres, closely applied to the surfaces of the lamellar cells. The amount of collagen increases with age. The intermediate zone is cellular, and its cells become incorporated into the capsule or core, so that it is not clearly defined in mature corpuscles. The core consists of approximately 60 bilateral, compacted lamellae that lie on both sides of a central nerve terminal.

Fig. 2.26 Pacinian corpuscle in transverse section, showing the central core region and lamellar cells surrounding the axon. Note the presence of large intercellular spaces between the lamellar cells and the numerous mitochondria in the axon (Rhesus monkey finger).

(Material provided by W. Hamann, Department of Anaesthetics, Guy’s Hospital Medical School, London.)

Each corpuscle is supplied by a myelinated axon, which loses its myelin sheath and, at the junction with the core, its ensheathing Schwann cell. The naked axon runs through the central axis of the core and ends in a slightly expanded bulb. It is in contact with the innermost core lamellae, is transversely oval and sends short projections of unknown function into clefts in the lamellae. It contains numerous large mitochondria and minute vesicles approximately 5 nm in diameter, which aggregate opposite the clefts. The cells of the capsule and core lamellae are thought to be specialized fibroblasts, but some may be Schwann cells. Elastic fibrous tissue forms an overall external capsule to the corpuscle. Pacinian corpuscles are supplied by capillaries that accompany the axon as it enters the capsule.

Pacinian corpuscles act as very rapidly adapting mechanoreceptors. They respond only to sudden disturbances and are especially sensitive to vibration. The rapidity may be partly due to the lamellated capsule acting as a high pass frequency filter, damping slow distortions by fluid movement between lamellar cells. Groups of corpuscles respond to pressure changes, such as the grasping or releasing of an object.

Golgi Tendon Organs

Golgi tendon organs are found mainly near musculotendinous junctions (Fig. 2.27), where more than 50 may occur at one site. Each terminal is closely related to a group of muscle fibres (up to 20) as they insert into the tendon. Golgi tendon endings are approximately 500 µm long and 100 µm in diameter and consist of small bundles of tendon fibres enclosed in a delicate capsule. The collagen bundles (intrafusal fasciculi) are less compact than elsewhere in the tendon; the collagen fibres are smaller, and the fibroblasts are larger and more numerous. One or more thickly myelinated axons enter the capsule and divide. Their branches, which may lose their Schwann cell sheaths, terminate in leaf-like enlargements containing vesicles and mitochondria, which wrap around the tendon. A basal lamina or process of Schwann cell cytoplasm separates the nerve terminals from the collagen bundles that make up the tendon. The endings are activated by passive stretch of the tendon but are much more sensitive to active contraction of the muscle. They are important in providing proprioceptive information, complementing that from neuromuscular spindles. Their responses are slowly adapting, and they signal maintained tension.

Fig. 2.27 Structure and innervation of a Golgi tendon organ. For clarity, the perineurium and endoneurium have been omitted to show the distribution of nerve fibres ramifying between the collagen fibre bundles of the tendon.

Neuromuscular Spindles

Neuromuscular spindles are essential for the control of muscle contraction. Each spindle contains a few small, specialized intrafusal muscle fibres innervated by both sensory and motor nerve fibres (Figs. 2.28, 2.29). The whole is surrounded equatorially by a fusiform spindle capsule of connective tissue, consisting of an outer perineurial-like sheath of flattened fibroblasts and collagen and an inner sheath that forms delicate tubes around individual intrafusal fibres. A gelatinous fluid rich in glycosaminoglycans fills the space between the two sheaths.

Fig. 2.28 Schematic three-dimensional representation of a neuromuscular spindle, showing nuclear bag and nuclear chain fibres; these are innervated by the sensory anulospiral and ‘flower spray’ terminals (blue) and by the γ- and β-fusimotor terminals (red). See also Fig. 2.29.

Fig. 2.29 Schematic three-dimensional representation of nuclear bag and nuclear chain fibres in a neuromuscular spindle. Dynamic β- and γ-efferents innervate dynamic bag 1 intrafusal fibres; whereas static β- and γ-efferents innervate static bag 2 and nuclear chain intrafusal fibres.

There are usually 5 to 14 intrafusal fibres (the number varies between muscles) and two major types of fibre—nuclear bag and nuclear chain fibres—which are distinguished by the arrangement of nuclei in their sarcoplasm. In the former, the equatorial cluster of nuclei makes the fibre bulge slightly, whereas in the latter, the nuclei form a single axial row. Nuclear bag fibres are greater in diameter than chain fibres and extend beyond the surrounding capsule to the endomysium of nearby extrafusal muscle fibres. Nuclear chain fibres are attached at their poles to the capsule or to the sheaths of nuclear bag fibres.

The intrafusal fibres resemble typical skeletal muscle fibres, except that the zone of myofibrils is thin around the nuclei. One subtype of nuclear bag fibre (dynamic bag 1) generally lacks M lines, possesses little sarcoplasmic reticulum and has an abundance of mitochondria and oxidative enzymes but little glycogen. A second subtype of bag fibre (static bag 2) has distinct M lines and abundant glycogen. Nuclear chain fibres have marked M lines, sarcoplasmic reticulum and T-tubules, abundant glycogen, but few mitochondria. These variations reflect, as they do in muscle generally, the contractile properties of different intrafusal fibres (Boyd 1985).

The sensory innervation of muscle spindles is of two types, both of which involve the unmyelinated terminations of large myelinated axons. Primary (anulospiral) endings are equatorially placed and form spirals around the nucleated parts of intrafusal fibres. They are the endings of large sensory fibres (group Ia afferents), each of which sends branches to a number of intrafusal muscle fibres. Each terminal lies in a deep sarcolemmal groove in the spindle plasma membrane beneath its basal lamina. Secondary (‘flower spray’) endings, which may be spray shaped or anular, are largely confined to nuclear chain fibres and are the branched terminals of somewhat thinner myelinated (group II) afferents. They are varicose and spread in a narrow band on both sides of the primary endings. They lie close to the sarcolemma, although not in grooves. In essence, primary endings are rapidly adapting, whereas secondary endings have a regular, slowly adapting response to static stretch.

There are three types of motor endings in muscle spindles. Two are from fine, myelinated, fusimotor (γ) efferents, and one is from myelinated (β) efferent collaterals of extrafusal slow twitch muscle fibres. The fusimotor efferents terminate nearer the equatorial region, where their terminals either resemble the motor end-plates of extrafusal fibres (plate endings) or are more diffuse (trail endings). Stimulation of the fusimotor and β-efferents causes contraction of the intrafusal fibres and activation of their sensory endings.

Muscle spindles signal the length of extrafusal muscle both at rest and throughout contraction and relaxation, the velocity of their contraction and changes in velocity. These modalities may be related to the different behaviours of the three major types of intrafusal fibres and their sensory terminals. The sensory endings of one type of nuclear bag fibre (dynamic bag 1) are particularly concerned with signalling rapid changes in length that occur during movement, whereas those of the second type of bag fibre (static bag 2) are less responsive to movement. The afferents from chain fibres have relatively slowly adapting responses at all times. These elements can therefore detect complex changes in the state of the extrafusal muscle surrounding spindles and can signal fluctuations in length, tension, velocity of length change and acceleration. Moreover, they are under complex central control: efferent (fusimotor) nerve fibres, by regulating the strength of contraction, can adjust the length of the intrafusal fibres and thereby the responsiveness of spindle sensory endings. In summary, the organization of spindles allows them to actively monitor muscle conditions and compare intended and actual movements and thus provide detailed input to spinal, cerebellar, extrapyramidal and cortical centres about the state of the locomotor apparatus.

Joint Receptors

The arrays of receptors situated in and near articular capsules provide information on the position and movement of joints and the stresses acting on them. Structural and functional studies have demonstrated at least four types of joint receptors; their proportions and distribution vary by site. Three are encapsulated endings, and the fourth is a free terminal arborization.

Type I endings are capsulated corpuscles of the slowly adapting mechanoreceptor (Ruffini) type, situated in the superficial layers of fibrous joint capsules in small clusters and supplied by myelinated afferent axons. Being slowly adapting, they provide awareness of joint position and movement and respond to patterns of stress in articular capsules. They are particularly common in joints where static positional sense is necessary for the control of posture (e.g. hip, knee).

Type II endings are lamellated receptors and resemble small versions of the large Pacinian corpuscles found in general connective tissue. They occur in small groups throughout joint capsules, particularly in the deeper layers and other articular structures (e.g. fat pad of the temporomandibular joint). They are rapidly adapting, low-threshold mechanoreceptors, sensitive to movement and pressure changes, and they respond to joint movement and transient stresses in the joint capsule. They are supplied by myelinated afferent axons but are probably not involved in the conscious awareness of joint sensation.

Type III endings are identical to Golgi tendon organs in structure and function; they occur in articular ligaments but not in joint capsules. They are high-threshold, slowly adapting receptors that apparently serve, at least in part, to prevent excessive stresses at joints by reflex inhibition of the adjacent muscles. They are innervated by large myelinated afferent axons.

Type IV endings are free terminals of myelinated and unmyelinated axons. They ramify in articular capsules and the adjacent fat pads and around the blood vessels of the synovial layer. They are high-threshold, slowly adapting receptors and are thought to respond to excessive movements, providing a basis for articular pain.