gene expression is not dependent on axon association. In marked con- interdigitate, unlike their counterparts overlying grey matter. No sub-
trast, Schwann cells in the developing PNS are associated with axons ependymal zone is present.
during the entire phase of axonal growth. Myelination does not occur Specialized areas of ependymal cells called the circumventricular
simultaneously in all parts of the body in late fetal and early postnatal organs are found in four areas around the margins of the third ventricle:
development. White matter tracts and nerves in the periphery have their namely, the lining of the median eminence of the hypothalamus; the
own specific temporal patterns that relate to their degree of functional subcommissural organ; the subfornical organ; and the vascular organ
maturity. of the lamina terminalis. The area postrema, at the inferoposterior limit
Mutations of the major myelin structural proteins have now been of the fourth ventricle, has a similar structure. In all of these sites the
recognized in a number of inherited human neurological diseases. As ependymal cells are only rarely ciliated and their ventricular surfaces
would be expected, these mutations produce defects in myelination and bear many microvilli and apical blebs. They have numerous mitochon-
in the stability of nodal and paranodal architecture that are consistent dria, well-formed Golgi complexes and rather flattened basal nuclei.
with the suggested functional roles of the relevant proteins in maintain- They are joined laterally by tight junctions, which form a barrier to the
ing the integrity of the myelin sheath. 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
EPENDYMA underlying capillaries. Significantly, these capillaries are fenestrated and
therefore do not form a blood–brain barrier. It is believed that neu-
Ependymal cells line the ventricles (Fig. 3.17; see Fig. 3.10) and central ropeptides can pass from nervous tissue into the CSF by active transport
canal of the spinal cord. They form a single-layered epithelium that through the ependymal cells in these specialized areas, and so access a


varies from squamous to columnar in form. At the ventricular surface, wide population of neurones via the permeable ependymal lining of
cells are joined by gap junctions and occasional desmosomes. Their the rest of the ventricle.
apical surfaces have numerous microvilli and/or cilia, the latter contrib- The ependyma is highly modified where it lies adjacent to the vas-
uting to the flow of CSF. There is considerable regional variation in the cular layer of the choroid plexuses.


Central glia
53
3
RETPAHC
Choroid plexus MICROGLIA
The choroid plexus forms the CSF and actively regulates the concentra- Microglia are the endogenous immune cells of the brain (Kettenmann
tion of molecules in the CSF. It consists of highly vascularized masses et al 2011, Eggen et al 2013). They originate from an embryonic mono-
of pia mater enclosed by pockets of ependymal cells. The ependymal cyte precursor and invade the brain early during development. While
cells resemble those of the circumventricular organs, except that they the invading cells have an ameboid morphology, microglial cells in a
do not have basal processes, but form a cuboidal epithelium that rests mature brain are highly ramified cells. They have elongated nuclei, scant
on a basal lamina adjacent to the enclosed fold of meningeal pia mater cytoplasm and several highly branched processes. They occupy a defined
and its capillaries (Fig. 3.18). The cells have numerous long microvilli territory in the brain parenchyma and are found in all areas of the CNS
with only a few cilia interspersed between them. They also have many including optic nerve, retina and spinal cord. Their density shows little
mitochondria, large Golgi complexes and basal nuclei, features consist- variation.
ent with their secretory activity; they produce most components of the Resting microglia, a term used to refer to microglia in the normal
CSF. They are linked by tight junctions forming a transepithelial barrier brain, should more accurately be described as surveying microglia.
(a component of the blood–CSF barrier), and by desmosomes. Their Microglial processes are fast-moving structures that rapidly scan their
lateral margins are highly folded. territory while the soma remains fixed in position. Microglial cells
The choroid plexus has a villous structure where the stroma is com- express receptors for neurotransmitters and thus can sense neuronal
posed of pial meningeal cells, and contains fine bundles of collagen activity. It is likely that they interact with synapses, from which it has
and blood vessels. Choroidal capillaries are lined by a fenestrated been inferred that they may influence synaptic transmission.


endothelium. During fetal life, erythropoiesis occurs in the stroma, All pathological changes in the brain result in the activation of
which is occupied by bone marrow-like cells. In adult life, the stroma microglial cells (Fig. 3.19), e.g. activated microglia are found in the
contains phagocytic cells, which, together with the cells of the choroid brain tissue of multiple sclerosis, Alzheimer’s disease and stroke
plexus epithelium, phagocytose particles and proteins from the ven- patients. The most common indication of their activation is a change
tricular lumen. from a ramified to an ameboid morphology, which may occur within
Age-related changes occur in the choroid plexus, which can be a few hours of the onset of injury or disease process.
detected by neuroimaging. Calcification of the choroid plexus can be In general, microglia respond to two types of signal: ‘on’ signals, which
detected by X-ray or CT scan very rarely in individuals in the first decade either appear de novo or are strongly upregulated, e.g. cell wall compo-
of life and in the majority in the eighth decade. The incidence of calci- nents of invading bacteria; and ‘off’ signals, which are normally present
fication rises sharply, from 35% of CT scans in the fifth decade to 75% but disappear or decrease in pathological states, e.g. defined cytokines
in the sixth decade. Visible calcification is usually restricted to the or neurotransmitters. Both types of event are interpreted as signals for
glomus region of the choroid plexus, i.e. the vascular bulge in the activation. The functional repertoire of activated microglia includes pro-
choroid plexus as it curves to follow the anterior wall of the lateral liferation; migration to the site of injury; expression of major histocom-
ventricle into the temporal horn. patibility complex (MHC) II molecules to interact with infiltrating
lymphocytes; and the release of a variety of different substances including
chemokines, cytokines and growth factors. These cells are therefore capa-
ble of significantly influencing ongoing pathological processes.
Microglial cells are the professional phagocytes of the nervous
system and actively migrate through tissue. A number of factors such as


ATP and complement factors act as chemoattractants. This behaviour is
relevant not only in pathology but also during development where
microglial cells remove apoptotic cells. After a pathological insult,
microglial cells revert to their surveying phenotype, re-acquiring a rami-
fied morphology.
Entry of inflammatory cells into the brain
Although the CNS has long been considered to be an immunologically
privileged site, lymphocyte and macrophage surveillance of the brain
may be a normal, but very low-grade, activity that is enhanced in
disease. Lymphocytes can enter the brain in response to virus infections
and as part of the autoimmune response in multiple sclerosis. Activated,
A
but not resting, lymphocytes pass through the endothelium of small
venules, a process that requires the expression of recognition and adhe-
sion molecules (induced following cytokine activation), and subse-
Arachnoid Pia mater Choroid Subarachnoid Capillary quently migrate into the brain parenchyma. Within the CNS, microglia
mater fissure space
can be induced by T-cell cytokines to act as efficient antigen-presenting
cells. After leaving the CNS, lymphocytes probably drain along lym-
phatic pathways to regional cervical lymph nodes.
CNS CNS
Choroid epithelium Choroid capillary Ependyma
B Ventricle
Fig. 3.18 A, A choroid plexus within the lateral ventricle. Frond-like
projections of vascular stroma derived from the pial meninges are Fig. 3.19 Activated microglial cells in the human central nervous system,
covered with a low columnar epithelium that secretes cerebrospinal fluid. in a biopsy from a patient with Rasmussen’s encephalitis, visualized using
Mouse tissue, toluidine blue stained resin section. B, The arrangement of MHC class II antigen immunohistochemistry. (Courtesy of Dr Norman
tissues forming the choroid plexus. Gregson, Division of Neurology, GKT School of Medicine, London.)


NERvOuS SySTEm
54
1
NOITCES
Monocytes enter the CNS in the early stages of infarction and fibres. B fibres are myelinated autonomic preganglionic efferent fibres.
autoimmune disease and, in particular, in pyogenic infections, probably C fibres are unmyelinated and have thermoreceptive, nociceptive and
by passing through the endothelium of local vessels. Once in the brain, interoceptive functions, including the perception of slow, burning pain
monocytes are difficult to distinguish from intrinsic microglia because and visceral pain. This scheme can be applied to fibres of both spinal
both cell types express a similar marker profile. During the inflamma- and cranial nerves except perhaps those of the olfactory nerve, where
tory phase of meningitis, polymorphonuclear leukocytes and lym- the fibres form a uniquely small and slow group. The largest somatic
phocytes pass into the CSF through the endothelium of large veins in efferent fibres (Aα) innervate extrafusal muscle fibres (at motor end-
the subarachnoid space. Recent developments in research on brain plates) exclusively and conduct at a maximum of 120 m/s. Fibres to fast
inflammatory disorders are reviewed in Anthony and Pitossi (2013). twitch muscles are larger than those to slow twitch muscle. Smaller (Aγ)
fibres of gamma motor neurones, and autonomic preganglionic (B) and
postganglionic (C) efferent fibres conduct, in order, progressively more
PERIPHERAL NERVES
slowly (40 m/s to less than 10 m/s).
A different classification, used for afferent fibres from muscles,
Afferent nerve fibres connect peripheral receptors to the CNS; they are divides fibres into groups I–IV on the basis of their calibre; groups I–III
derived from neuronal somata located either in special sense organs are myelinated and group IV is unmyelinated. Group I fibres are large
(e.g. the olfactory epithelium) or in the sensory ganglia of the cranio- (12–22 µm), and include primary sensory fibres of muscle spindles
spinal nerves. Efferent nerve fibres connect the CNS to the effector cells (group Ia) and smaller fibres of Golgi tendon organs (group Ib). Group


and tissues and are the peripheral axons of neurones with somata in II fibres are the secondary sensory terminals of muscle spindles, with
the central grey matter. diameters of 6–12 µm. Group III fibres, 1–6 µm in diameter, have free
Peripheral nerve fibres are grouped in widely variable numbers into sensory endings in the connective tissue sheaths around and within
bundles (fasciculi). The size, number and pattern of fasciculi vary in muscles and are nociceptive and, in skin, also thermosensitive. Group
different nerves and at different levels along their paths (Fig. 3.20). IV fibres are unmyelinated, with diameters below 1.5 µm; they include
Their number increases and their size decreases some distance proximal free endings in skin and muscle, and are primarily nociceptive.
to a point of branching. Where nerves are subjected to pressure, e.g.
deep to a retinaculum, fasciculi are increased in number but reduced
in size, and the amount of associated connective tissue and degree of CONNECTIVE TISSUE SHEATHS
vascularity also increase. At these points, nerves may occasionally show
a pink, fusiform dilation, sometimes termed a pseudoganglion or gan- Nerve trunks, whether uni- or multifascicular, are limited externally by
gliform enlargement. an epineurium, which is connected to surrounding tissues by mesoneu-
rium. Mesoneurium is a loose connective tissue sheath (see Ch. 2)
containing the extrinsic, segmental blood supply of the nerve, and so
CLASSIFICATION OF PERIPHERAL NERVE FIBRES
is of clinical importance in nerve injury. Individual fasciculi of the nerve
trunk are enclosed by a multilayered perineurium, which in turn sur-
Classification of peripheral nerve fibres is based on various parameters rounds the endoneurium or intrafascicular connective tissue (see
such as conduction velocity, function and fibre diameter. Of two clas- Fig. 3.20).
sifications in common use, the first divides fibres into three major
classes, designated A, B and C, corresponding to peaks in the distribu- Epineurium
tion of their conduction velocities. In humans, this classification is used
mainly for afferent fibres from the skin. Group A fibres are subdivided


Epineurium is a condensation of loose (areolar) connective tissue
into α, β, γ and δ subgroups; fibre diameter and conduction velocity
derived from mesoderm. As a general rule, the more fasciculi present
are proportional in most fibres. Group Aα fibres are the largest and
in a peripheral nerve, the thicker the epineurium. Epineurium contains
conduct most rapidly, and C fibres are the smallest and slowest.
fibroblasts, collagen (types I and III) and variable amounts of fat, and
The largest afferent axons (Aα fibres) innervate encapsulated cutane-
it cushions the nerve it surrounds. Loss of this protective layer may be
ous mechanoreceptors, Golgi tendon organs and muscle spindles, and
associated with pressure palsies seen in wasted, bedridden patients. The
some large alimentary enteroceptors. Aβ fibres form secondary endings
epineurium also contains lymphatics (which probably pass to regional
on some muscle spindle (intrafusal) fibres and also innervate cutaneous
lymph nodes) and blood vessels, vasa nervorum, that pass across the
and joint capsule mechanoreceptors. Aδ fibres innervate thermorecep-
perineurium to communicate with a network of fine vessels within the
tors, stretch-sensitive free endings, hair receptors and nociceptors,
endoneurium, forming the intrinsic system of vascular plexuses.
including those in dental pulp, skin and connective tissue. Aγ fibres are
exclusively fusimotor to plate and trail endings on intrafusal muscle
Perineurium
Perineurium extends from the CNS–PNS transition zone to the periph-
ery, where it is continuous with the capsules of muscle spindles and
encapsulated sensory endings, but ends openly at unencapsulated
endings and neuromuscular junctions. It consists of alternating layers
of flattened polygonal cells (thought to be derived from fibroblasts) and
collagen. It can often contain 15–20 layers of such cells, each layer
enclosed by a basal lamina up to 0.5 µm thick. Within each layer the
cells interdigitate along extensive tight junctions; their cytoplasm typi-
cally contains vesicles and bundles of microfilaments and their plasma


membrane often shows evidence of pinocytosis. These features are con-
sistent with the function of the perineurium as a metabolically active
E
P diffusion barrier; together with the blood–nerve barrier, the perineu-
rium is thought to play an essential role in maintaining the osmotic
milieu and fluid pressure within the endoneurium. Lymphatic vessels
Ep have not been detected in the perineurium.
Endoneurium
Strictly speaking, the term endoneurium is restricted to intrafascicular
connective tissue and excludes the perineurial partitions within fasci-
cles. Endoneurium consists of a fibrous matrix composed predomi-
Fig. 3.20 A transverse section of a biopsied human sural nerve, showing nantly of type III collagen (reticulin) fibres, characteristically organized
the arrangement of the connective tissue sheaths. Individual axons, in fine bundles lying parallel to the long axis of the nerve, and con-
myelinated and unmyelinated, are arranged in a small fascicle bounded densed around individual Schwann cell–axon units and endoneurial
by a perineurium. Abbreviations: P, perineurium; Ep, epineurium; vessels. The fibrous and cellular components of the endoneurium are
E, endoneurium. (Courtesy of Professor Susan Standring, GKT School bathed in endoneurial fluid at a slightly higher pressure than that
of Medicine, London.) outside in the surrounding epineurium. The major cellular constituents


Peripheral nerves
55
3
RETPAHC
of the endoneurium are Schwann cells and endothelial cells; minor
components are fibroblasts (constituting approximately 4% of the total
endoneurial cell population), resident macrophages and mast cells.
Schwann cell–axon units and blood vessels are enclosed within indi-
vidual basal laminae and therefore isolated from the other cellular and A
extracellular components of the endoneurium.
Endoneurial arterioles have a poorly developed smooth muscle layer
and do not autoregulate well. In sharp contrast, epineurial and perineu-
rial vessels have a dense perivascular plexus of peptidergic, serotonin-
ergic and adrenergic nerves. There are free nerve endings in all layers of
neural connective tissue sheaths and there are some encapsulated
(Pacinian) corpuscles in the endoneurium. These probably contribute
A
to the acute sensitivity of nerves trapped in fibrosis after injury or
surgery. S
SCHWANN CELLS
Schwann cells are the major glial type in the PNS. In vitro they are A
fusiform in appearance. Both in vitro and in vivo, Schwann cells ensheathe S
peripheral axons, and myelinate those greater than 2 µm in diameter.
In a mature peripheral nerve, they are distributed along the axons in
longitudinal chains; the geometry of their association depends on
whether the axon is myelinated or unmyelinated. In myelinated axons Fig. 3.21 An electron micrograph of a transverse section of biopsied
the territory of a Schwann cell defines an internode. human sural nerve, showing a myelinated axon and several unmyelinated
The molecular phenotype of mature myelin-forming Schwann cells axons (A), ensheathed by Schwann cells (S). (Courtesy of Professor Susan
is different from that of mature non-myelin-forming Schwann cells. Standring, GKT School of Medicine, London.)
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 (p75NTR) and GFAP intermediate et al 2008). The region under the compact myelin sheath that extends
between two juxtaparanodes is the internode. The molecular domains
filament protein (which differs from the CNS form in its post-
of myelinated axons, including that of the axon initial segment are
translational modification) characterizes adult non-myelin-forming
reviewed in Buttermore et al (2013)).
Schwann cells.
Schwann cell cytoplasm forms a continuous layer only in the peri-
Schwann cells arise from Schwann cell precursors that, in turn, are
nuclear (mid-internodal) and paranodal regions, where it forms a collar
generated from multipotent cells of the neural crest. Neuronal signals
from which microvilli project into the nodal gap substance. Elsewhere
regulate many aspects of Schwann cell behaviour in developing and
it is dispersed as a lace-like network over the inner (adaxonal) and outer
postnatal nerves. Axon-associated signals appear to control the prolif-
(abaxonal) surfaces of the myelin sheath.
eration of developing Schwann cells and their precursors; the develop-
mentally programmed death of those precursors in order to match
Nodes of Ranvier
numbers of axons and glia within each peripheral nerve bundle; the
production of basal laminae by Schwann cells; and the induction and The nodal compartment consists of a short length of exposed axo-
maintenance of myelination. Axonal neuregulin 1 signalling via ErbB2/ lemma, typically 0.8–1.1 µm long, surrounded by a nodal gap sub-
B3 receptors on Schwann cells is essential for Schwann cell myelination stance composed of various extracellular components, some of which
and also determines myelin thickness. An extensive literature supports may possess nerve growth-repulsive characteristics. Multiple processes
the view that Schwann cells are key players in the acute injury response (microvilli) protrude into the gap substance from the outer collar of
in the PNS (see Commentary 1.6), helping to provide a microenviron- Schwann cytoplasm and contact the nodal axolemma. Voltage-gated


ment that facilitates axonal regrowth (Birch 2011). Few Schwann cells Na+ channels, the cell adhesion molecules NrCAM and neurofascin-186,
persist in chronically denervated nerves. For further reading about the cytoskeletal adaptor ankyrin G25,26 and the actin-binding protein
Schwann cells, see Kidd et al (2013). spectrin βIV are clustered at nodes. The calibre of the nodal axon is
usually significantly less than that of the internodal axon, particularly
Unmyelinated axons in large-calibre fibres.
Paranodes
Unmyelinated axons are commonly 1.0 µm in diameter, although some
The axolemma on either side of a node is contacted by paranodal loops
may be 1.5 µm or even 2 µm in diameter. Groups of up to 10 or more
of Schwann cell cytoplasm via specialized septate junctions that spiral
small axons (0.15–2.0 µm in diameter) are enclosed within a chain of
around the axon. The junctions are thought to form a partial diffusion
overlapping Schwann cells that is surrounded by a basal lamina. Within barrier into the peri-axonal space; restrict the movement of K+ channels
each Schwann cell, individual axons are usually sequestered from their
from under the compact myelin; and limit lateral diffusion of mem-
neighbours by delicate processes of cytoplasm. It seems likely, on the
brane components. Caspr, contactin and their putative ligand NF155
basis of quantitative studies in subhuman primates, that axons from
(an isoform of neurofascin) are concentrated in paranodes.
adjacent cord segments may share Schwann cell columns; this phenom-
enon may play a role in the evolution of neuropathic pain after nerve Juxtaparanodes
injury. In the absence of a myelin sheath and nodes of Ranvier, action
The region of the axon lying just beyond the innermost paranodal junc-
potential propagation along unmyelinated axons is not saltatory but
tion is now recognized as a distinct domain defined by the localization
continuous, and relatively slow (0.5–4.0 m/s).
of voltage-gated K+ channels (delayed-rectifier K+ channels Kv1.1, Kv1.2


and their Kvb2 subunit). Clustering of Kv1 channels at the juxtapara-
Myelinated axons
nodal region depends on their association with the Caspr2/TAG-1 adhe-
sion complex.
Myelinated axons (Fig. 3.21) have a 1 : 1 relationship with their
Schmidt–Lanterman incisures
ensheathing Schwann cells. The territorial extent of individual Schwann
cells varies directly with the diameter of the axon they surround, from Schmidt–Lanterman incisures are helical decompactions of internodal
150 to 1500 µm. Specialized domains of axo-glial interaction define myelin that appear as funnel-like profiles in teased fibre preparations
nodes of Ranvier and their neighbouring compartments, paranodes and labelled for markers of non-compacted myelin (e.g. MAG, Cx32). At an
juxtaparanodes (Pereira et al 2012; Fig. 3.22). These domains contain incisure the major dense line of the myelin sheath splits to enclose a
multiprotein complexes characterized by unique sets of transmembrane continuous spiral band of cytoplasm passing between abaxonal and
and cytoskeletal proteins and clusters of ion channels; the mechanisms adaxonal layers of Schwann cell cytoplasm. The minor dense line of
regulating channel clustering and node formation remain a subject of incisural myelin is also split, creating a channel connecting the peri-
intense scrutiny (Peles and Salzer 2000, Poliak and Peles 2003, Horresh axonal space with the endoneurial extracellular fluid. The function of


NERvOuS SySTEm
56
1
NOITCES
A B
BL
CM
PNL PNL PNL MV
CM
Internode Juxtaparanode Paranode Node
• Caspr 2 • Caspr • Na+ ch
EP • Kv1.1, 1.2, β2 • Contactin • ank G
• NF155 • NrCAM
• NF186
Fig. 3.22 The general plan of a peripheral 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, A transverse electron microscope section through the
centre of a node of Ranvier, with numerous finger-like processes of adjacent Schwann cells converging towards the nodal axolemma. Many microtubules
and neurofilaments are visible within the axoplasm. B, The arrangement of the axon, myelin sheath and Schwann cell cytoplasm at the node of Ranvier,
in the paranodal bulbs and in the juxtaparanodal region. The axon is myelinated by a Schwann cell surrounded by a basal lamina (BL). Only a portion of
the internode, which is located beneath the compact myelin (CM) sheath, is shown. A spiral of paranodal (green) and juxtaparanodal (blue) proteins
extends into the internode; this spiral is apposed to the inner mesaxon of the myelin sheath (not shown). K+ channels and Caspr2 are concentrated in the
juxtaparanodal region. In the paranodal region, the compact myelin sheath opens up into a series of paranodal cytoplasmic loops (PNL) that invaginate
and closely appose the axon, forming a series of septum-like junctions that spiral around the axon. Caspr, contactin and an isoform of neurofascin
(NF155) are concentrated in this region. At the node, numerous microvilli (MV) project from the outer collar of the Schwann cell to contact the axolemma.
The axon is enormously enriched in intramembranous particles at the node that correspond to Na+ channels (Na+ ch). Ankyrin G (ank G) isoforms and the


cell adhesion molecules NrCAM and NF186 are also concentrated in this region. (A, Courtesy of Professor Susan Standring, GKT School of Medicine,
London. B, Redrawn from Peles and Salzer 2000.)
incisures is not known; their structure suggests that they may participate from horizontal basal stem cells in the olfactory epithelium (Leung et al
in transport of molecules across the myelin sheath. 2007, Forni and Wray 2012). They extend new axons through the
lamina propria and cribriform plate into the CNS environment of the
olfactory bulb, where they synapse with second-order neurones. Olfac-
SATELLITE CELLS
tory ensheathing cells (OECs, also known as olfactory ensheathing glia)
accompany olfactory axons from the lamina propria of the olfactory
Many non-neuronal cells of the nervous system have been called satel-
epithelium to their synaptic contacts in the glomeruli of the olfactory
lite cells, including small, round extracapsular cells in peripheral
bulbs and are thought to play a role in directing them to their correct
ganglia, ganglionic capsular cells, Schwann cells, any cell that is closely
position in the olfactory bulb (Higginson and Barnett 2011). This
associated with neuronal somata, and precursor cells associated with
unusual arrangement is unique; elsewhere in the nervous system the
striated muscle fibres (Hanani 2010). Within the nervous system, the
territories of peripheral and central glia are clearly demarcated at CNS–
term is most commonly reserved for flat, epithelioid cells (ganglionic
PNS transition zones. OECs and the end-feet of astrocytes lying between
glial cells, capsular cells) that surround the neuronal somata of periph-
the bundles of olfactory axons both contribute to the glia limitans at
eral ganglia (see Fig. 3.23). Their cytoplasm resembles that of Schwann
the pial surface of the olfactory bulbs.
cells, and their deep surfaces interdigitate with reciprocal infoldings in
OECs share many properties with Schwann cells and express similar
the membranes of the enclosed neurones.
antigenic and morphological properties. They ensheathe olfactory


sensory axons in a manner comparable to the relationship that exists
Enteric glia
transitorily between Schwann cells and axons in very immature periph-
eral nerves, i.e. they surround, but do not segregate, bundles of up to
Enteric nerves lack an endoneurium and so do not have the collagenous 50 fine unmyelinated axons to form approximately 20 fila olfactoria.
coats of other peripheral nerves. The enteric ganglionic neurones are Both OECs and Schwann cells can myelinate axons, even though nor-
supported by glia that closely resemble astrocytes; they contain more mally none of the axons in the olfactory nerve is myelinated. It was
GFAP than non-myelinating Schwann cells and do not produce a basal thought that OECs shared a common origin with olfactory receptor
lamina. Evidence for their roles in gut function is reviewed in Gul- neurones in the olfactory placode, but recent fate-mapping experiments
bransen and Sharkey (2012). in chicken embryos and genetic linkage-tracing studies in mice have
shown that OECs are derived from neural crest cells (Forni and Wray
Olfactory ensheathing glia
2012).
OECs have a malleable phenotype. There may be several subtypes:
The olfactory system is unusual because it supports neurogenesis some OECs express GFAP as either fine filaments or more diffusely in
throughout life. Olfactory receptor neurones are continuously renewed their cytoplasm, and some express p75NTR and the O4 antigen.


Peripheral nerves
57
3
RETPAHC
BLOOD SUPPLY OF PERIPHERAL NERVES processes; in myelinated fibres the junction occurs at a node of Ranvier.
The peripheral process terminates in a sensory ending and, because it
The blood vessels supplying a nerve, end in a capillary plexus that conducts impulses towards the soma, it functions as an elongated den-
pierces the perineurium. The branches of the plexus run parallel with drite, strictly speaking. However, it has the typical structural and func-
the fibres, connected by short transverse vessels, forming narrow, rec- tional properties of a peripheral axon, and is conventionally described
tangular meshes similar to those found in muscle. The blood supply of as an axon.
peripheral nerves is unusual. Endoneurial capillaries have atypically Each neuronal soma is surrounded by a sheath of satellite glial cells
large diameters and intercapillary distances are greater than in many (SGCs). (A notable exception is the spiral, or cochlear, ganglion, where
other tissues. Peripheral nerves have two separate, functionally inde- most neuronal somata are myelinated, presumably contributing to fast
pendent vascular systems: an extrinsic system (regional nutritive vessels electrical transmission.) The axodendritic process and its peripheral and
and epineurial vessels) and an intrinsic system (longitudinally running central divisions, ensheathed by Schwann cells, lie outside the SGC
microvessels in the endoneurium). Anastomoses between the two sheath. All the cells in the ganglion lie within a highly vascularized
systems produce considerable overlap between the territories of the connective tissue that is continuous with the endoneurium of the nerve
segmental arteries. This unique pattern of vessels, together with a high root. In dorsal root ganglia there is no clear regional mapping of the
basal nerve blood flow relative to metabolic requirements, means that innervated body regions. In contrast, each of the three nerve branches
peripheral nerves possess a high degree of resistance to ischaemia. (ophthalmic, maxillary and mandibular) of the trigeminal nerve is
mapped to a different part of the trigeminal ganglion. Although sensory
Blood–nerve barrier neurones receive no synapses, they are endowed with receptors for
numerous neurotransmitters and hormones, and can thus communi-


cate chemically amongst themselves and with SGCs.
Just as the neuropil within the CNS is protected by a blood–brain
SGCs are the main type of glial cell in sensory ganglia. They share
barrier, the endoneurial contents of peripheral nerve fibres are protected
several properties with astrocytes, including expression of glutamine
by a blood–nerve barrier and by the cells of the perineurium. The
synthetase and various neurotransmitter transporters. In addition, like
blood–nerve barrier operates at the level of the endoneurial capillary
astrocytes, the SGCs that surround a neurone are coupled by gap junc-
walls, where the endothelial cells are joined by tight junctions, and are
tions and express receptors for ATP. Unlike astrocytes, SGCs completely
non-fenestrated and surrounded by continuous basal laminae. The
surround individual sensory neurones (and more rarely two or three
barrier is much less efficient in dorsal root ganglia and autonomic
neurons) in a glial sheath. They undergo major changes as a result of
ganglia and in the distal parts of peripheral nerves.
injury to peripheral nerves, and appear to contribute to chronic pain in
a number of animal pain models.
GANGLIA
Herpes zoster Primary infection with the varicella zoster virus causes
Ganglia are aggregations of neuronal somata and are of varying form chickenpox. Following recovery, the virus remains dormant within
and size. They occur in the dorsal roots of spinal nerves; in the sensory dorsal root ganglia or trigeminal ganglia, mostly in the neurones, and
roots of the trigeminal, facial, vestibulocochlear, glossopharyngeal and less commonly in the SGCs. Reactivation of the virus leads to herpes
vagal cranial nerves; and in the peripheral autonomic nervous system zoster (shingles), which involves the dermatome(s) supplied by the
(ANS). Each ganglion is enclosed within a capsule of fibrous connective affected sensory nerve(s). Diagnostic signs are severe pain, erythema
tissue and contains neuronal somata and neuronal processes. Enteric and blistering as occurs in chickenpox, often confined to one of the


ganglia are an exception to this rule; they resemble the CNS in both divisions of the trigeminal nerve or to a spinal nerve dermatome.
structure and function, and are not covered by a connective tissue Herpes zoster involving the geniculate ganglion compresses the facial
capsule. Some ganglia, particularly in the ANS, contain axons that nerve and results in a lower motor neurone facial paralysis, known as
originate from neuronal somata that lie elsewhere in the nervous system Ramsay Hunt syndrome. Occasionally, if the vestibulocochlear nerve
and which pass through the ganglia without synapsing. becomes involved, there is vertigo, tinnitus and some deafness. The
most important complication of herpes zoster is post-herpetic neural-
Sensory ganglia gia, a severe and persistent pain that is highly refractory to treatment.
The sensory ganglia of dorsal spinal roots (Fig. 3.23) and the ganglia Autonomic ganglia
of the trigeminal, facial, glossopharyngeal and vagal cranial nerves are
enclosed in a periganglionic connective tissue capsule that resembles The main types of cell in autonomic ganglia are the ganglionic neu-
the perineurium surrounding peripheral nerves. Ganglionic neurones rones, small intensely fluorescent (SIF) cells and satellite glial cells
are unipolar (sometimes called pseudounipolar, see above). They have (SGCs). Most of the neurones have somata ranging from 25 to 50 µm
spherical or oval somata of varying size, aggregated in groups between and complex dendritic fields; dendritic glomeruli have been observed
fasciculi of myelinated and unmyelinated nerve fibres. For each neurone, in ganglia in experimental animals. Ganglionic neurones receive many
a single axodendritic process bifurcates into central and peripheral axodendritic synapses from preganglionic axons; axosomatic synapses
are less numerous. Postganglionic fibres commonly arise from the
initial stem of a large dendrite and produce few or no collateral proc-
esses. Given their close relationship to the ganglionic neurones, auto-
nomic SGCs may have the potential to influence synaptic transmission.
SIF cells are characterized by being smaller than the neurones and by


having numerous granules that contain noradrenaline (norepine-
phrine), dopamine and serotonin. They are almost completely invested
by a sheath of SGCs and receive and make synapses; their physiological
role is currently obscure, but they lend credence to the idea that auto-
S nomic ganglia are far more than simple relay stations.
N Sympathetic neurones are multipolar and their dendritic trees, on
which preganglionic motor axons synapse, are more elaborate than
those of parasympathetic neurones (Fig. 3.24). The neurones are sur-
rounded by a mixed neuropil of afferent and efferent fibres, dendrites,
S
synapses and non-neural cells. There is considerable variation in the
ratio of pre- and postganglionic fibres in different types of ganglion.
Preganglionic sympathetic axons may synapse with many postgangli-
onic neurones for the wide dissemination and perhaps amplification of
sympathetic activity, a feature not found to the same degree in para-
sympathetic ganglia. Dissemination may also be achieved by connec-
Fig. 3.23 Sensory neurones in a dorsal root ganglion (rat). Neurones (N) tions with ganglionic interneurones or by the diffusion within the
are typically variable in size but all are encapsulated by satellite cells (S). ganglion of transmitter substances produced either locally (paracrine
Myelinated axons are seen above and below the neuronal somata. effect) or elsewhere (endocrine effect). Some axons within a ganglion
Toluidine blue stained resin section. (Courtesy of Dr Clare Farmer, King’s may be efferent fibres en route to another ganglion, or afferents from
College, London.) viscera and glands. These fibres may synapse with neurones in the


NERvOuS SySTEm
58
1
NOITCES
the neonatal period. Treatment usually consists of removing the dis-
eased intestinal segment.
The enteric plexuses consist of sensory neurones, interneurones and
a variety of motor neurones. These neurones are endowed with recep-
tors for a large number of neurotransmitters and also release a variety
of neurotransmitters. All classes of enteric neurone are equally distrib-
uted along the entire ganglionic network; consequently the ENS con-
sists of numerous repeating modules.
The myenteric plexus contains the motor neurones that control the
movements of gastrointestinal smooth muscle. The main excitatory
neurotransmitter is acetylcholine, which may be co-localized with an
excitatory peptide (usually a tachykinin, such as substance P). The main
inhibitory neurotransmitter is nitric oxide (NO), released from neu-
rones that may also release the inhibitory peptide vasoactive intestinal
peptide (VIP).
An important function of myenteric neurones is to mediate the peri-
staltic reflex, which is induced by intestinal wall distension or by
mechanical stimulation of the mucosa. These stimuli initiate contrac-
tion oral to the site of the stimulus, and relaxation anal to the site, creat-
ing a pressure gradient that propels the intestinal contents. Interstitial
cells of Cajal (ICC) are pacemaker cells believed to integrate neuronal
Fig. 3.24 A parasympathetic autonomic ganglion from a human stomach. signals with rhythmic oscillations of muscle contraction; disturbance of
Large neuronal somata, some with nuclei and prominent nucleoli in the ICC function may be a factor in a number of gastrointestinal disorders
plane of section, are encapsulated by satellite cells and surrounded by
(Huizinga et al 2009).
nerve fibres and non-neuronal cells. (Courtesy of Mr Peter Helliwell and
Enteric glia are the main type of glial cell in the ENS. In some
the late Dr Joseph Mathew, Department of Histopathology, Royal
respects they resemble astrocytes, e.g. they form end-feet with blood
Cornwall Hospitals Trust, UK.)
vessels, respond to numerous chemical mediators, and are extensively
coupled among themselves by gap junctions. They appear to play an


important role in neuroprotection and in maintaining the integrity of
the intestinal mucosal barrier.
M
DISPERSED NEUROENDOCRINE SYSTEM
Although the nervous, neuroendocrine and endocrine systems all
operate by intercellular communication, they differ in the mode, speed
and degree or localization of the effects produced (Day and Salzet
2002). The autonomic nervous system uses impulse conduction and
neurotransmitter release to transmit information, and the responses
induced are rapid and localized. The dispersed neuroendocrine system
uses only secretion. It is slower and the induced responses are less local-
ized, because the secretions, e.g. neuromediators, can act either on
contiguous cells, or on groups of nearby cells reached by diffusion, or
on distant cells via the blood stream. Many of its effector molecules
operate in both the nervous system and the neuroendocrine system.
M
The endocrine system proper, which consists of clusters of cells and
discrete, ductless, hormone-producing glands, is even slower and less
localized, although its effects are specific and often prolonged. These
regulatory systems overlap in function, and can be considered as a
Fig. 3.25 An enteric ganglion (outlined) of the myenteric (Auerbach’s)
single neuroendocrine regulator of the metabolic activities and internal
plexus between the inner circular and outer longitudinal layers of smooth
environment of the organism, acting to provide conditions in which it
muscle (M) in the wall of the human intestine. An enteric ganglionic
can function successfully. Neural and neuroendocrine axes appear to
neurone is arrowed. (Courtesy of Mr Peter Helliwell and the late Dr
cooperate to modulate some forms of immunological reaction; the
Joseph Mathew, Department of Histopathology, Royal Cornwall Hospitals
extensive system of vessels, circulating hormones and nerve fibres that
Trust, UK.)
link the brain with all viscera are thought to constitute a neuroimmune
network (Fig. 3.26).
ganglion, e.g. substance P-containing axons of dorsal root neurones
Some cells can take up and decarboxylate amine precursor com-
synapse on neurones in prevertebral ganglia, thereby enabling interac-
pounds (amine precursor uptake and decarboxylation, or APUD, cells).


tions between the sensory system and the ANS.
They are characterized by dense-core cytoplasmic granules (see Fig. 2.6),
similar to the neurotransmitter vesicles seen in some types of neuronal
Enteric ganglia
terminal. The group includes cells described as chromaffin cells (phaeo-
chromocytes), derived from neuroectoderm and innervated by pregan-
The enteric nervous system (ENS) lies within the walls of the gastroin- glionic sympathetic nerve fibres. Chromaffin cells synthesize and secrete
testinal tract (see Fig. 2.15 for the layers of a typical viscus) and includes catecholamines (dopamine, noradrenaline (norepinephrine) or adren-
the myenteric and submucosal plexuses and associated ganglia (Furness aline (epinephrine)). Their name refers to the finding that their cyto-
2012, Neunlist et al 2013). The ganglionic neurones (Fig. 3.25) serve plasmic store of catecholamines is sufficiently concentrated to give an
different functions, including the regulation of gut motility (in conjunc- intense yellow–brown colouration, the positive chromaffin reaction,
tion with interstitial cells of Cajal (Huizinga et al 2009)), mucosal when they are treated with aqueous solutions of chromium salts, par-
transport and mucosal blood flow. Unlike the other two divisions of ticularly potassium dichromate. Classic chromaffin cells include clus-
the ANS, the ENS is largely independent of the CNS, and the extrinsic ters of cells in the suprarenal medulla; the para-aortic bodies, which
autonomic fibres that supply the gut wall exert only modulatory effects secrete noradrenaline; paraganglia; certain cells in the carotid bodies;
on it. Submucosal neurones, together with sympathetic axons, regulate and small groups of cells irregularly dispersed among the paravertebral
the local blood flow. sympathetic ganglia, splanchnic nerves and prevertebral autonomic
Hirschsprung’s disease is a congenital disease in which dysfunctional plexuses.
neural crest migration means that the ganglia of both the myenteric and The alimentary tract contains a large population of cells of a similar


submucosal plexuses in the distal bowel fail to develop. The resulting type (previously called neuroendocrine or enterochromaffin cells)
lack of propulsive activity in the aganglionic bowel leads to functional in its wall. These cells act as sensory transducers, activating intrinsic
obstruction and megacolon, which can be life-threatening. Around 1 in and extrinsic primary afferent neurones via their release of 5-
5,000 infants is born with the condition and is typically diagnosed in hydroxytryptamine (5-HT, serotonin). The neonatal respiratory tract


Sensory endings
59
3
RETPAHC
Brainstem receptor and partly in the neurone that innervates it, in the case of
epithelial receptors. Transduction varies with the modality of the stimu-
Sensory vagal neurone lus, and usually causes depolarization of the receptor membrane (or
hyperpolarization, in the retina). In mechanoreceptors, transduction
may involve the deformation of membrane structure, which causes
Prevertebral sympathetic ganglion either strain or stretch-sensitive ion channels to open. In chemorecep-
tors, receptor action may resemble that for ACh at neuromuscular
Spinal sensory neurone Immune and tissue junctions. Visual receptors share similarities with chemoreceptors:
defence signals:
light causes changes in receptor proteins, which activate G proteins,
Spinal cord local and systemic
Intestinofugal resulting in the release of second messengers and altered membrane
neurone permeability.
Neurocrine signals: The quantitative responses of sensory endings to stimuli vary greatly
local and circulating and increase the flexibility of the functional design of sensory systems.
Although increased excitation with increasing stimulus level is a
Intrinsic common pattern (‘on’ response), some receptors respond to decreased
sensory stimulation (‘off’ response). Even unstimulated receptors show varying
neurone degrees of spontaneous background activity against which an increase
or decrease in activity occurs with changing levels of stimulus. In all
Stretch
Gut lumen
r thec ee rp
e
to isr s
a
nst u ind ii te id a,
l
w buh re sn
t
(s tt him
e
u dl ya nti ao mn icis pm ha ai sn e)ta i fn oe lld
o
wa et da bs yte a ad gy
r
ale dv ue al l,
adaptation to steady level (the static phase). Though all receptors show
Signals from lumen these two phases, one or other may predominate, providing a distinc-
e.g. nutrients, antigens,
tion between rapidly adapting endings that accurately record the rate
irritants, secretions
of stimulus onset, and slowly adapting endings that 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


Fig. 3.26 The ways in which the nervous system, neuroendocrine system and also in the frequency of action potentials in the sensory fibres. The
and immune system are integrated, demonstrated in the intestine. stimulus strength necessary to elicit a response in a receptor, i.e. its
Neurocrine signals from enteric neuroendocrine cells and signals from threshold level, varies greatly between receptors, and provides an extra
immune defence cells (e.g. lymphocytes, macrophages and mast cells) level of information about stimulus strength.
act on other cells of those systems and on neurones with sensory For further information on sensory receptors, see Nolte (2008).
endings in the intestinal wall, either locally or at a distance. Some
neuronal soma lie within enteric ganglia in the gut wall; others have their
bodies in peripheral ganglia. Neuronal signals may act locally, be FUNCTIONAL CLASSIFICATION OF RECEPTORS
transmitted to the CNS or enter a reflex pathway via sympathetic ganglia.
Receptors have been classified in several ways. They may be classified
by the modalities to which they are sensitive, such as mechanoreceptors
contains a prominent system of neuroendocrine cells, both dispersed (which are responsive to deformation, e.g. touch, pressure, sound waves,
and aggregated (neuroepithelial bodies); the numbers of both types etc.), chemoreceptors, photoreceptors and thermoreceptors. Some re-
decline during childhood. Merkel cells (see Commentary 1.3) in the ceptors are polymodal, i.e. they respond selectively to more than one
basal epidermis of the skin store neuropeptides, which they release modality; they usually have high thresholds and respond to damaging
to associated nerve endings or other cells in a neuroendocrine role, in stimuli associated with irritation or pain (nociceptors).
response to pressure and possibly other stimuli (Lucarz and Brand Another widely used classification divides receptors on the basis of
2007). Experimental animal studies have revealed 5-HT-containing their distribution in the body into exteroceptors, proprioceptors and
intraepithelial paraneurones in the urothelial lining of the urethra; interoceptors. Exteroceptors and proprioceptors are receptors of the
these cells are thought to relay information from the luminal surface somatic afferent components of the nervous system, while interoceptors


of the urethra to underlying sensory nerves. are receptors of the visceral afferent pathways.
A number of descriptions and terms have been applied to cells of Exteroceptors respond to external stimuli and are found at, or close
this system in the older literature (see online text for details). to, body surfaces. They can be subdivided into the general or cutaneous
For further reading, see Day and Salzet (2002). sense organs and special sensory organs. General sensory receptors
include free and encapsulated terminals in skin and near hairs; none
of these has absolute specificity for a particular sensory modality.
SENSORY ENDINGS
Special sensory organs are the olfactory, visual, acoustic, vestibular and
taste receptors.
GENERAL FEATURES OF SENSORY RECEPTORS Proprioceptors respond to stimuli to deeper tissues, especially of the
locomotor system, and are concerned with detecting movement,
There are three major forms of sensory receptor: neuroepithelial, epi- mechanical stresses and position. They include Golgi tendon organs,
thelial and neuronal (Fig. 3.27). muscle spindles, Pacinian corpuscles, other endings in joints, and ves-
A neuroepithelial receptor is a neurone with a soma lying near a tibular receptors. Proprioceptors are stimulated by the contraction of
sensory surface and an axon that conveys sensory signals into the CNS muscles, movements of joints and changes in the position of the body.
to synapse on second-order neurones. This is an evolutionarily primi- They are essential for the coordination of muscles, the grading of mus-
tive arrangement, and the only examples remaining in humans are the cular contraction, and the maintenance of equilibrium.
sensory neurones of the olfactory epithelium. Interoceptors are found in the walls of the viscera, glands and vessels,
An epithelial receptor is a cell that is modified from a non-nervous where their terminations include free nerve endings, encapsulated ter-
sensory epithelium and innervated by a primary sensory neurone with minals and endings associated with specialized epithelial cells. Nerve
a soma lying near the CNS, e.g. auditory receptors and taste buds. When terminals are found in the layers of visceral walls and the adventitia of
activated, this type of receptor excites its neurone by neurotransmission blood vessels, but the detailed structure and function of many of these


across a synaptic gap. endings are not well established. Encapsulated (lamellated) endings
A neuronal receptor is a primary sensory neurone that has a soma occur in the heart, adventitia and mesenteries. Free terminal arboriza-
in a craniospinal ganglion and a peripheral axon ending in a sensory tions occur in the endocardium, the endomysium of all muscles, and
terminal. All cutaneous sensors and proprioceptors are of this type; connective tissue generally. Tension produced by excessive muscular
their sensory terminals may be encapsulated or linked to special meso- contraction or by visceral distension often causes pain, particularly in
dermal or ectodermal structures to form a part of the sensory apparatus. pathological states, which is frequently poorly localized and of a deep-
The extraneural cells are not necessarily excitable, but create an appro- seated nature. Visceral pain is often referred to the corresponding der-
priate environment for the excitation of the neuronal process. matome (see Fig. 16.10). Polymodal nociceptors (irritant receptors)
The receptor stimulus is transduced into a graded change of electrical respond to a variety of stimuli such as noxious chemicals or damaging
potential at the receptor surface (receptor potential), and this initiates mechanical stimuli. They are mainly the free endings of fine, unmyeli-
an all-or-none action potential that is transmitted to the CNS. This may nated fibres that are widely distributed in the epithelia of the alimentary
occur either in the receptor, when this is a neurone, or partly in the and respiratory tracts; they may initiate protective reflexes.


Nervous system
59.e1
3
RETPAHC
They include: clear cells (so named because of their poor staining
properties in routine preparations); argentaffin cells (reduce silver
salts); argyrophil cells (absorb silver); small intensely fluorescent cells;
peptide-producing cells (particularly of the hypothalamus, hypophysis,
pineal and parathyroid glands, and placenta); Kulchitsky cells in the
lungs; and paraneurones. Many cells of the dispersed (or diffuse) neu-
roendocrine system are derived embryologically from the neural crest.
Some – in particular, cells from the gastrointestinal system – are now
known to be endodermal in origin.


NERvOuS SySTEm
60
1
NOITCES
Free endings:
Rapidly adapting mechanoreceptor
Thermoreceptor (hot and cold)
Type I Slowly adapting mechanoreceptor
(Merkel cell ending)
Nociceptor
Type II Slowly adapting mechanoreceptor Rapidly adapting lamellated (Pacinian) corpuscle Rapidly adapting ‘field’ mechanoreceptor
(Ruffini ending) (Meissner’s corpuscle)
Fig. 3.27 Some major types of sensory ending of general afferent fibres (omitting neuromuscular, neurotendinous and hair-related types). The traces
below each type of ending indicate (top) their response (firing rate (vertical lines) and adaption with time) to an appropriate stimulus (below) of the
duration indicated. The Pacinian corpuscle’s response to vibration (rapid sequence of on–off stimuli) is also shown.
Interoceptors include vascular chemoreceptors, e.g. the carotid body, Special types of free ending are associated with epidermal structures
and baroceptors, which are concerned with the regulation of blood flow in the skin. They include terminals associated with hair follicles (peri-
and pressure and the control of respiration. trichial 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
FREE NERVE ENDINGS respond mainly to movement when hair is deformed and belong to the
rapidly adapting mechanoreceptor group.
Sensory endings that branch to form plexuses occur in many sites (see Merkel tactile endings (see Commentary 1.3) lie either at the base
Fig. 3.27). They occur in all connective tissues, including those of the of the epidermis or around the apical ends of some hair follicles, and
dermis, fasciae, capsules of organs, ligaments, tendons, adventitia of most are innervated by large myelinated axons. Each axon expands into
blood vessels, meninges, articular capsules, periosteum, perichon- a disc that is applied closely to the base of a Merkel cell in the basal


drium, Haversian systems in bone, parietal peritoneum, walls of viscera layer of the epidermis. The cells are believed to be derived from the
and the endomysium of all types of muscle. They also innervate the epidermis, although a neural crest origin remains possible. They contain
epithelium of the skin, cornea, buccal cavity, and the alimentary and many large (50–100 nm) dense-core vesicles, presumably containing
respiratory tracts and their associated glands. Within epithelia, free transmitters. Merkel endings are thought to be slow-adapting mech-
sensory endings lack Schwann cell ensheathment and are enveloped anoreceptors, responsive to sustained pressure and sensitive to the
instead by epithelial cells. Afferent fibres from free terminals may be edges of applied objects. Their functions are controversial, however, and
myelinated or unmyelinated but are always of small diameter and low likely to be more varied.
conduction velocity. When afferent axons are myelinated, their termi-
nal arborizations lack a myelin sheath. These terminals serve several
sensory modalities. In the dermis, they may be responsive to moderate ENCAPSULATED ENDINGS
cold or heat (thermoreceptors); light mechanical touch (mechanore-
ceptors); damaging heat, cold or deformation (unimodal nociceptors); Encapsulated endings are a major group of special endings that includes
and damaging stimuli of several kinds (polymodal nociceptors). lamellated corpuscles of various kinds (e.g. Meissner’s, Pacinian), Golgi
Similar fibres in deeper tissues may also signal extreme conditions, tendon organs, neuromuscular spindles and Ruffini endings (see Fig.
which are experienced, as with all nociceptors, as ache or pain. Free 3.27). They exhibit considerable variety in their size, shape and distribu-
endings in the cornea, dentine and periosteum may be exclusively tion but share a common feature: namely, that each axon terminal is
nociceptive. encapsulated by non-excitable cells (Proske and Gandevia 2012).


Sensory endings
61
3
RETPAHC
Meissner’s corpuscles into the capsule or core, so that it is not clearly defined in mature cor-
puscles. The core consists of approximately 60 bilateral, compacted
lamellae lying on both sides of a central nerve terminal.
Meissner’s corpuscles are found in the dermal papillae of all parts of
Each corpuscle is supplied by a myelinated axon, which initially
the hand and foot, the anterior aspect of the forearm, the lips, palpebral
loses its myelin sheath and subsequently loses its ensheathing Schwann
conjunctiva and mucous membrane of the apical part of the tongue.
cell at its junction with the core. The naked axon runs through the
They are most concentrated in thick hairless skin, especially of the finger
pads, where there may be up to 24 corpuscles per cm2 in young adults. 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
Mature corpuscles are cylindrical in shape, approximately 80 µm long
short projections of unknown function into clefts in the lamellae. The
and 30 µm across, with their long axes perpendicular to the skin surface.
axon contains numerous large mitochondria, and minute vesicles,
Each corpuscle has a connective tissue capsule and central core com-
approximately 5 nm in diameter, which aggregate opposite the clefts.
posed of a stack of flat modified Schwann cells (Fig. 3.28). Meissner’s
The cells of the capsule and core lamellae are thought to be specialized
corpuscles are rapidly adapting mechanoreceptors, sensitive to shape
fibroblasts but some may be Schwann cells. Elastic fibrous tissue forms
and textural changes in exploratory and discriminatory touch; their
an overall external capsule to the corpuscle. Pacinian corpuscles are
acute sensitivity provides the neural basis for reading Braille text.
supplied by capillaries that accompany the axon as it enters the capsule.
Pacinian corpuscles act as very rapidly adapting mechanoreceptors.
Pacinian corpuscles
They respond only to sudden disturbances and are especially sensitive
to very-high-frequency vibration. The rapidity may be partly due to the


Pacinian corpuscles are situated subcutaneously in the palmar and
lamellated capsule acting as a high pass frequency filter, damping slow
plantar aspects of the hand and foot and their digits, the external geni-
distortions by fluid movement between lamellar cells. Groups of cor-
talia, arm, neck, nipple, periosteal and interosseous membranes, and
puscles respond to pressure changes, e.g. on grasping or releasing an
near joints and within the mesenteries (Fig. 3.29). They are oval, spheri-
object.
cal or irregularly coiled and measure up to 2 mm in length and
100–500 µm or more across; the larger ones are visible to the naked Ruffini endings
eye. Each corpuscle has a capsule, an intermediate growth zone and a
central core that contains an axon terminal. The capsule is formed by
Ruffini endings are slowly adapting mechanoreceptors. They are found
approximately 30 concentrically arranged lamellae of flat cells approxi-
in the dermis of thin, hairy skin, where they function as dermal stretch
mately 0.2 µm thick (see Fig. 3.28). Adjacent cells overlap and succes-
receptors and are responsive to maintained stresses in dermal collagen.
sive lamellae are separated by an amorphous proteoglycan matrix that
They consist of the highly branched, unmyelinated endings of myeli-
contains circularly orientated collagen fibres, closely applied to the
nated afferents. They ramify between bundles of collagen fibres within
surfaces of the lamellar cells. The amount of collagen increases with
a spindle-shaped structure, which is enclosed partly by a fibrocellular
age. The intermediate zone is cellular and its cells become incorporated
sheath derived from the perineurium of the nerve. Ruffini endings
appear electrophysiologically similar to Golgi tendon organs, which
they resemble, although they are less organized structurally. Similar
structures appear in joint capsules (see below).
Golgi tendon organs
Epidermis
Golgi tendon organs are found mainly near musculotendinous junc-
tions (Fig. 3.30), where more than 50 may occur at any one site. Each
terminal is closely related to a group of muscle fibres (up to 20) as they


insert into the tendon. Golgi tendon organs are approximately 500 µm
Tactile corpuscle
long and 100 µm in diameter, and consist of small bundles of tendon
Fig. 3.30 The 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.
Fig. 3.28 A tactile Meissner’s corpuscle in a dermal papilla in the skin,
demonstrated using the modified Bielschowsky silver stain technique.
(Courtesy of Professor N Cauna, University of Pittsburgh.)
Fig. 3.29 A Pacinian corpuscle in human dermis. (Courtesy of Mr Peter
Helliwell and the late Dr Joseph Mathew, Department of Histopathology,
Royal Cornwall Hospitals Trust, UK.)


NERvOuS SySTEm
62
1
NOITCES
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 larger and more numerous. A
single, thickly myelinated 1b afferent nerve fibre enters the capsule and
divides. Its branches, which may lose their ensheathing Schwann cells,
terminate in leaf-like enlargements containing vesicles and mitochon-
dria, which wrap around the tendon. A basal lamina or process of
Schwann cell cytoplasm separates the nerve terminals from the collagen
bundles that constitute the tendon. Golgi tendon organs are activated External capsule
by passive stretch of the tendon but are much more sensitive to active
contraction of the muscle. They are important in providing propriocep-
tive information that complements the information coming from neu-
Internal capsule
romuscular spindles. Their responses are slowly adapting and they
signal maintained tension.
Neuromuscular spindles
Neuromuscular spindles are mechanosensors essential for propriocep-
tion (Boyd 1985). Each spindle contains a few small, specialized Nuclear bag fibre
intrafusal muscle fibres, innervated by both sensory and motor nerve
fibres (Figs 3.31–3.32). The whole is surrounded equatorially by a Nuclear chain fibre
fusiform spindle capsule of connective tissue, consisting of an outer
perineurium-like sheath of flattened fibroblasts and collagen, and an Subcapsular space
inner sheath that forms delicate tubes around individual intrafusal
fibres (Fig. 3.33). A gelatinous fluid rich in glycosaminoglycans fills the
space between the two sheaths. Primary (anulospiral)
ending of group 1a
There are usually 5–14 intrafusal fibres (the number varies between afferent fibre
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 nuclear bag fibres, an equatorial cluster of nuclei makes
the fibre bulge slightly, whereas the nuclei in nuclear chain fibres form
a single axial row. Nuclear bag fibres are subdivided into bag1 and bag2


fibres, are greater in diameter than chain fibres and extend beyond the
surrounding capsule to the endomysium of nearby extrafusal muscle Secondary (flower
spray) ending of
fibres. Nuclear chain fibres are attached at their poles to the capsule or
group II afferent fibre
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. Dynamic bag1
fibres generally lack M lines, possess little sarcoplasmic reticulum, and
have an abundance of mitochondria and oxidative enzymes, but little
glycogen. Static bag2 fibres have distinct M lines and abundant glyco-
gen. Nuclear chain fibres have marked M lines, sarcoplasmic reticulum Trail ending of
γ-efferent fibre
and T-tubules, and abundant glycogen, but few mitochondria. Each
fibre type carries distinct myosin heavy chain isoforms. These variations
reflect the contractile properties of different intrafusal fibres.
Muscle spindles receive two types of sensory innervation via the Plate ending of
γ-efferent fibre
unmyelinated terminations of large myelinated axons. Primary (anulo-
spiral) 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.
M
Secondary (flower spray) endings, which may be spray-shaped or anular,
Plate ending of
are largely confined to bag2 and nuclear chain fibres, and are the
β-efferent fibre
branched terminals of somewhat thinner myelinated (group II) affer-
ents. They are varicose and spread in a narrow band on both sides of
the primary endings. They lie close to the sarcolemma, though not in
grooves. In essence, primary endings are rapidly adapting, while second-
Fig. 3.31 A neuromuscular spindle, showing nuclear bag and nuclear
ary endings have a regular, slowly adapting response to static stretch.
chain fibres within the spindle capsule (green); these are innervated by


There are three types of motor endings in muscle spindles. Two are
the sensory anulospiral and ‘flower spray’ afferent fibre endings (blue) and
from fine, myelinated, fusimotor (γ) efferents and one is from myeli-
by the γ and β fusimotor (efferent fibre) endings (red). The β efferent fibres
nated (β) efferent collaterals of axons that supply extrafusal slow twitch are collaterals of fibres innervating extrafusal slow twitch muscle cells (M).
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). acceleration. Moreover, they are under complex central control; efferent
Stimulation of the fusimotor and β-efferents causes contraction of the (fusimotor) nerve fibres, by regulating the strength of contraction, can
intrafusal fibres and, consequently, activation of their sensory endings. adjust the length of the intrafusal fibres and thereby the responsiveness
Muscle spindles signal the length of extrafusal muscle both at rest of spindle sensory endings. In summary, the organization of spindles
and throughout contraction and relaxation, the velocity of their con- allows them to monitor muscle conditions actively in order to compare
traction and changes in velocity. These modalities may be related to the intended and actual movements, and to provide a detailed input to
different behaviours of the three major types of intrafusal fibre and their spinal, cerebellar, extrapyramidal and cortical centres about the state of
sensory terminals. The sensory fusimotor endings of one type of nuclear the locomotor apparatus.
bag fibre (dynamic bag1) are particularly concerned with signalling
rapid changes in length that occur during movement, whilst those of
the second bag fibre type (static bag2) and of chain fibres are less JOINT RECEPTORS
responsive to movement. These elements can therefore detect complex
changes in the state of the extrafusal muscle surrounding spindles and The arrays of receptors situated in and near articular capsules provide
can signal fluctuations in length, tension, velocity of length change and information on the position, movements and stresses acting on joints.


Neuromuscular junctions
63
3
RETPAHC
Static bag2 deeper layers and other articular structures (e.g. the fat pad of the tem-
fibre poromandibular joint). They are rapidly adapting, low-threshold mech-
anoreceptors, sensitive to movement and pressure changes, and they
Dynamic bag1
fibre Long-chain respond to joint movement and transient stresses in the joint capsule.
fibre They are supplied by myelinated afferent axons but are probably not
Short-chain
fibres 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 and may serve, at
least in part, to prevent excessive stresses at joints by reflex inhibition
of the adjacent muscles. They are innervated by large myelinated affer-
Dynamic γ-efferent
ent axons.
Type IV endings are free terminals of myelinated and unmyelinated
Static γ-efferent
axons that ramify in articular capsules and the adjacent fat pads, and
II around the blood vessels of the synovial layer. They are high-threshold,
slowly adapting receptors and are thought to respond to excessive
II
movements, providing a basis for articular pain.
Afferent fibres
Ia
NEUROMUSCULAR JUNCTIONS
Static γ-efferent
Static β-efferent SKELETAL MUSCLE
Dynamic β-efferent
The most intensively studied effector endings are those that innervate
muscle, particularly skeletal muscle. All neuromuscular (myoneural)
junctions are axon terminals of motor neurones. They are specialized
for the release of neurotransmitter on to the sarcolemma of skeletal
muscle fibres, causing a change in their electrical state that leads to
contraction. Each axon branches near its terminal to innervate from
several to hundreds of muscle fibres, the number depending on the
precision of motor control required (Shi et al 2012).
The detailed structure of a motor terminal varies with the type of
muscle innervated. Two major types of ending are recognized, innervat-
Collaterals to
extrafusal muscle ing either extrafusal muscle fibres or the intrafusal fibres of neuromus-


cular spindles. In the former type, each axonal terminal usually ends
Fig. 3.32 Nuclear bag and nuclear chain fibres in a neuromuscular midway along a muscle fibre in a discoidal motor end-plate (Fig.
spindle. Dynamic β- and γ-efferents innervate dynamic bag1 intrafusal
3.34A), and usually initiates action potentials that are rapidly con-
fibres, whereas static β- and γ-efferents innervate static bag2 and nuclear
ducted to all parts of the muscle fibre. In the latter type, the axon gives
chain intrafusal fibres.
off numerous branches that form a cluster of small expansions extend-
ing along the muscle fibre; in the absence of propagated muscle excita-
tion, these excite the fibre at several points. Both types of ending are
associated with a specialized receptive region of the muscle fibre, the
sole plate, where a number of muscle cell nuclei are grouped within the
granular sarcoplasm.
MM The sole plate contains numerous mitochondria, endoplasmic retic-
ulum and Golgi complexes. The terminal branches of the axon are
plugged into shallow grooves in the surface of the sole plate (primary
CC
clefts), from where numerous pleats extend for a short distance into the
underlying sarcoplasm (secondary clefts) (Fig. 3.34B,C). The axon ter-
minal contains mitochondria and many clear, 60 nm spherical vesicles
similar to those in presynaptic boutons, which are clustered over the
zone of membrane apposition. It is ensheathed by Schwann cells whose
cytoplasmic projections extend into the synaptic cleft. The plasma
membranes of the axon terminal and the muscle cell are separated by
IIFF
a 30–50 nm gap and an interposed basal lamina, which follows the
CC surface folding of the sole-plate membrane into the secondary clefts.
Endings of fast and slow twitch muscle fibres differ in detail: the sarco-
lemmal grooves are deeper, and the presynaptic vesicles more numer-
ous, in the fast fibres.
Fig. 3.33 A neuromuscular spindle in transverse section in a human Junctions with skeletal muscle are cholinergic: the release of ACh
extraocular muscle. The spindle capsule (C) encloses intrafusal fibres (IF)


changes the ionic permeability of the muscle fibre (Sine 2012). Cluster-
of varying diameters. Typical muscle fibres (M) in transverse section are
ing of ACh receptors at the neuromuscular junction depends in part on
shown above the spindle. Toluidine blue stained resin section.
the presence in the muscle basal lamina of agrin, which is secreted by
the motor neurone, and is important in establishing the postjunctional
Structural and functional studies have demonstrated at least four types molecular machinery. When the depolarization of the sarcolemma
of joint receptor; their proportions and distribution vary with site. Three reaches a particular threshold, it initiates an action potential in the
are encapsulated endings, the fourth a free terminal arborization. sarcolemma, which is then propagated rapidly over the whole cell
Type I endings are encapsulated corpuscles of the slowly adapting surface and also deep within the fibre via the invaginations (T-tubules)
mechanoreceptor type and resemble Ruffini endings. They lie in the of the sarcolemma, causing contraction. The amount of ACh released
superficial layers of the fibrous capsules of joints in small clusters and by the arrival of a single nerve impulse is sufficient to trigger an action
are innervated by myelinated afferent axons. Being slowly adapting, potential. However, because ACh is very rapidly hydrolysed by the
they provide awareness of joint position and movement, and respond enzyme AChE, present at the sarcolemmal surface of the sole plate, a
to patterns of stress in articular capsules. They are particularly common single nerve impulse only gives rise to one muscle action potential, i.e.
in joints where static positional sense is necessary for the control of there is a one-to-one relationship between neuronal and muscle action
posture (e.g. hip, knee). potentials. Thus the contraction of a muscle fibre is controlled by the
Type II endings are lamellated receptors and resemble small versions firing frequency of its motor neurone.
of the large Pacinian corpuscles found in general connective tissue. They Neuromuscular junctions are partially blocked by high concentra-
occur in small groups throughout joint capsules, particularly in the tions of lactic acid, as in some types of muscle fatigue.


NERvOuS SySTEm
64
1
NOITCES
A Fig. 3.34 The neuromuscular junction. A, Whole-mount preparation of teased
skeletal muscle fibres (pale, faintly striated, diagonally orientated structures).
The terminal part of the axon (silver-stained, brown) branches to form motor
end-plates on adjacent muscle fibres. The sole plate recesses in the
sarcolemma, into which the motor end-plates fit, are demonstrated by the
presence of acetylcholinesterase (shown by enzyme histochemistry, blue).
B, The axonal motor end-plate and the deeply infolded sarcolemma.
C, Electron micrograph showing the expanded motor end-plate of an axon
filled with vesicles containing synaptic transmitter (ACh) (above); the deep
infoldings of the sarcolemmal sole plate (below) form subsynaptic gutters.
(A, Courtesy of Dr Norman Gregson, Division of Neurology, GKT School of
Medicine, London. C, Courtesy of Professor DN Landon, Institute of
Neurology, University College London.)
AUTONOMIC MOTOR TERMINATIONS
Autonomic neuromuscular junctions differ in several important ways
from the skeletal neuromuscular junction and from synapses in the
Motor axon Schwann cell CNS and PNS. There is no fixed junction with well-defined pre- and
postjunctional specializations. Unmyelinated, highly branched, post-
ganglionic autonomic axons become beaded or varicose as they reach
the effector smooth muscle. These varicosities are not static but move
along axons. They are packed with mitochondria and vesicles contain-
ing neurotransmitters, which are released from the varicosities during
B conduction of an impulse along the axon. The distance (cleft) between
the varicosity and smooth muscle membrane varies considerably
depending on the tissue, from 20 nm in densely innervated structures
such as the vas deferens to 1–2 µm in large elastic arteries. Unlike skel-
etal muscle, the effector tissue is a muscle bundle rather than a single
cell. Gap junctions between individual smooth muscle cells are low-
resistance pathways that allow electronic coupling and the spread of
activity within the effector bundle; they vary in size from punctate junc-


tions to junctional areas of more than 1 µm in diameter.
Adrenergic sympathetic postganglionic terminals contain dense-
cored vesicles. Cholinergic terminals, which are typical of all parasym-
pathetic and some sympathetic endings, contain clear spherical vesicles
like those in the motor end-plates of skeletal muscle. A third category
of autonomic neurones has non-adrenergic, non-cholinergic endings
Muscle cell
Muscle nucleus that contain a wide variety of chemicals with transmitter properties.
sole plate Motor end-plate with ATP is a neurotransmitter at these terminals, which express purinergic
synaptic vesicles receptors (Burnstock et al 2011). The axons typically contain large,
Motor end-plate
80–200 nm, dense opaque vesicles, congregated in varicosities at inter-
vals along their length. These terminals are formed in many sites,
including the lungs, blood vessel walls, the urogenital tract and the
C external muscle layers and sphincters of the gastrointestinal tract. In the
intestinal wall, neuronal somata lie in the myenteric plexus, and their
axons spread caudally for a few millimetres, mainly to innervate circular
muscle. Purinergic neurones are under cholinergic control from pregan-
glionic sympathetic neurones. Their endings mainly hyperpolarize
smooth muscle cells, causing relaxation, e.g. preceding peristaltic waves,
opening sphincters and, probably, causing reflex distension in gastric
filling. Autonomic efferents innervate exocrine glands, myoepithelial
cells, adipose tissue (noradrenaline (norepinephrine) released from
postganglionic sympathetic axons binds to β-receptors on adipocytes
3
to stimulate lipolysis) and the vasculature and parenchymal fields of
lymphocytes and associated cells in several lymphoid organs, including
the thymus, spleen and lymph nodes.
CNS–PNS TRANSITION ZONE
The transition between CNS and PNS usually occurs some distance
from the point at which nerve roots emerge from the brain or the spinal
cord. The segment of root that contains components of both CNS and
PNS tissue is called the CNS–PNS transition zone (TZ). All axons in the


PNS, other than postganglionic autonomic neurones, cross such a TZ.
Macroscopically, as a nerve root is traced towards the spinal cord or the
brain, it splits into several thinner rootlets that may, in turn, subdivide
into minirootlets. The TZ is located within either rootlet or minirootlet
(Fig. 3.35). The arrangement of roots and rootlets varies according to
whether the root trunk is ventral, dorsal or cranial. Thus, in dorsal roots,
the main root trunk separates into a fan of rootlets and minirootlets
that enter the spinal cord in sequence along the dorsolateral sulcus. In
certain cranial nerves, the minirootlets come together central to the TZ
and enter the brain as a stump of white matter.


Conduction of the nervous impulse
65
3
RETPAHC
R R Nerve root
R CNS tissue
Glial fringe
Mantle zone
TZ
r1 r2 r3
R
R R R
SC BS
A B C D E F G
Fig. 3.35 The nerve root–spinal cord junction. A–G, Different CNS–PNS borderline arrangements. A, A pointed borderline. The extent of the transitional
zone (TZ) is indicated. B–G, Glial fringe omitted. B, A concave borderline (white line) and inverted TZ. C, A flat borderline situated at the level of the root
(R)–spinal cord junction. D and E, A convex, dome-shaped borderline; the CNS expansion into the rootlet is moderate in D and extensive in E. F, The
root (R) splits into rootlets (r), each with its own TZ and attaching separately to the spinal cord (SC). G, The arrangement found in several cranial nerve
roots (e.g. vestibulocochlear nerve). The PNS component of the root separates into a bundle of closely packed minirootlets, each equipped with a TZ.
The minirootlets reunite centrally. BS, brainstem. (Adapted with permission from Dyck PJ, Thomas PK, Griffin JW, et al (eds) Peripheral Neuropathy,
3rd ed. Philadelphia: Saunders, 1993.)
All-or-none action potentials
Graded potentials generated at nodes along axon
Membrane
potential
Excitation Inhibition Net effect at axon
(depolarization) (hyperpolarization) hillock is excitation
+40 mV
Time
0
-80 mV
Inhibitory
axon
Excitatory
axon
Conduction
Fig. 3.36 The types of change in electrical potential that can be recorded across the cell membrane of a motor neurone at the points indicated.
Excitatory and inhibitory synapses on the surfaces of the dendrites and soma cause local graded changes of potential that summate at the axon hillock
and may initiate a series of all-or-none action potentials, which in turn are conducted along the axon to the effector terminals.
Microscopically, the TZ is characterized by an axial CNS compart- thought to prevent cell mixing at these interfaces not only by helping


ment surrounded by a PNS compartment. The zone lies more peripher- dorsal root ganglion afferents navigate their path to targets in the spinal
ally in sensory nerves than in motor nerves, but in both, the apex of cord but also by inhibiting motoneurone cell bodies exiting to the
the TZ is described as a glial dome, whose convex surface is usually periphery. For further reading, see Zujovic et al (2011).
directed distally. The centre of the dome consists of fibres with a typical
CNS organization, surrounded by an outer mantle of astrocytes (cor-
CONDUCTION OF THE NERVOUS IMPULSE
responding to the glia limitans). From this mantle, numerous glial
processes project into the endoneurial compartment of the peripheral
nerve, where they interdigitate with its Schwann cells. The astrocytes All cells generate a steady electrical potential across their plasma mem-
form a loose reticulum through which axons pass. Peripheral myeli- brane (the membrane potential). This potential is generated by an
nated axons usually cross the zone at a node of Ranvier, which is here uneven distribution of potassium ions across the membrane (higher in
termed a PNS–CNS compound node. the intracellular compartment than in the extracellular compartment),
Boundary cap (BC) cells are neural crest derivatives that form tran- and by a selective permeability of the membrane for potassium (Fig.
sient, discrete clusters localized at the presumptive dorsal root entry 3.36). The distribution of sodium ions is opposite to that for potassium
zones and motor exit points of the embryonic spinal cord. They are ions, but at rest the sodium conductance of the membrane is low. In


NERvOuS SySTEm
66
1
NOITCES
neurones this membrane potential is known as the resting potential, tion of neighbouring membrane. Sodium channels within the newly
and amounts to approximately −60 mV (potential inside the cell meas- depolarized segment open and positively charged sodium ions enter,
ured relative to the outside of the cell). Non-excitable cells have an even driving the local potential inside the axon towards positive values. This
higher membrane potential. Neurones receive, conduct and transmit inward current in turn depolarizes the neighbouring, downstream, non-
information by changes in membrane conductance for sodium, potas- depolarized membrane, and the cyclic propagation of the action poten-
sium, calcium or chloride ions. Increase in the sodium or calcium tial is completed. Several milliseconds after the action potential, the
conductance causes an influx of these ions and results in a depolariza- sodium channels are inactivated, a period known as the refractory
tion of the cell, while chloride influx or potassium efflux results in period. The length of the refractory period determines the maximum
hyperpolarization. Plasma membrane permeability to these ions is frequency at which action potentials can be conducted along a nerve
altered by the opening or closing of ion-specific transmembrane chan- fibre; it varies in different neurones and affects the amount of informa-
nels, triggered by voltage changes or chemical signals such as transmit- tion that can be carried by an individual fibre.
ters (Catterall 2010). Myelinated fibres are electrically insulated by their myelin sheaths
Chemically triggered ionic fluxes may be either direct, where the along most of their lengths, except at nodes of Ranvier. The distance
chemical agent (neurotransmitter) binds to the channel itself to cause between nodes, referred to as the internodal distance, is directly related
it to open, or indirect, where the neurotransmitter is bound by a trans- to axon diameter and varies between 0.2 and 2.0 mm. Voltage-gated
membrane receptor molecule that activates a complex second messen- sodium channels are clustered at nodes, and the nodal membrane is
ger system within the cell to open separate transmembrane channels. the only place where high densities of inward sodium current can be
Electrically induced changes in membrane potential depend on the generated across the axon membrane. Conduction in myelinated axons


presence of voltage-sensitive ion channels, which, when the transmem- is self-propagating, but instead of physically adjacent regions of mem-
brane potential reaches a critical level, open to allow the influx or efflux brane acting to excite one another (as occurs along unmyelinated
of specific ions. In all cases, the channels remain open only transiently, axons), it is the depolarization occurring in the neighbouring upstream
and the numbers that open and close determine the total flux of ions node that excites a node to threshold. Reaching threshold causes the
across the membrane (Bezanilla 2008). sodium channels at the node to open and generate inward sodium
The types and concentrations of transmembrane channels and current, but instead of this acting on the adjacent membrane, the high
related proteins, and therefore the electrical activity of the membranes, resistance and low capacitance of the myelin sheath directs the current
vary in different parts of the cell. Dendrites and neuronal somata depend towards the next downstream node, exciting it to threshold and com-
mainly on neurotransmitter action and show graded potentials, whereas pleting the cycle. The action potential thus jumps from node to node,
axons have voltage-gated channels that give rise to action potentials. a process known as saltatory conduction, which greatly increases the
In graded potentials, a flow of current occurs when a synapse is conduction velocity.
activated; the influence of an individual synapse on the membrane A number of disorders of the CNS and PNS include demyelination
potential of neighbouring regions decreases with distance. Thus syn- as a characteristic feature. Perhaps most common amongst these is
apses on the distal tips of dendrites may, on their own, have relatively multiple sclerosis, which is characterized by primary demyelination at
little effect on the membrane potential of the cell body. The electrical scattered sites within the CNS (it is now recognized that axonal loss
state of a neurone therefore depends on many factors, including the also contributes to the progression of multiple sclerosis). Primary
numbers and positions of thousands of excitatory and inhibitory syn- demyelination is the loss of the myelin sheath with axonal preservation,
apses, their degree of activation, and the branching pattern of the den- and is usually segmental, i.e. it rarely extends along the entire length of
dritic tree and geometry of the cell body. The integrated activity directed an affected axon. The phenomenon is associated with conduction block


towards the neuronal cell body is converted to an output directed away because the newly exposed, previously internodal, axolemma contains
from the soma at the site where the axon leaves the cell body, at its relatively few voltage-sensitive Na+ channels. There is experimental evi-
junction with the axon hillock. Voltage-sensitive channels are concen- dence that conduction can be restored in some demyelinated axons,
trated at this trigger zone, the axon initial segment, and when this and experimental and clinical evidence that remyelinated axons can
region is sufficiently depolarized, an action potential is generated and conduct at near-normal speeds, because even though their sheaths are
is subsequently conducted along the axon. thinner than the original myelin sheaths, the safety factor (i.e. the factor
by which the outward current at a quiescent node next to an excited
node exceeds the minimum current required to evoke a response) is
ACTION POTENTIAL greater than 1. The myelin loss that occurs in the early stages of Walle-
rian degeneration in both CNS and PNS, usually distal to a site of
The action potential is a brief, self-propagating reversal of membrane trauma but also in response to a prolonged period of ischaemia or
polarity. It depends on an initial influx of sodium ions, which causes a exposure to a neuronotoxic substance, is accompanied by axonal degen-
reversal of polarity to about +20 mV, followed by a rapid return towards eration (the term secondary demyelination is sometimes used to
the resting potential as potassium ions flow out. The rapid reversal describe this form of myelin loss).
process is completed in approximately 0.5 msec, followed by a slower Axonal conduction is naturally unidirectional, from dendrites and
recovery phase of up to 5 msec, when the resting potential is even soma to axon terminals. When an action potential reaches the axonal
hyperpolarized. Once the axon hillock reaches threshold, propagation terminals, it causes depolarization of the presynaptic membrane, and
of the action potential is independent of the initiating stimulus; thus as a result, quanta of neurotransmitter (which correspond to the content
the size and duration of action potentials are always the same (described of individual vesicles) are released to change the degree of excitation of


as all-or-none) for a particular neurone, no matter how much a stimulus the next neurone, muscle fibre or glandular cell.
may exceed the threshold value.
Once initiated, an action potential spreads spontaneously and at a
relatively constant velocity, within the range of 4–120 m/s. Conduction
Bonus e-book image
velocity depends on a number of factors related to the way in which
the current spreads, e.g. axonal cross-sectional area, the numbers and
positioning of ion channels, and membrane capacitance (influenced
particularly by the presence of myelin). In axons lacking myelin, action Fig. 3.1 A section through the human cerebellum stained to show
potential conduction is analogous to a flame moving along a fuse. Just the arrangement in the brain of the central white matter and the
as each segment of fuse is ignited by its upstream neighbour, each highly folded outer grey matter.
segment of axon membrane is driven to threshold by the depolariza-


67
3
RETPAHC
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