medical-notes/content/Anatomi & Histologi 2/12 CNS histologi/12 Nerve Tissue.md

# NERVE TISSUE



**OVERVIEW OF THE NERVOUS SYSTEM**

**COMPOSITION OF NERVE TISSUE**

**THE NEURON**


Cell Body

Dendrites and Axons

Neuronal Transport Systems
Synapses

**SUPPORTING CELLS OF THE NERVOUS SYSTEM: THE**

**NEUROGLIA**


Peripheral Neuroglia
Schwann Cell Development and Synthesis of Myelin Sheath

Satellite Cells

Enteric Neuroglial Cells
Central Neuroglia
Impulse Conduction

**ORIGIN OF NERVE TISSUE CELLS**

**ORGANIZATION OF THE PERIPHERAL NERVOUS SYSTEM**


Peripheral Nerves
Connective Tissue Components of a Peripheral Nerve
Afferent (Sensory) Receptors

**ORGANIZATION OF THE AUTONOMIC NERVOUS SYSTEM**


Sympathetic and Parasympathetic Divisions of the Autonomic

Nervous System
Enteric Division of the Autonomic Nervous System

A Summarized View of Autonomic Distribution

**ORGANIZATION OF THE CENTRAL NERVOUS SYSTEM**


Cells of the Gray Matter
Organization of the Spinal Cord
Connective Tissue of the Central Nervous System

Blood–Brain Barrier

**RESPONSE OF NEURONS TO INJURY**


Degeneration
Regeneration

**Folder 12.1** Clinical Correlation: Parkinson Disease

**Folder 12.2** Clinical Correlation: Demyelinating Diseases

**Folder 12.3** Clinical Correlation: Reactive Gliosis: Scar Formation

in the Central Nervous System
**Folder 12.4** Clinical Correlation: Cognitive Impairments After

COVID-19 Infections


**HISTOLOGY**

### **OVERVIEW OF THE NERVOUS SYSTEM**


The **nervous system** enables the body to respond to continuous changes in
its external and internal environment. It controls and integrates the
functional activities of organs and organ systems. Anatomically, the nervous
system is divided into the following:


The **central nervous system (CNS)** consists of the brain and the spinal
cord, which are located in the cranial cavity and spinal canal, respectively.
The **peripheral nervous system (PNS)** consists of cranial, spinal, and
peripheral **nerves** that conduct impulses from (efferent or motor nerves)
and to (the afferent or sensory nerves of) the CNS; collections of nerve
cell bodies outside the CNS called **ganglia** ; and specialized nerve
endings (both motor and sensory). Interactions between sensory (afferent)
nerves that receive stimuli, the CNS that interprets them, and motor
(efferent) nerves that initiate responses create **neural pathways** . These
pathways mediate reflex actions called **reflex arcs** . In humans, most
sensory neurons do not pass directly into the brain but instead
communicate by specialized terminals (synapses) with motor neurons in
the spinal cord.


Functionally, the nervous system is divided into the following:


The **somatic nervous system (SNS)** consists of somatic _[Gr. soma,_
_body]_ parts of the CNS and PNS. The SNS controls functions that are
under conscious voluntary control, with the exception of reflex arcs. It
provides sensory and motor innervation to all parts of the body except
viscera, smooth and cardiac muscle, and glands.
The **autonomic nervous system (ANS)** consists of autonomic parts of
the CNS and PNS. The ANS provides efferent involuntary motor
innervation to smooth muscle, the conducting system of the heart, and
glands. It also provides afferent sensory innervation from the viscera
(pain and autonomic reflexes). The ANS is further subdivided into a
**sympathetic division** and a **parasympathetic division** . A third
division of ANS, the **enteric division**, serves the alimentary canal. It


communicates with the CNS through the parasympathetic and
sympathetic nerve fibers; however, it can also function independently of
the other two divisions of the ANS (see page 418).

### **COMPOSITION OF NERVE TISSUE**


**Nerve tissue consists of two principal types of cells: neurons and**
**supporting cells.**


The **neuron** or **nerve cell** is the functional unit of the nervous system. It
consists of a cell body, containing the nucleus, and several processes of
varying length. Nerve cells are specialized to receive stimuli from other
cells and to conduct electrical impulses to other parts of the system via their
processes. Several neurons are typically involved in sending impulses from
one part of the system to another. These neurons are arranged in a chain-like
manner as an integrated communications network. Specialized contacts
between neurons that provide for transmission of information from one
neuron to the next are called **synapses** .

**Supporting cells** are nonconducting cells that are located close to the
neurons. They are referred to as **neuroglial cells** or simply **glia** . The CNS
contains four types of glial cells: oligodendrocytes, astrocytes, microglia,
and ependymal cells (see page 409). Collectively, these cells are called the
**central neuroglia** . In the PNS, supporting cells are called **peripheral**
**neuroglia** and include Schwann cells, satellite cells, and a variety of other
cells associated with specific structures. Schwann cells surround the
processes of nerve cells and isolate them from adjacent cells and
extracellular matrix. Within the ganglia of the PNS, peripheral neuroglial
cells are called **satellite cells** . They surround the nerve cell bodies, the part
of the cell that contains the nucleus, and are analogous to nonmyelinating
Remak Schwann cells. The supporting cells of the ganglia in the wall of the
alimentary canal are called **enteric neuroglial cells** . They are
morphologically and functionally similar to central neuroglia (see page
409).

Functions of the various neuroglial cell types include the following:


Physical support (protection) for neurons
Insulation for nerve cell bodies and processes, which facilitates rapid
transmission of nerve impulses
Repair of neuronal injury
Regulation of the internal fluid environment of the CNS
Clearance of neurotransmitters from synaptic clefts


Metabolic exchange between the vascular system and the neurons of the
nervous system


In addition to neurons and supporting cells, an extensive vasculature is
present in both the CNS and the PNS. The **blood vessels** are separated
from the nerve tissue by the basal laminae and variable amounts of
connective tissue, depending on vessel size. The boundary between blood
vessels and nerve tissue in the CNS excludes many substances that normally
leave blood vessels to enter other tissues. This selective restriction of blood
borne substances in the CNS is called the **blood–brain barrier**, which is
discussed on page 424.


**The nervous system allows rapid response to external stimuli.**


The nervous system evolved from the simple neuroeffector system of
invertebrate animals. In primitive nervous systems, only simple receptor–
effector reflex loops exist to respond to external stimuli. In higher level
animals and humans, the SNS retains the ability to respond to stimuli from
the external environment through the action of effector cells (such as
skeletal muscle), but the neuronal responses are infinitely more varied. They
range from simple reflexes that require only the spinal cord to complex
operations of the brain, including memory and learning.


**The autonomic part of the nervous system regulates the function of**
**internal organs.**


The specific effectors in the internal organs that respond to the information
carried by autonomic neurons include the following:


**Smooth muscle** . Contraction of smooth muscle modifies the diameter or
shape of tubular or hollow viscera, such as the blood vessels, gut,
gallbladder, and urinary bladder.
**Cardiac-conducting cells (Purkinje fibers)** . These cells are located
within the conductive system of the heart. The inherent frequency of
Purkinje fiber depolarization regulates the rate of cardiac muscle
contraction and can be modified by autonomic impulses.
**Glandular epithelium** . The ANS regulates the synthesis, composition,
and release of secretions.


The regulation of the function of internal organs involves close
cooperation between the nervous system and the endocrine system. Neurons
in several parts of the brain and other sites behave as secretory cells and are
referred to as **neuroendocrine tissue** . The varied roles of neurosecretions


in regulating the functions of the endocrine, digestive, respiratory, urinary,
and reproductive systems are described in subsequent chapters.

### **THE NEURON**


**The neuron is the structural and functional unit of the nervous**

**system.**


The human nervous system contains more than 10 billion neurons. Although
neurons show the greatest variation in size and shape of any group of cells
in the body, they can be grouped into three general categories.


**Sensory neurons** convey impulses from receptors to the CNS.
Processes of these neurons are included in somatic afferent and visceral
afferent nerve fibers. **Somatic afferent fibers** convey sensations of pain,
temperature, touch, and pressure from the body surface. In addition, these
fibers convey pain and proprioception (nonconscious sensation) from
organs within the body (e.g., muscles, tendons, and joints) to provide the
brain with information related to the orientation of the body and limbs.
**Visceral afferent fibers** transmit pain impulses and other sensations
from internal organs, mucous membranes, glands, and blood vessels.
**Motor neurons** convey impulses from the CNS or ganglia to effector
cells. Processes of these neurons are included in somatic efferent and
visceral efferent nerve fibers. **Somatic efferent neurons** send voluntary
impulses to skeletal muscles. **Visceral efferent neurons** transmit
involuntary impulses to smooth muscle, cardiac-conducting cells
(Purkinje fibers), and glands (Fig. 12.1).


**FIGURE 12.1.** **Diagram of a motor neuron.** The nerve cell body,
dendrites, and proximal part of the axon are within the central nervous
system (CNS). The axon leaves the CNS and, while in the peripheral
nervous system (PNS), is part of a nerve (not shown) as it courses to its
effectors (striated muscle). In the CNS, the myelin for the axon is


produced by, and is part of, an oligodendrocyte; in the PNS, the myelin is
produced by, and is part of, a Schwann cell.


**Interneurons**, also called **intercalated** **neurons**, form a
communicating and integrative network between the sensory and motor
neurons. It is estimated that more than 99.9% of all neurons belong to this
integrative network.


**The functional components of a neuron include the cell body, axon,**
**dendrites, and synaptic junctions.**


The **cell body (perikaryon)** of a neuron contains the nucleus and the
organelles that maintain the cell. The processes extending from the cell body
constitute the single common structural characteristic of all neurons. Most
neurons have only one **axon**, usually the longest process extending from the
cell, which transmits impulses away from the cell body to a specialized
terminal (synapse). The synapse makes contact with another neuron or an
effector cell (e.g., a muscle cell or glandular epithelial cell). A neuron
usually has many **dendrites**, shorter processes that transmit impulses from
the periphery (i.e., other neurons) toward the cell body.


**Neurons are classified on the basis of the number of processes**
**extending from the cell body.**


Most neurons can be anatomically characterized as the following:


**Multipolar** neurons have one axon and two or more dendrites (Fig. 12.2).
The direction of impulses is from dendrite to cell body to axon or from
cell body to axon. Functionally, the dendrites and cell body of multipolar
neurons are the receptor portions of the cell, and their plasma membrane
is specialized for impulse generation. The axon is the conducting portion
of the cell, and its plasma membrane is specialized for impulse
conduction. The terminal portion of the axon, the synaptic ending,
contains various neurotransmitters—that is, small molecules released at
the synapse that affect other neurons as well as muscle cells and glandular
epithelium. **Motor neurons** and **interneurons** constitute most of the
multipolar neurons in the nervous system.


**FIGURE 12.2.** **Diagram illustrating different types of neurons.** The cell
bodies of pseudounipolar (unipolar), bipolar, and postsynaptic autonomic
neurons are located outside the central nervous system (CNS). Purkinje
and pyramidal cells are restricted to the CNS; many of them have
elaborate dendritic arborizations that facilitate their identification. The
central axonal branch and all axons are indicated in _green_ .


**Bipolar** neurons have one axon and one dendrite (see Fig. 12.2). Bipolar
neurons are rare. They are most often associated with the receptors for the
**special senses** (taste, smell, hearing, sight, and equilibrium). They are
generally found within the retina of the eye and the ganglia of the


vestibulocochlear nerve (cranial nerve VIII) of the ear. Some neurons in
this group do not fit the abovementioned generalizations. For example,
amacrine cells of the retina have no axons, and olfactory receptors
resemble neurons of primitive neural systems in that they retain a surface
location and regenerate at a much slower rate than other neurons.
**Pseudounipolar** (unipolar) neurons have one process, the axon that
divides close to the cell body into two long axonal branches. One branch
extends to the periphery ( **peripheral dendritic branch** ), and the other
extends to the CNS ( **central axonal branch** ; see Fig. 12.2). The two
axonal branches are the conducting units. Impulses are generated in the
peripheral arborizations (branches) of the neuron that are the receptor
portions of the cell. Each pseudounipolar neuron develops from a bipolar
neuron as its axon and dendrite migrate around the cell body and fuse into
a single process. The majority of pseudounipolar neurons are **sensory**
**neurons** located close to the CNS (Fig. 12.3). Cell bodies of sensory
neurons are situated in the **dorsal root ganglia** and **cranial nerve**
**ganglia** .


**FIGURE 12.3.** **Schematic diagram showing arrangement of motor and**
**sensory neurons.** The cell body of a motor neuron is located in the
ventral (anterior) horn of the gray matter of the spinal cord. Its axon,
surrounded by myelin, leaves the spinal cord via a ventral (anterior) root


and becomes part of a spinal nerve that carries it to its destination on
striated (skeletal) muscle fibers. The sensory neuron originates in the skin
within a receptor (here, a Pacinian corpuscle) and continues as a
component of a spinal nerve, entering the spinal cord via the dorsal
(posterior) root. Note the location of its cell body in the dorsal root ganglion
(sensory ganglion). A segment of the spinal nerve is enlarged to show the
relationship of the nerve fibers to the surrounding connective tissue
(endoneurium, perineurium, and epineurium). In addition, segments of the
sensory, motor, and autonomic unmyelinated neurons have been enlarged
to show the relationship of the axons to the Schwann cells. _ANS_,
autonomic nervous system.

### **Cell Body**


**The cell body of a neuron has characteristics of a protein-**
**producing cell.**


The **cell body** is the dilated region of the neuron that contains a large,
euchromatic **nucleus** with a prominent nucleolus and surrounding
**perinuclear cytoplasm** (Fig.12.4a and Plate 12.1, page 432). The
perinuclear cytoplasm reveals abundant rough-surfaced endoplasmic
reticulum (rER) and free ribosomes when observed with the transmission
electron microscope (TEM), a feature consistent with its protein synthetic
activity. In the light microscope (LM), the ribosomal content appears as
small bodies called **Nissl bodies** that stain intensely with basic dyes and
metachromatically with thionine dyes (see Fig. 12.4a). Each Nissl body
corresponds to a stack of rER.


**FIGURE 12.4.** **Nerve cell bodies. a.** This photomicrograph shows a region
of the ventral (anterior) horn of a human spinal cord stained with toluidine
blue. Typical features of the nerve cell bodies visible in this image include
large, spherical, pale-stained nuclei with a single prominent nucleolus and
abundant Nissl bodies within the cytoplasm of the nerve cell body. Most of
the small nuclei belong to neuroglial cells. The remainder of the field consists
of nerve fibers and cytoplasm of central neuroglial cells. ×640. **b.** Electron
micrograph of a nerve cell body. The cytoplasm is occupied by aggregates of


free ribosomes and profiles of rough-surfaced endoplasmic reticulum ( _rER_ )
that constitute the Nissl bodies of light microscopy. The Golgi apparatus ( _G_ )
appears as isolated areas containing profiles of flattened sacs and vesicles.
Other characteristic organelles include mitochondria ( _M_ ) and lysosomes ( _L_ ).
The neurofilaments and neurotubules are difficult to discern at this relatively
low magnification. ×15,000.


The perinuclear cytoplasm also contains numerous mitochondria, a large
perinuclear Golgi apparatus, lysosomes, microtubules, microtubuleorganizing center (MTOC) (centrosome), neurofilaments (intermediate
filaments), transport vesicles, and inclusions (Fig. 12.4b). Nissl bodies, free
ribosomes, and, occasionally, the Golgi apparatus extend into the dendrites,
but not into the axon. The euchromatic nucleus, large nucleolus, prominent
Golgi apparatus, and Nissl bodies indicate the high level of anabolic activity
needed to maintain these large cells.

Location of the MTOC in the perinuclear cytoplasm usually corresponds
to the site of the axon origin. This area of the cell body, called the **axon**
**hillock**, lacks large cytoplasmic organelles and serves as a landmark to
distinguish between axons and dendrites in both LM and TEM preparations.


**Neurons do not divide; however, in some areas of the brain, neural**
**stem cells are present and are able to differentiate and replace**
**damaged nerve cells.**


Although neurons do not replicate, the subcellular components of the
neurons are regularly renewed and have life spans measured in hours, days,
and weeks. The constant need to replace enzymes, neurotransmitter
substances, membrane components, and other complex molecules is
consistent with the morphologic features characteristic of a high level of
synthetic activity. Newly synthesized protein molecules are transported to
distant locations within a neuron in a process referred to as **neuronal**
**transport** (pages 396-397).

It is generally accepted that nerve cells do not divide. However, recently,
it has been shown that the adult brain retains some cells that exhibit the
potential to regenerate. In certain regions of the brain, such as the olfactory
bulb and dentate gyrus of the hippocampus, these **neural stem cells** are
able to divide and generate new neurons. They are characterized by
continuous expression of a 240-kDa intermediate filament protein **nestin**,
which is used to identify these cells by histochemical methods. **Neural**
**stem cells** are also able to migrate to the sites of injury and
differentiate into new nerve cells. Research studies on animal models
demonstrate that newly generated cells mature into functional
neurons in the adult mammalian brain. These findings may lead to


therapeutic strategies that use neural cells to replace nerve cells lost
or damaged by neurodegenerative disorders, such as Alzheimer and
Parkinson diseases.

### **Dendrites and Axons**


As mentioned earlier, neurons extend two distinct types of nerve processes:
dendrites and axons, which contain different types of proteins and organelles
and thus differ in both structure and function.


**Dendrites are receptor processes that receive stimuli from other**
**neurons or the external environment.**


The main function of **dendrites** is to receive information from other
neurons or the external environment and carry that information to the cell
body. Generally, dendrites are located in the vicinity of the cell body. They
have a greater diameter than axons and are usually unmyelinated and
tapered. Dendrites form extensive arborizations called **dendritic trees** .
Dendritic trees significantly increase the receptor surface area of a neuron.
Many neuron types are characterized by the extent and shape of their
dendritic trees (see Fig. 12.2). In most of the excitatory neurons, they
possess **dendritic spines** .

In general, the contents of the perinuclear cytoplasm of the cell body and
cytoplasm of dendrites are quite similar. Other organelles characteristic of
the cell body, including **ribosomes** and **rER**, are found in the dendrites,
especially in the base of the dendrites. In addition, small **Golgi outposts**,
which are discrete functional Golgi structures not connected with the Golgi
apparatus in the cell body, are present in the cytoplasm of dendrites and may
serve as nucleation centers for microtubules.


**Dendrites are characterized by the presence of dendritic spines that**
**are involved in synaptic plasticity, learning, and memory formation.**


Many neurons in the CNS have dendrites that can be identified by the
presence of **dendritic spines** (Fig. 12.5). They represent small protrusions
of the dendritic plasma membrane containing actin filaments and
postsynaptic density. Their shape varies considerably from short projections,
resembling thin filopodia–like structures to mushroom-shaped structures.
The mushroom-shaped spines are regarded as mature spines and account for
the majority (~70%–80%) of spines found on dendrites.


**FIGURE 12.5.** **Three-dimensional (3D) computer reconstructions of**
**nerve cell processes from the mouse somatosensory cerebral cortex** .
These images represent computer-generated 3D renderings of nerve cells
and their processes extracted from a high-resolution stack of 1,850 scanning
electron microscope (SEM) images of serially sectioned brain tissue. The
automated tape-collecting ultramicrotome (ATUM) was used to cut 29-nmthick sections that were stained with osmium and carbon coated for imaging
with the SEM at sufficient resolution to detect individual synaptic vesicles. A
multiscale digital volume image set was then processed for automated
annotation and segmentation of nerve cell processes and organelles.
Segmented structures were manually painted with a computer-assisted
program and combined in a 3D data set. **a.** This image shows the 3D
rendering of a single dendrite containing spines. Note the branching pattern
of the dendrite. **b.** Semitransparent rendering of synaptic interactions
between dendrite ( _red_ ) and axon ( _green_ ). In this image, dendritic spines form
five synapses (arrows) with the same axon; the postsynaptic densities are
indicated in _yellow_ . ×13,000. (Courtesy of Drs. Daniel Berger and Jeff W.
Lichtman, Harvard University, Cambridge, MA.)


Electron micrographs of mature dendritic spines reveal the presence of a
**postsynaptic density** that contains clusters of neurotransmitter receptors
as well as voltage-gated Na [+] and K [+] channels similar to those found in nerve
synapses. The spines also appear to have a well-developed actin
cytoskeleton associated with a variety of actin-binding proteins, occasional
microtubules, and vesicles with elongated profiles of endoplasmic reticulum.
The postsynaptic density is apposed by a plasma membrane of the
neighboring axon containing an active zone with round synaptic vesicles
(Fig. 12.6) that forms a fully functional synapse. Most of the synapses
formed between dendritic spines and axons contain the neurotransmitter
**glutamate** **(GLU)**, which mediates fast **excitatory** **synaptic**
**transmission** in the CNS (see pages 401-403).


**FIGURE 12.6.** **Electron micrograph of dendritic spines in proximal**
**dendrites of pyramidal nerve cells in the mouse hippocampus.** Thin
slices (300 μm) of brain tissue were cultured for a period of 1–2 weeks,
allowing for damaged tissue to recover and reorganize in vitro by removing
cell debris from the tissue slices. After incubation, slices were prepared for
electron microscopy (EM) using high-pressure freezing followed by
cryosubstitution of tissue water with acetone, stained with osmium, and
embedded in an EM-suitable medium. This preparation provides exceptional
quality of EM images by avoiding that distortion of the tissue by protein
denaturation that occurs in conventional fixation in aldehydes. Note that
dendritic spines are surrounded by a large synaptic button ( _SB_ ) containing


synaptic vesicles. _Arrowheads_ indicate postsynaptic densities. In these
areas, synaptic clefts are visible separating active zones of presynaptic
elements from postsynaptic densities. Spine cytoplasm contains an actin
cytoskeleton with occasional profiles of smooth-surfaced endoplasmic
reticulum ( _sER_ ) and transport vesicles visible in the narrow part of the spine.
Note an electron-dense organelle, which most likely represents
mitochondrion ( _M_ ). Several profiles of dendrites ( _D_ ) are also visible. The
large profile on the _left_ most likely represents an oblique section of the
unmyelinated axon with visible profiles of microtubules. ×95,000. (Courtesy
of Prof. Michael Frotscher, Institute for Structural Neurobiology, Center for
Molecular Neurobiology Hamburg, Germany.)


Dendritic spines are dynamic and can quickly be formed and dismantled;
however, some remain stable and persist for months and years. In
experimental animal models, acquisition of new memories is associated with
increased spine density in pyramidal cells in the CNS. The learning process
induces the formation of stable spines that are able to persist for months
after training. These experimental findings provide evidence that dendritic
spines are involved in **synaptic plasticity and learning** and mediate the
long-term encoding for **memory** in the brain cortex.


**Axons are effector processes that transmit stimuli to other neurons**
**or effector cells.**


The main function of the **axon** is to convey information away from the cell
body to another neuron or to an effector cell, such as a muscle cell. _Each_
_neuron has only one axon_, and it may be extremely long. Axons that
originate from neurons in the motor nuclei of the CNS **(Golgi type I**
**neurons)** may travel more than a meter to reach their effector targets,
skeletal muscle. In contrast, interneurons of the CNS **(Golgi type II**
**neurons)** have very short axons. Although an axon may give rise to a
recurrent branch near the cell body (i.e., one that turns back toward the cell
body) and to other collateral branches, the branching of the axon is most
extensive in the vicinity of its targets.

The axon originates from the **axon hillock** . The axon hillock usually
lacks large cytoplasmic organelles, such as Nissl bodies and Golgi cisternae.
Microtubules, neurofilaments, mitochondria, and vesicles, however, pass
through the axon hillock into the axon (Fig. 12.7). The surface region of the
axon between the apex of the axon hillock and the beginning of the myelin
sheath (see later in this chapter) is called the **axon initial segment (AIS)** .
The molecular composition of the plasma membrane of the AIS acts as a
diffusion barrier or “picket fence” to exclude passage of proteins and lipids
that do not belong to the axonal plasma membrane. The underlying actin


cytoskeleton also acts as a selective filter for organelles and transport
vesicles that attempt to enter the axonal cytoplasm. This function can be
likened to that of a border crossing checkpoint, where travelers are inspected
for proper authorization required to enter the country.


**FIGURE 12.7.** **Organization of microtubules in axons and dendrites.**
Organization of the microtubule network in the neuron differs between
dendrites and axons. All microtubules in axons originate from the
microtubule-organizing center ( _MTOC_ ), and they are uniformly oriented with
their plus (+) ends directed distally. In contrast, microtubules in dendrites
display a mixed polar orientation. The majority of microtubules in dendrites
have reversed polarity with their minus (−) ends directed distally away from
the cell body. Microtubules of normal polarity (with plus [+] ends directed
distally) in dendrites are in the minority. In the central nervous system (CNS),
some of them terminate in the cytoplasm of dendritic spines. Note the
location of the axon hillock, an area where cargo materials destined for
axonal transport are loaded on microtubule-associated motor proteins known
as _kinesins_ . Also, the axon initial segment ( _AIS_ ) separates proteins and lipids
of the axonal plasma membrane from the plasma membrane of the rest of
the axon. Note also that dendritic spines form axodendritic synapses with
neighboring presynaptic axons. A Golgi apparatus is positioned within the
nerve cell body; however, a more characteristic feature of dendrites is the
inclusion of small Golgi outposts. These are functional Golgi structures not
connected with the main Golgi apparatus that can be found within dendrites


and at their junctions with the nerve cell body. Reversed polarity
microtubules are not anchored in the _MTOC_, and the Golgi outpost may
serve as their nucleation centers.


The AIS is the site at which an **action potential** is generated in the
axon. The action potential (described in more detail later) is stimulated by
impulses carried to the axon hillock on the membrane of the cell body after
other impulses are received on the dendrites or the cell body itself.


**Organization of microtubules and their arrangement in axons and**
**dendrites are unique and critical to the functional polarity of**

**neurons.**


Microtubules are important regulators of cell polarity. As discussed in
Chapter 2, Cell Cytoplasm (pages 65-69), microtubules are part of the cell’s
cytoskeleton. They are composed of tubulin heterodimers and consist of two
distinct ends: a plus (+) end and a minus (−) end. At the plus (+) end,
microtubules elongate via tubulin polymerization and extend into the cell’s
periphery. The minus ends are often anchored to an MTOC.

The microtubule network within neurons has certain unique
characteristics. In general, microtubules are more stable in axons than in
dendrites owing to post-translational modification of tubulin and the
protective role of microtubule-associated proteins (MAPs). **Microtubules**
**in axons** are uniformly **oriented with their plus (+) ends directed**
**distally** (see Fig 12.7). These microtubules originate from the area of the
MTOC located in the perinuclear cytoplasm. In contrast, **microtubules in**
**dendrites** display a **mixed polar orientation** : Both plus (+) and minus (−)
ends are directed distally away from the cell body, although microtubules
with reverse polarity (those with their minus [−] ends directed distally)
comprise most of the microtubules within dendrites (see Fig. 12.7). These
microtubules are generally more stable and are comparable to the plus (+)
end–oriented microtubules in axons. These findings suggest that
microtubules of reverse polarity are not anchored in the MTOC and that
their nucleation occurs independently from the MTOC in the cytoplasm of
dendrites. This arrangement is a critical regulator of cell polarity and thus
has implications for dendritic transport.


**Some large axon terminals are capable of local protein synthesis,**
**which may be involved in memory processes.**


Almost all of the structural and functional protein molecules are synthesized
in the nerve cell body. These molecules are distributed to the axons and
dendrites via **neuronal transport systems** (described on pages 396-397).
However, contrary to the common view that the nerve cell body is the only


site of protein synthesis, recent studies indicate that limited local synthesis
of axonal proteins takes place in some large nerve terminals. Some vertebral
axon terminals (i.e., from the retina) contain polyribosomes with complete
translational machinery for protein synthesis. These discrete areas within the
axon terminals, called **periaxoplasmic plaques**, possess biochemical and
molecular characteristics of active protein synthesis. Protein synthesis
within the periaxoplasmic plaques is modulated by neuronal activity. These
proteins may be involved in the processes of **neuronal cell memory** .

### **Neuronal Transport Systems**


**Substances needed in the axons and dendrites are synthesized in**
**the cell body and require transport to those sites.**


Because the synthetic activity of the neuron is concentrated in the nerve cell
body, microtubule-based **neuronal transport** is required to convey newly
synthesized material to the correct neuronal compartment. Transport often
takes place over long distances from the site of synthesis to its target
destination in the axons or dendrites. Neuronal transport serves as a mode of
intracellular communication, carrying molecules and information along the
microtubules. Neuronal transport is bidirectional and occurs in both neurons
and axons. Neurons are especially vulnerable to defects in neuronal
transport because of the extreme length of the neuronal processes.
Mutations in α-or β-tubulin and microtubule-based molecular motors
have been directly linked to several neurologic disorders in both the
CNS and the PNS. Disruption of neuronal transport is most likely
responsible for abnormal accumulations of cytoskeletal proteins and
organelles in axons in **Alzheimer disease**, **Parkinson disease**,
**Huntington disease**, and **amyotrophic lateral sclerosis (ALS)** .


**Kinesin and dynein motors drive axonal transport by directing the**
**movement of cargo vesicles and organelles between the nerve cell**
**body and the axon terminal.**


**Axonal transport** is essential for supplying the distal part of the axon and
its terminal with newly synthesized proteins, lipids, and neurotransmitters
required to maintain synaptic transmission. In addition, aging proteins and
organelles from the distal axon are transported for degradation and recycling
to the nerve cell body. Molecular motors drive axonal transport along tracks
formed by a uniform arrangement of microtubules with their plus (+) ends
extending distally toward the axon terminal. Axonal transport is described
as follows:


**Anterograde transport** carries material from the nerve cell body to the
axon periphery. Because all microtubules in axons are polarized in the
same directions with their plus (+) ends directed toward the axon
terminal, **kinesins**, microtubule-associated motor proteins, are involved
in anterograde transport. Kinesins move the transport vesicles destined for
axons along the microtubules toward their plus (+) ends. They utilize
energy from adenosine triphosphate (ATP) hydrolysis to power their

movement.

**Retrograde transport** carries material from the axon terminal to the
nerve cell body. This transport is mediated by the microtubule-associated
motor proteins called **dyneins** that travel along the microtubules toward
their minus (−) ends (see page 69).


The **motor properties** of both **kinesin** and **dynein** are regulated by
external signals to allow transported cargo vesicles to slow down or speed
up their movement. This is most likely achieved by alternate use of active
and inactive conformations of these motor proteins that are attached to the
same cargo vesicle. The presence of several motor proteins on the same
cargo vesicle allows them to step around obstacles to resolve “road blocks”
or “traffic jams” by switching to different microtubule tracks without
exchanging the motors attached to the cargo vesicle.

Transport systems may also be distinguished by the rate at which
substances are transported.


A **slow anterograde transport system** conveys substances from the
cell body to the axon terminal at the speed of 0.2–4 mm/d. Structural
elements, such as tubulin molecules (microtubule precursors), actin
molecules, and the proteins that form neurofilaments, are carried from the
nerve cell body by this transport system. Cytoplasmic matrix proteins
such as actin, calmodulin, and various metabolic enzymes are also
transported this way.
A **fast transport system** conveys substances in both directions at a rate
of 20–400 mm/d. Thus, it is both an anterograde and a retrograde system.
The **fast anterograde** transport system carries different membranelimited organelles, such as smooth-surfaced endoplasmic reticulum (sER)
components, synaptic vesicles, and mitochondria, and low-molecularweight materials, such as sugars, amino acids, nucleotides, some
neurotransmitters, and calcium to the axon terminal. The **fast retrograde**
transport system carries many of the same materials as well as proteins
and other molecules endocytosed at the axon terminal to the nerve cell
body. Fast transport in either direction requires ATP, which is used by
microtubule-associated motor proteins, and depends on the microtubule


arrangement that extends from the nerve cell body to the termination of
the axon. Retrograde transport is the pathway followed by toxins and
viruses that enter the CNS at nerve endings. Retrograde transport of
exogenous enzymes, such as horseradish peroxidase, and radiolabeled or
immunolabeled tracer materials is now used to trace neuronal pathways
and to identify the nerve cell bodies related to specific nerve endings.


**Dynein molecular motors are preferentially involved in dendritic**
**transport, which is more complex than axonal transport owing to**
**the antiparallel organization of microtubules.**


**Dendritic transport** progresses along bundles of **mixed polarity**
**microtubules**, which contain both “normal” microtubules’ plus (+) ends
and “reversed” microtubules’ minus (−) ends oriented away from the nerve
cell body. Therefore, a single unidirectional type of motor protein carrying
transport vesicle could mediate bidirectional (anterograde and retrograde)
transport by switching between normal and reverse polarity microtubule
tracts. Recent studies indicate that **dyneins** play an important role in the
initial sorting of vesicles that are destined for dendritic transport. Dyneins,
which travel along the microtubules toward their minus (−) ends, are also
**exclusively involved in anterograde transport** of cargo vesicles into
dendrites utilizing microtubules with reversed polarity. Dyneins are also
responsible for retrograde transport of vesicles from the dendritic processes
into the body of the neuron. Kinesins play only a supporting role and
providing assistance in dendritic transport once the transport vesicle is
inside the dendrite.

### **Synapses**


**Neurons communicate with other neurons and effector cells by**

**synapses.**


**Synapses** are specialized junctions between neurons that facilitate the
transmission of impulses from one (presynaptic) neuron to another
(postsynaptic) neuron. Synapses also occur between axons and effector
(target) cells, such as muscle and gland cells. Synapses between neurons
may be classified morphologically as follows:


**Axodendritic** . These synapses occur between axons and dendrites. In the
CNS, some axodendritic synapses are found between axons and dendritic
spines (Fig. 12.8).


**FIGURE 12.8.** **Schematic diagram of different types of synapses.**
Axodendritic synapses represent the most common type of connection
between the presynaptic axon terminal and the dendrites of the
postsynaptic neuron. Note that some axodendritic synapses possess
dendritic spines, which are linked to learning and memory. Axosomatic
synapses are formed between a presynaptic axon terminal and the
postsynaptic nerve cell body; axoaxonic synapses are formed between the
axon terminal of a presynaptic neuron and the axon of a postsynaptic
neuron. The axoaxonic synapse may enhance or inhibit axodendritic (or
axosomatic) synaptic transmission.


**Axosomatic** . These synapses occur between axons and the cell body.
**Axoaxonic** . These synapses occur between axons and axons (see Fig.
12.8).


Synapses are not resolvable in routine hematoxylin and eosin (H&E)
preparations. However, silver precipitation staining methods (e.g., Golgi
method) not only demonstrate the overall shape of some neurons but also
show synapses as oval bodies on the surface of the receptor neuron.
Typically, a presynaptic axon makes several of these button-like contacts
with the receptor portion of the postsynaptic neuron. Often, the axon of the
presynaptic neuron travels along the surface of the postsynaptic neuron,
making several synaptic contacts along the way that are called **boutons en**
**passant** _[Fr. buttons in passing]_ . The axon then continues, ending finally as


a terminal branch with an enlarged tip, a **bouton terminal** _[Fr. terminal_
_button]_, or end bulb. The number of synapses on a neuron or its processes
vary from a few to tens of thousands per neuron (Fig. 12.9); this number
appears to be directly related to the number of impulses that a neuron is
receiving and processing.


**FIGURE 12.9.** **Scanning electron micrograph of the nerve cell body.** This
micrograph shows the cell body of a neuron. Axon endings forming
axosomatic synapses are visible, as are numerous oval bodies with tail-like
appendages. Each oval body represents a presynaptic axon terminal from
different neurons making contact with the large postsynaptic nerve cell body.
×76,000. (Courtesy of Dr. George Johnson.)


**Parkinson disease** is a slowly progressive neurologic disorder caused
by the loss of dopamine (DA)-secreting cells in the substantia nigra and
basal ganglia of the brain. DA is a neurotransmitter responsible for
synaptic transmission in the nerve pathways coordinating smooth and


focused activity of skeletal muscles. Loss of DA-secreting cells is
associated with a classic pattern of symptoms, including the following:


Resting tremor in the limb, especially of the hand when in a relaxed
position; tremor usually increases during stress and is often more
severe on one side of the body
Rigidity or increased tone (stiffness) in all muscles
Slowness of movement (bradykinesia) and inability to initiate
movement (akinesia)
Lack of spontaneous movements
Loss of postural reflexes, which leads to poor balance and abnormal
walking (festinating gait)
Slurred speech, slowness of thought, and small, cramped handwriting


The cause of **idiopathic Parkinson disease**, in which DAsecreting neurons in the substantia nigra are damaged and lost by
degeneration or apoptosis, is not known. However, some evidence
suggests a hereditary predisposition; about 20% of Parkinson patients
have a family member with similar symptoms.

Symptoms that resemble idiopathic Parkinson disease may also
result from infections (e.g., encephalitis), toxins (e.g., MPTP), drugs
used in the treatment of neurologic disorders (e.g., neuroleptics used to
treat schizophrenia), and repetitive trauma. Symptoms with these
causes are called **secondary parkinsonism** .

On the microscopic level, degeneration of neurons in the substantia
nigra is very evident. This region loses its typical pigmentation, and an
increase in the number of glial cells is noticeable ( **gliosis** ). In addition,
nerve cells in this region display characteristic intracellular inclusions
called **Lewy bodies**, which represent accumulation of intermediate
neurofilaments in association with proteins α-synuclein and ubiquitin.

Treatment of Parkinson disease is primarily symptomatic and must
strike a balance between relieving symptoms and minimizing psychotic
side effects. L -Dopa is a precursor of DA that can cross the blood–brain
barrier and is then converted to DA. It is often the primary agent used to
treat Parkinson disease. Other drugs that are used include a group of
cholinergic receptor blockers and amantadine, a drug that stimulates the
release of DA from neurons.

Some patients may benefit from a therapeutic approach called _deep_
_brain stimulation_ . In this procedure, electrodes attached to a pulsegenerating electrical stimulator are implanted into the subthalamic
nucleus of the brain. The electrical pulses act on neurons to modulate
nerve impulses. This therapy has been shown to reduce tremor,
slowness of movement, and rigidity associated with Parkinson disease.
It also reduces the need for L -Dopa to control signs and symptoms,
which helps mitigate the debilitating side effects of this medication.


**Synapses are classified as chemical or electrical.**


Classification of synapses depends on the mechanism of conduction of the
nerve impulses and the way the action potential is generated in the target
cells. Thus, synapses may also be classified as follows:


**Chemical synapses** . Conduction of impulses is achieved by the release
of chemical substances (neurotransmitters) from the presynaptic neuron.
Neurotransmitters then diffuse across the narrow intercellular space that
separates the presynaptic neuron from the postsynaptic neuron or target
cell. A specialized type of chemical synapse called a **ribbon synapse** is
found in the receptor hair cells of the internal ear and photoreceptor cells
of the retina (see Chapter 25, Ear, pages 1028-1029).
**Electrical synapses** . Common in invertebrates, these synapses contain
gap junctions that permit the movement of ions between cells and
consequently permit the direct spread of electrical current from one cell to
another. These synapses do not require neurotransmitters for their
function. Mammalian equivalents of electrical synapses include **gap**
**junctions** in smooth muscle and cardiac muscle cells.


**A typical chemical synapse contains a presynaptic element,**
**synaptic cleft, and postsynaptic membrane.**


Components of a typical chemical synapse include the following:


A **presynaptic element** (presynaptic knob, presynaptic component, or
synaptic bouton) is the end of the neuronal process from which
neurotransmitters are released. The presynaptic element is characterized
by the presence of **synaptic vesicles**, membrane-bound structures that
range from 30 to 100 nm in diameter and contain neurotransmitters (Fig.
12.10). The binding and fusion of synaptic vesicles to the presynaptic
plasma membrane are mediated by a family of transmembrane proteins
called **SNAREs** (which stands for “ **S** oluble **N** SF **A** ttachment **RE** ceptors”;
see pages 42-43). The specific SNARE proteins involved in this activity
include **synaptobrevin**, a vesicle-bound v-SNARE, and **syntaxin** and
**SNAP-25**, which are target membrane-bound t-SNARE proteins found in
specialized areas of the presynaptic membrane. Another vesicle-bound
protein called **synaptotagmin 1** then displaces the SNARE complex,
which is subsequently dismantled and recycled by NSF/SNAP25 protein
complexes. Dense accumulations of proteins are present on the
cytoplasmic side of the presynaptic plasma membrane. These presynaptic
densities represent specialized areas called **active zones** where synaptic
vesicles are docked and where neurotransmitters are released. Active


zones are rich in **Rab-GTPase docking complexes** (see pages 42-43),
**t-SNAREs**, and **synaptotagmin-binding proteins** . The vesicle
membrane that is added to the presynaptic membrane is retrieved by
endocytosis and reprocessed into synaptic vesicles by the sER located in
the nerve ending. Numerous small mitochondria are also present in the
presynaptic element.


**FIGURE 12.10.** **Diagram of a chemical axodendritic synapse.** This
diagram illustrates three components of a typical synapse. The
presynaptic knob is located at the distal end of the axon from which
neurotransmitters are released. The presynaptic element of the axon is
characterized by the presence of numerous neurotransmitter-containing
synaptic vesicles. The plasma membrane of the presynaptic knob is
recycled by the formation of clathrin-coated endocytotic vesicles. The
synaptic cleft separates the presynaptic knob of the axon from the
postsynaptic membrane of the dendrite. The postsynaptic membrane of
the dendrite is frequently characterized by a postsynaptic density and
contains receptors with an affinity for the neurotransmitters. Note two
types of receptors: _Green_ -colored molecules represent transmitter-gated
channels, and the _purple_ -colored structure represents a G-protein–
coupled receptor that, when bound to a neurotransmitter, may act on Gprotein–gated ion channels or on enzymes producing a second
messenger. **a.** Diagram showing neurotransmitter release from a
presynaptic knob by fusion of the synaptic vesicles with the presynaptic
membrane. The fusion mechanism that involves SNARE proteins is


described in Chapter 2, Cell Cytoplasm **(pages 42-44)** . Note the _cis-_
SNARE complex, which is formed after the vesicle fuses to the
presynaptic membrane. **b.** Diagram showing a proposed model of
neurotransmitter release via porocytosis. In this model, the synaptic
vesicle is anchored and juxtaposed to calcium-selective channels in the
presynaptic membrane. In the presence of Ca [2+], the bilayers of the vesicle
and presynaptic membranes are reorganized to create a 1-nm transient
fusion pore connecting the lumen of the vesicle, with the synaptic cleft
allowing the release of a neurotransmitter. Note the presence of the _trans-_
SNARE complex and the synaptotagmin that anchor the vesicle to the
active zones within the plasma membrane of the presynaptic element.


The **synaptic cleft** is the 20-to 30-nm space that separates the
presynaptic neuron from the postsynaptic neuron or target cell, which the
neurotransmitter must cross.
The **postsynaptic membrane** (postsynaptic component) contains
receptor sites with which the neurotransmitter interacts. This component
is formed from a portion of the plasma membrane of the postsynaptic
neuron (Fig. 12.11) and is characterized by an underlying layer of dense
material. This **postsynaptic density** represents an elaborate complex of
interlinked proteins that serve numerous functions, such as translation of
the neurotransmitter–receptor interaction into an intracellular signal,
anchoring of and trafficking neurotransmitter receptors to the plasma
membrane, and anchoring various proteins that modulate receptor
activity.


**FIGURE 12.11.** **Electron micrograph of nerve processes in the**
**cerebral cortex.** A synapse can be seen in the _center_ of the micrograph,
where an axon ending is in apposition to a dendrite. The ending of the
axon exhibits numerous neurotransmitter-containing synaptic vesicles that
appear as circular profiles. The postsynaptic membrane of the dendrite
shows a postsynaptic density. A substance of similar density is also


present in the synaptic cleft (intercellular space) at the synapse. ×76,000.
(Courtesy of Drs. George D. Pappas and Virginia Kriho.)

###### **Synaptic Transmission**


**Voltage-gated Ca** **[2+]** **channels in the presynaptic membrane regulate**
**transmitter release.**


When a nerve impulse reaches the synaptic bouton, the voltage reversal
across the membrane produced by the impulse (called **depolarization** )
causes **voltage-gated Ca** **[2+]** **channels** to open in the plasma membrane of
the bouton. The influx of Ca [2+] from the extracellular space causes the
synaptic vesicles to migrate, anchor, and fuse with the presynaptic
membrane, thereby releasing the neurotransmitter into the synaptic cleft by
exocytosis. Vesicle docking and fusion are mainly driven by the actions of
SNARE and synaptotagmin proteins. An alternative process that releases
neurotransmitter following vesicle fusion is called **porocytosis**, in which
vesicles anchored at the active zones release neurotransmitters through a
transient fusion pore connecting the lumen of the vesicle with the synaptic
cleft. At the same time, the presynaptic membrane of the synaptic bouton
that released the neurotransmitter quickly forms endocytotic vesicles that
return to the endosomal compartment of the bouton for recycling or
reloading with neurotransmitter.


**The neurotransmitter binds to either transmitter-gated channels or**
**G-protein–coupled receptors on the postsynaptic membrane.**


The released neurotransmitter molecules bind to the extracellular part of
postsynaptic membrane receptors called **transmitter-gated channels** .
Binding of neurotransmitter induces a conformational change in these
channel proteins that causes their pores to open. The response that is
ultimately generated depends on the identity of the ion that enters the cell.
For instance, influx of Na [+] causes local depolarization in the postsynaptic
membrane, which, under favorable conditions (sufficient amount and
duration of neurotransmitter release), prompts the opening of **voltage-**
**gated Na** **[+]** **channels**, thereby generating a nerve impulse.

Some amino acid and amine neurotransmitters may bind to **G-protein–**
**coupled receptors** to produce longer lasting and more diverse
postsynaptic responses. The neurotransmitter binds to a transmembrane
receptor protein on the postsynaptic membrane. Receptor binding activates
G-proteins, which move along the intracellular surface of the postsynaptic
membrane and eventually activate effector proteins. These effector proteins
may include transmembrane **G-protein–gated ion channels** or **enzymes**


that synthesize second messenger molecules (page 401). Several
neurotransmitters (e.g., acetylcholine [ACh]) can generate different
postsynaptic actions, depending on which receptor system they act (see later
in this chapter).


**Porocytosis describes the secretion of neurotransmitter that does**
**not involve the fusion of synaptic vesicles with the presynaptic**
**membrane.**


Based on evaluation of physiologic data and the structural organization of
nerve synapses, an alternate model of neurotransmitter secretion called
**porocytosis** has recently been proposed to explain the regulated release of
neurotransmitters. In this model, secretion from the vesicles occurs without
the fusion of the vesicle membrane with the presynaptic membrane. Instead,

                                              the synaptic vesicle is anchored to the presynaptic membrane next to Ca [2+]
selective channels by SNARE and synaptotagmin proteins. In the presence
of Ca [2+], the vesicle and presynaptic membranes are reorganized to create a
1-nm transient **fusion pore** that connects the lumen of the vesicle with the
synaptic cleft. Neurotransmitters can then be released in a controlled manner
through these transient membrane pores (see Fig. 12.10).


**The chemical nature of the neurotransmitter determines the type of**
**response at that synapse in the generation of neuronal impulses.**


The release of neurotransmitter by the presynaptic component can cause
either **excitation** or **inhibition** at the postsynaptic membrane.


In **excitatory synapses**, the release of neurotransmitters such as
**acetylcholine**, **glutamine**, or **serotonin** opens **transmitter-gated Na** **[+]**

**channels** (or other cation channels), prompting an influx of Na [+] that
causes local reversal of voltage of the postsynaptic membrane to a
threshold level (depolarization). This leads to initiation of an action
potential and generation of a nerve impulse.
In **inhibitory synapses**, the release of neurotransmitters such as **γ-**
**aminobutyric acid (GABA)** or **glycine** opens **transmitter-gated Cl** **[–]**

**channels** (or other anion channels), causing Cl [−] to enter the cell and
hyperpolarize the postsynaptic membrane, making it even more negative.
In these synapses, the generation of an action potential then becomes
more difficult.


The ultimate generation of a nerve impulse in a postsynaptic neuron
(firing) depends on the summation of excitatory and inhibitory impulses
reaching that neuron. This allows precise regulation of the reaction of a
postsynaptic neuron (or muscle fiber or gland cell). The function of synapses


is not simply to transmit impulses in an unchanged manner from one neuron
to another. Rather, synapses allow for the processing of neuronal input.
Typically, the impulse passing from the presynaptic to the postsynaptic
neuron is modified at the synapse by other neurons that, although not in the
direct pathway, nevertheless have access to the synapse (see Fig. 12.8).
These other neurons may influence the membrane of the presynaptic neuron
or the postsynaptic neuron and facilitate or inhibit the transmission of
impulses. The firing of impulses in the postsynaptic neuron is caused by the
summation of the actions of hundreds of synapses.

###### **Neurotransmitters**


Many molecules that serve as **neurotransmitters** have been identified in
various parts of the nervous system. A neurotransmitter that is released from
the presynaptic element diffuses through the synaptic cleft to the
postsynaptic membrane, where it interacts with a specific receptor. Action of
the neurotransmitter depends on its chemical nature and the characteristics
of the receptor present on the postsynaptic plate of the effector cell.


**Neurotransmitters act on either ionotropic receptors to open**
**membrane ion channels or metabotropic receptors to activate G-**
**protein signaling cascade.**


Almost all known neurotransmitters act on multiple receptors, which are
integral membrane proteins. These receptors can be divided into two major
classes: ionotropic and metabotropic receptors. **Ionotropic receptors**
contain integral transmembrane ion channels, also referred to as
**transmitter-gated channels** or **ligand-gated channels** . Binding of
neurotransmitter to ionotropic receptors triggers a conformational change of
the receptor proteins that leads to the opening of the channel and subsequent
movement of selective ions into or out of the cell. This generates an action
potential in the effector cell. In general, signaling using ionotropic channels
is very rapid and occurs in the major neuronal pathways of the brain and
somatic motor pathways in the PNS. **Metabotropic channels** are
responsible not only for binding a specific neurotransmitter but also for
interacting with **G-protein** at their intracellular domain. G-protein is an
important protein that is involved in intracellular signaling. It conveys
signals from the outside to the inside of the cell by altering the activities of
enzymes involved in the synthesis of a second messenger. Activation of
metabotropic receptors is mostly involved in the modulation of neuronal
activity.

The most common neurotransmitters are described as follows. A
summary of selected neurotransmitters and their characteristics in both the
PNS and the CNS is provided in Table 12.1.


**Characterizations of the Most Common**
**TABLE 12.1**
**Neurotransmitters**


_5-HT_, 5-hydroxytryptamine; _ACh_, acetylcholine; _AMPA_, α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid; _cGMP_, cyclic guanosine monophosphate; _CNS_, central
nervous system; _GABA_, γ-aminobutyric acid; _mGluR_, metabotropic glutamate
receptor; _NA_, not applicable; _NMDA_, N-methyl D -aspartate receptor; _NO_, nitric oxide;
_PNS_, peripheral nervous system.


**Acetylcholine (ACh)** . ACh is the neurotransmitter between axons and
striated muscle at the neuromuscular junction (see page 357) and serves
as a neurotransmitter in the ANS. ACh is released by the presynaptic
sympathetic and parasympathetic neurons and their effectors. ACh is also
secreted by postsynaptic parasympathetic neurons as well as by a specific
type of postsynaptic sympathetic neuron that innervates sweat glands.
Neurons that use ACh as their neurotransmitter are called **cholinergic**


**neurons** . The receptors for ACh in the postsynaptic membrane are
known as **cholinergic receptors** and are divided into two classes.
Metabotropic receptors interact with muscarine, a substance isolated from
poisonous mushrooms **(muscarinic ACh receptors)**, and ionotropic
receptors interact with nicotine isolated from tobacco plants **(nicotinic**
**ACh receptors)** . The muscarinic ACh receptor in the heart is an example
of a G-protein–coupled receptor that is linked to K [+] channels.
Parasympathetic stimulation of the heart releases ACh, which, in turn,
opens K [+] channels, causing hyperpolarization of cardiac muscle fibers.
This hyperpolarization slows rhythmic contraction of the heart. In
contrast, the nicotinic ACh receptor in skeletal muscles is an ionotropic
ligand–gated Na [+] channel. Opening of this channel causes rapid
depolarization of skeletal muscle fibers and initiation of contraction.
Various drugs affect the release of ACh into the synaptic cleft as well as
its binding to its receptors. For instance, **curare**, the South American
arrow-tip poison, binds to nicotinic ACh receptors, blocking their
integral Na [+] channels and causing muscle paralysis. **Atropine**, an
alkaloid extracted from the belladonna plant _(Atropa belladonna)_,
blocks the action of muscarinic ACh receptors.
**Catecholamines** such as **norepinephrine (NE)**, **epinephrine (EPI,**
**adrenaline)**, and **dopamine (DA)** . These neurotransmitters are
synthesized in a series of enzymatic reactions from the amino acid
tyrosine. Neurons that use catecholamines as their neurotransmitter are
called **catecholaminergic neurons** . Catecholamines are secreted by
cells in the CNS that are involved in the regulation of movement, mood,
and attention. Neurons that utilize EPI (adrenaline) as their
neurotransmitter are called **adrenergic neurons** . They all contain an
enzyme that converts NE to adrenaline (EPI), which serves as a
transmitter between postsynaptic sympathetic axons and effectors in the
ANS. EPI is also released into the bloodstream by the endocrine
cells (chromaffin cells) of the adrenal medulla during the **fight-or-**

.
**flight response**
**Serotonin** or **5-hydroxytryptamine (5-HT)** . Serotonin is formed by the
hydroxylation and decarboxylation of tryptophan. It functions as a
neurotransmitter in the neurons of the CNS and enteric nervous system.
Neurons that use serotonin as their neurotransmitter are called
**serotonergic** . After the release of serotonin, a portion is recycled by
reuptake into presynaptic serotonergic neurons. Serotonin has been
found to be an important molecule that helps establish
**asymmetrical right–left development** in embryos.
**Amino acids** such as GABA, GLU, aspartate (ASP), and glycine (GLY)
act as neurotransmitters, mainly in the CNS.


**Nitric oxide (NO)**, a simple gas with free radical properties, also has
been identified as a neurotransmitter. At low concentrations, NO carries
nerve impulses from one neuron to another. Unlike other
neurotransmitters, which are synthesized in the nerve cell body and stored
in synaptic vesicles, NO is synthesized within the synapse and used
immediately. It is postulated that excitatory neurotransmitter GLU
induces a chain reaction in which **NO synthase** is activated to produce
NO, which, in turn, diffuses from the presynaptic knob via the synaptic
cleft and postsynaptic membrane to the adjacent cell. Biological actions
of NO are due to the activation of guanylyl cyclase, which then produces
cyclic guanosine monophosphate (cGMP) in target cells. cGMP, in turn,
acts on G-protein synthesis, ultimately resulting in generation/modulation
of neuronal action potentials.
**Small peptides** have been shown to act as synaptic transmitters. Among
these are **substance P** (so named because it was originally found in a
powder of acetone extracts of brain and intestinal tissue), **hypothalamic-**
**releasing hormones**, **endogenous opioid peptides** (e.g., **β-**
**endorphin**, **enkephalins**, **dynorphins** ), **vasoactive** **intestinal**
**peptide (VIP)**, **cholecystokinin (CCK)**, and **neurotensin** . Many of
these same substances are synthesized and released by **enteroendocrine**
**cells** of the intestinal tract. They may act immediately on neighboring
cells (paracrine secretion) or be carried in the bloodstream as hormones to
act on distant target cells (endocrine secretion). They are also synthesized
and released by endocrine organs and the neurosecretory neurons of the
hypothalamus.


**Neurotransmitters released into the synaptic cleft may be degraded**
**or recaptured.**


The degradation or recapture of neurotransmitters is necessary to limit the
duration of stimulation or inhibition of the postsynaptic membrane. The
most common process of neurotransmitter removal after its release into the
synaptic cleft is called **high-affinity reuptake** . About 80% of released
neurotransmitters are removed by this mechanism, in which they are bound
into **specific neurotransmitter transport proteins** located in the
presynaptic membrane. Neurotransmitters that were transported into the
cytoplasm of the presynaptic bouton are either enzymatically destroyed or
reloaded into empty synaptic vesicles. For example, the action of
**catecholamines** on postsynaptic receptors is terminated by the reuptake of
neurotransmitters into the presynaptic bouton utilizing **Na** **[+]** **-dependent**
**transporters** . The efficiency of this uptake can be regulated by
several pharmacologic agents such as amphetamine and cocaine,


which block catecholamine reuptake and prolong the actions of
neurotransmitters on the postsynaptic neurons. Once inside the
presynaptic bouton, catecholamines are reloaded into synaptic vesicles for
future use. The excess of catecholamines is inactivated by the enzyme
**catechol** _**O**_ **-methyltransferase (COMT)** or is destroyed by another
enzyme found on the outer mitochondrial membrane, **monoamine oxidase**
**(MAO)** . Therapeutic substances that inhibit the action of MAO are
frequently used in the treatment of **clinical depression** ; selective
COMT inhibitors have been also developed.

Enzymes associated with the postsynaptic membrane degrade the
remaining 20% of neurotransmitters. For example, **acetylcholinesterase**
**(AChE)**, which is secreted by the muscle cell into the synaptic cleft, rapidly
degrades ACh into acetic acid and choline. Choline is then taken up by the
cholinergic presynaptic bouton and reused for ACh synthesis. The **AChE**
**action** at the **neuromuscular junction** can be inhibited by various
pharmacologic compounds, nerve agents, and pesticides, resulting in
prolonged muscle contraction. Clinically, **AChE inhibitors** have been
used in the treatment of **myasthenia gravis** (see Folder 11.3 in
Chapter 11, Muscle Tissue, page 358), an autoimmune
neuromuscular disorder, and **glaucoma** . AChE inhibitors also
improve many of the symptoms of **Alzheimer disease** and are
considered the first-line therapeutic agents for these patients.

### **SUPPORTING CELLS OF THE NERVOUS** **SYSTEM: THE NEUROGLIA**


In the PNS, supporting cells are called **peripheral neuroglia** ; in the CNS,
they are called **central neuroglia** .

### **Peripheral Neuroglia**


Peripheral neuroglia include **Schwann cells**, **satellite cells**, and a variety
of other cells associated with specific organs or tissues. Examples of the
latter include **terminal neuroglia (terminal Schwann cells, teloglia)**,
which are associated with the motor end plate; **enteric neuroglia**
associated with the ganglia located in the wall of the alimentary canal; and
**Müller cells** in the retina.

### **Schwann Cell Development and Synthesis of** **Myelin Sheath**


In mature peripheral nerves, **Schwann cells** adopt one of the three distinct
phenotypes: (1) a **myelinating phenotype** that is responsible for
myelinating large-diameter axons in the PNS; (2) a **nonmyelinating**
**phenotype** (also known as a **Remak Schwann cell)**, which is
characterized by the enclosure of multiple small-diameter axons within
grooves of the plasma membrane that invaginate deep into the cell
cytoplasm; and (3) a **repair cell** phenotype that plays a major role during
nerve injury, repair, and regeneration. Although Remak Schwann cells do
not produce myelin, they are essential for the proper development and
function of the peripheral nerves. During nerve injury, both myelinating
Schwann cells and Remak Schwann cells undergo reprogramming and
dedifferentiation into repair cells. For the purpose of this discussion, the
term “Schwann cell” is used to describe myelin-producing cells, and
“Remak Schwann cells” refers to the nonmyelin-producing cells that
provide support for unmyelinated nerve fibers in the PNS.


**Myelinating Schwann cells** are the major glial cell type in PNS. They
produce the myelin that surrounds all large-diameter peripheral nerve
processes and play essential roles in the development, maintenance,
function, and regeneration of peripheral nerves. A detailed description of
Schwann cell development, structure, and function is explained.

**Nonmyelinating Remak Schwann cells** are the second major
phenotype of Schwann cells. In the PNS, Remak Schwann cells do not
produce myelin; instead, they envelope multiple small-diameter axons to
form **unmyelinated fibers** called _Remak bundles_ . Most unmyelinated
fibers are composed of postsynaptic sympathetic and parasympathetic
axons. Some nonmyelinating Schwann cells migrate toward the
neuromuscular junction and cover the axon terminals, where they become
**perisynaptic/terminal Schwann cells (teloglia)** . These cells are found
at the distal ends of motor nerve terminals at neuromuscular junctions
(see Fig. 11.14).
**Repair Schwann cells** are the third phenotype of Schwan cells and are
specialized to promote the repair of injured nerves in the PNS. Repair
Schwann cells are derived from the conversion of myelinating Schwann
cells and nonmyelinating Remak Schwann cells in response to nerve
injury (Fig 12.12). This injury-induced conversion of Schwann and
Remak Schwann cells is driven by the dedifferentiation of mature cells
and cell reprogramming that involves the downregulation of myelin genes
combined with activation of specific features used in nerve repair. These
features include upregulation of trophic factors, increased synthesis of
cytokines (i.e., for macrophage recruitment), activation of myelin
autophagy (myelin clearance), and the formation of **regeneration tracks**


called **bands of Büngner** that direct growing axonal sprouts to their
targets. A detailed description of nerve regeneration is found in the
section on response of neurons to injury (see pages 426-429).


**Schwann cell precursors originate from neural crest cells and**
**further** **differentiate** **into** **myelinating** **Schwann** **cells** **or**
**nonmyelinating Remak Schwan cells according to axon-derived**
**signals.**


During nerve development in the PNS, some **neural crest cells** give rise to
**Schwann cell precursors** under the influence of transcription factor
SOX10 (see Fig 12.12). Schwann cell precursors migrate along developing
axons to their final destination. Once this migration is complete, the
Schwann cell precursors transition into **immature Schwann cells** and
perform **radial sorting**, which sorts the axons based on their diameter. This
process determines the final phenotype of the Schwann cell and the
designation of the nerve fiber as myelinated or unmyelinated.


**FIGURE 12.12.** **Schwann cell development and transformation after**
**peripheral nerve injury.** Schwann cell precursors originate from neural crest
cells under the influence of transcription factor Sox-10. They further transition
into immature Schwann cells and perform radial sorting of the axons based
on their diameter. Immature Schwann cells, which have a one-to-one
relationship with large-diameter axons, under influence of NF-κB, Oct-6, and
Brn2 transcription factors, become promyelinating Schwan cells. Under
further influence of Krox-20 transcription factor, these cells develop into


myelinating Schwann cells. The remaining small-diameter fibers are engulfed
in the cytoplasm of the remaining immature Schwan cells and eventually,
under the influence of Krox-24 and Ncam1, differentiate into nonmyelinated
Remak Schwann cells. Some immature Schwann cells near the
neuromuscular junctions develop into perisynaptic/terminal Schwann cells,
which also do not produce myelin. Radial sorting determines the final
phenotype of the Schwann cell and the designation of the nerve fiber as
myelinated or unmyelinated. Following peripheral nerve injury, c-Jun
transcription factor is rapidly upregulated, downregulating the expression of
Krox-20 and causing dedifferentiation of Schwann cells into repair Schwann
cells. Similar processes occur in the Remak Schwan cells, leading to their
differentiation during nerve injury.


**Radial sorting** begins by secluding a cohort of axons of mixed
diameters into small bundles. These bundles are surrounded by three to eight
immature Schwann cells that organize a common external lamina around
them. Next, the immature Schwan cells extend their cytoplasmic processes
between axons to progressively choose, segregate, and reposition larger
axons (>6–7 μm in diameter) toward their own cell body at the periphery of
the bundle. As immature Schwann cells continue to proliferate, largediameter axons are sorted into a one-to-one relationship with immature
Schwann cells. This close interaction with a single large axon allows
immature Schwann cells to receive axonal signals from a transmembrane
protein expressed on the axolemma of the axon called **neuregulin-1**
**(Nrg1)** . The Nrg1 signal upregulates the expression of **promyelinating**
**transcription factors**, including nuclear factor κB (NF-κB), octamerbinding transcription factor 6 (Oct-6), and brain 2 class III POU-domain
protein (Brn2) (see Fig 12.12). These transcription factors promote
promyelination, in which **promyelinating Schwann cells** express early
myelin markers. Further upregulation of KROX20 is required for maturation
to **myelinated Schwann cells**, which express myelin-specific proteins and
produce myelin sheaths.

As myelinating Schwann cell development progresses, large axons are
pooled out from the initial axonal bundles. The bundles become smaller and
smaller until they contain only the remaining small-diameter axons (<1 μm
in diameter). They are subsequently engulfed by the cytoplasm of the
remaining immature Schwan cells and eventually differentiate into
**nonmyelinated Remak Schwann cells** (see Fig 12.12).


**In the PNS, myelinating Schwann cells produce the myelin sheath.**


The main function of Schwann cells is to support myelinated and
unmyelinated nerve cell fibers. In the PNS, **Schwann cells** produce a lipid

rich layer called the **myelin sheath** that surrounds the axons (Fig. 12.13).
The myelin sheath isolates the axon from the surrounding extracellular
compartment of endoneurium. Its presence ensures the rapid conduction of
nerve impulses. The axon hillock and the terminal arborizations where the
axon synapses with its target cells are not covered by myelin. Unmyelinated
fibers are also enveloped and nurtured by Remak Schwann cell’s cytoplasm.
In addition, Schwann cells aid in removing PNS debris and guide the
regrowth of PNS axons (see pages 426-429).


**FIGURE 12.13.** **Photomicrographs of a peripheral nerve in cross and**
**longitudinal sections. a.** Photomicrograph of an osmium-fixed, toluidine
blue–stained peripheral nerve cut in cross section. The axons ( _A_ ) appear
clear. The myelin is represented by the _dark ring_ surrounding the _A_ . Note the
variation in diameter of the individual _A_ . In some of the nerves, the myelin
appears to consist of two separate rings ( _asterisks_ ). This is caused by the
section passing through a Schmidt–Lanterman cleft. _Epi_, epineurium. ×640.
**b.** Photomicrograph showing longitudinally sectioned myelinated nerve _A_ in
the same preparation as earlier. A node of Ranvier ( _NR_ ) is seen _near the_
_center_ of the micrograph. In the same _A_, a Schmidt–Lanterman cleft ( _SL_ ) is
seen on each side of the node. In addition, a number of _SL_ clefts can be
seen in the adjacent _A_ . The perinodal cytoplasm of the Schwann cell at the
_NR_ and the Schwann cell cytoplasm at the _SL_ cleft appear virtually
unstained. ×640.


**Myelination begins when a Schwann cell surrounds the axon and**
**its cell membrane becomes polarized.**


During formation of the myelin sheath (also called **myelination** ), the axon
initially lies in a groove on the surface of the Schwann cell (Fig. 12.14a). A
0.08-to 0.1-mm segment of the axon then becomes enclosed within each
Schwann cell that lies along the axon. The Schwann cell surface becomes
polarized into two functionally distinct membrane domains. The part of the
Schwann cell membrane that is exposed to the external environment or
endoneurium, the **abaxonal plasma membrane**, represents one domain.
The other domain is represented by the **adaxonal** or **periaxonal plasma**
**membrane**, which is in direct contact with the axon. When the axon is
completely enclosed by the Schwann cell membrane, a third domain, the
**mesaxon**, is created (Fig. 12.14b). This third domain is a double membrane
that connects the abaxonal and adaxonal membranes and encloses the
narrow extracellular space.


**FIGURE 12.14.** **Diagram showing successive stages in the formation of**
**myelin sheath by a Schwann cell. a.** The axon initially lies in a groove on
the surface of the immature Schwann cell. **b.** The axon is surrounded by a
promyelinating Schwann cell. Note the two domains of the Schwann cell, the
adaxonal plasma membrane domain and abaxonal plasma membrane
domain. The mesaxon plasma membrane links these domains. The mesaxon
membrane initiates myelination by surrounding the embedded axon. **c.** A
sheet-like extension of the mesaxon membrane then wraps around the axon,
forming multiple membrane layers. **d.** During the wrapping process, the
cytoplasm is extruded from between the two apposing plasma membranes of
the Schwann cell, which then become compacted to form myelin. The outer
mesaxon represents the invaginated plasma membrane extending from the
abaxonal surface of the Schwann cell to the myelin sheath. The inner
mesaxon extends from the adaxonal surface of the Schwann cell (the part


facing the axon) to the innermost layer of the myelin sheath. The _inset_ shows
the major proteins responsible for compaction of the myelin sheath. _MBP_,
myelin basic protein; _Nrg1_, neuregulin; _P0_, protein 0; _PMP22_, peripheral
myelin protein of 22 kDa.


**The myelin sheath develops from compacted layers of Schwann**
**cell mesaxon wrapped concentrically around the axon.**


**Myelin sheath** formation is initiated when the Schwann cell mesaxon
surrounds the axon. A sheet-like extension of the mesaxon then wraps
around the axon in a spiraling motion. The first few layers or **lamellae** of
the spiral are not compactly arranged—that is, some cytoplasm is left in the
first few concentric layers (Fig. 12.14c). The TEM reveals the presence of a
12-to 14-nm gap between the outer (extracellular) leaflets and the Schwann
cell’s cytoplasm that separates the inner (cytoplasmic) leaflets. As the
wrapping progresses, cytoplasm is squeezed out from between the
membrane of the concentric layers of the Schwann cell.

External to, and contiguous with, the developing myelin sheath is a thin
**outer collar of perinuclear cytoplasm** called the **sheath of Schwann** .
This part of the cell is enclosed by an abaxonal plasma membrane and
contains the nucleus and most of the organelles of the Schwann cell.
Surrounding the Schwann cell is a basal or external lamina. The apposition
of the mesaxon of the last layer to itself as it closes the ring of the spiral
produces the **outer mesaxon**, the narrow intercellular space adjacent to the
external lamina. Internal to the concentric layers of the developing myelin
sheath is a narrow **inner collar of Schwann cell cytoplasm** surrounded
by the adaxonal plasma membrane. The narrow intercellular space between
mesaxon membranes communicates with the adaxonal plasma membrane to
produce the **inner mesaxon** (Fig. 12.14d).

Once the mesaxon spirals on itself, the 12-to 14-nm gaps disappear and
the membranes form the compact **myelin sheath** . Compaction of the sheath
corresponds with the expression of transmembrane **myelin-specific**
**proteins**, such as **protein 0 (P0)**, a **peripheral myelin protein of 22 kDa**
**(PMP22)**, and **myelin basic protein (MBP)** . The inner (cytoplasmic)
leaflets of the plasma membrane come close together as a result of the
positively charged cytoplasmic domains of P0 and MBP. With the TEM,
these closely aligned inner leaflets are electron opaque, appearing as the
**major dense lines** in the TEM image of myelin (see Fig. 12.14d). The
concentric dense lamellae alternate with the slightly less dense **intraperiod**
**lines** that are formed by closely apposed, but not fused, outer (extracellular)
membrane leaflets. The narrow 2.5-nm gap corresponds to the remaining
extracellular space containing the extracellular domains of P0 protein (see


Fig. 12.14d). P0 is a 30-kDa cell adhesion molecule expressed within the
mesoaxial plasma membrane during myelination. This transmembrane
glycoprotein mediates strong adhesions between the two opposite membrane
layers and represents a key structural component of peripheral nerve myelin.
Structural and genetic studies indicate that mutations in human
genes encoding P0 produce unstable myelin and may contribute to
the development of **demyelinating diseases** (see Folder 12.2).




immune cells. For more severe, progressive forms, immunosuppressive
drugs may be used.


**The thickness of the myelin sheath at myelination is determined by**
**axon diameter and not by the Schwann cell.**


Myelination is an example of cell-to-cell communication in which the axon
interacts with the Schwann cell. Experimental studies show that the number
of layers of myelin is determined by the axon and not by the Schwann cell.
Myelin sheath thickness is regulated by a glial growth factor (GGF) called
**neuregulin (Ngr1)** that induces growth, differentiation, and migration of
Schwann cells throughout their development. Ngr1 is a transmembrane
protein expressed on the axolemma (cell membrane) of the axon.


**The node of Ranvier represents the junction between two adjacent**
**Schwann cells.**


The myelin sheath is segmented because it is formed by numerous Schwann
cells arrayed sequentially along the axon. The junction where two adjacent
Schwann cells meet is devoid of myelin. This site is called the **node of**
**Ranvier** . Therefore, the myelin between two sequential nodes of Ranvier is
called an **internodal segment** (Plate 12.2, page 434). The node of Ranvier
constitutes a region where the electrical impulse is regenerated for highspeed propagation down the axon. The highest density of voltage-gated Na [+]

channels in the nervous system occurs at the node of Ranvier; their
expression is regulated by interactions with the perinodal cytoplasm of
Schwann cells.

Myelin is composed of about 80% lipids because, as the Schwann cell
membrane winds around the axon, the cytoplasm of the Schwann cell, as
noted, is extruded from between the opposing layers of the plasma
membranes. Electron micrographs, however, typically show small amounts
of cytoplasm in several locations (Figs. 12.15 and 12.16): the inner collar of
Schwann cell cytoplasm, between the axon and the myelin; the **Schmidt–**
**Lanterman clefts**, small islands within successive lamellae of the myelin;
**perinodal cytoplasm**, at the node of Ranvier; and the outer collar of
perinuclear cytoplasm, around the myelin (Fig. 12.17). These areas of
cytoplasm are what light microscopists identified as the Schwann sheath.


**FIGURE 12.15.** **Electron micrograph of an axon in the process of**
**myelination.** At this stage of development, the myelin ( _M_ ) sheath consists of
about six membrane layers. The inner mesaxon ( _IM_ ) and outer mesaxon
( _OM_ ) of the Schwann cell ( _SC_ ) represent parts of the mesaxon membrane.
Another axon (see _upper left A_ ) is present that has not yet been embedded
within an _SC_ mesaxon. Other notable features include the _SC_ basal
(external) lamina ( _BL_ ) and the considerable amount of Schwann cell
cytoplasm associated with the myelination process. ×50,000. (Courtesy of
Dr. Stephen G. Waxman.)


**FIGURE 12.16.** **Electron micrograph of a mature myelinated axon.** The
myelin sheath ( _M_ ) shown here consists of 19 paired layers of Schwann cell
membrane. The pairing of membranes in each layer is caused by the
extrusion of the Schwann cell’s cytoplasm. The axon displays an abundance
of neurofilaments, most of which have been cross-sectioned, giving the axon
a stippled appearance. Also evident in the axon are microtubules ( _MT_ ) and
several mitochondria ( _Mit_ ). The outer collar of Schwann cell’s cytoplasm
( _OCS_ ) is relatively abundant compared with the inner collar of Schwann cell’s
cytoplasm ( _ICS_ ). The collagen fibrils ( _C_ ) constitute the fibrillar component of
the endoneurium. _BL_, basal (external) lamina. ×70,000. **Inset.** Higher
magnification of the myelin. The _arrow_ points to cytoplasm within the myelin
that would contribute to the appearance of the Schmidt–Lanterman cleft as
seen in the light microscope. It appears as an isolated region here because
of the thinness of the section. The intercellular space between the axon and
Schwann cell is indicated by the _arrowhead_ . A coated vesicle ( _CV_ ) in an
early stage of formation appears in the outer collar of the Schwann cell
cytoplasm. ×130,000. (Courtesy of Dr. George D. Pappas.)


**FIGURE 12.17.** **Diagram of the node of Ranvier and associated Schwann**
**cells.** This diagram shows a longitudinal section of the axon and its
relationships to the myelin, cytoplasm of the Schwann cell, and node of
Ranvier. Schwann cell’s cytoplasm is present at four locations: the inner and
the outer cytoplasmic collar of the Schwann cell, the nodes of Ranvier, and
the Schmidt–Lanterman clefts. Note that the cytoplasm throughout the
Schwann cell is continuous (see Fig. 12.18); it is not a series of cytoplasmic
islands as it appears on the longitudinal section of the myelin sheath. The
node of Ranvier is the site at which successive Schwann cells meet. The
adjacent plasma membranes of the Schwann cells are not tightly apposed at
the node, and extracellular fluid has free access to the neuronal plasma
membrane. The node of Ranvier is also the site of depolarization of the
neuronal plasma membrane during nerve impulse transmission and contains
clusters of high-density, voltage-gated Na [+] channels.


However, if one conceptually unrolls the Schwann cell process, as
shown in Fig. 12.18, its full extent can be appreciated, and the inner collar
of Schwann cell cytoplasm can be seen to be continuous with the body of
the Schwann cell through the Schmidt–Lanterman clefts and the perinodal
cytoplasm. Cytoplasm of the clefts contains lysosomes and occasional
mitochondria and microtubules, as well as cytoplasmic inclusions, or dense


bodies. The number of Schmidt–Lanterman clefts correlates with the
diameter of the axon; larger axons have more clefts.


**FIGURE** **12.18.** **Three-dimensional** **diagram** **conceptualizing** **the**
**relationship of myelin and cytoplasm of a Schwann cell.** This diagram
shows a hypothetically uncoiled Schwann cell. Note how the inner collar of
the Schwann cell’s cytoplasm is continuous with the outer collar of Schwann
cell’s cytoplasm via Schmidt–Lanterman clefts.


**Unmyelinated axons in the peripheral nervous system are**
**enveloped by nonmyelinating Remak Schwan cells and their**
**external lamina.**


The nerves in the PNS described as **unmyelinated** are nevertheless
enveloped by **nonmyelinating Remak Schwann cell’s** cytoplasm, as
shown in Fig. 12.19, and can accommodate multiple small-diameter axons.
The Remak Schwann cells are elongated in parallel to the long axis of the
axons, and the axons fit into grooves on the cell surface. The lips of the
groove may be open, exposing a portion of the axolemma of the axon to the
adjacent external lamina of the Remak Schwann cell, or the lips may be
closed, forming a mesaxon.


**FIGURE 12.19.** **Electron micrograph of unmyelinated nerve fibers.** The
individual fibers or axons ( _A_ ) are engulfed by the cytoplasm of a
nonmyelinating Remak Schwann cell. The _arrows_ indicate the site of
mesaxons. In effect, each _A_ is enclosed by the Remak Schwann cell’s
cytoplasm, except for the intercellular space of the mesaxon. Other features
evident in the Remak Schwann cell are its nucleus ( _N_ ), the Golgi apparatus
( _G_ ), and the surrounding basal (external) lamina ( _BL_ ). In the _upper part_ of the
micrograph, myelin ( _M_ ) of two myelinated nerves is also evident. ×27,000.
**Inset.** Schematic diagram showing the relationship of _A_ engulfed by the
Remak Schwann cell.


A single axon or a group of axons may be enclosed in a single
invagination of the Remak Schwann cell surface. Large Remak Schwann
cells in the PNS may have 20 or more grooves, each containing either one
completely isolated axon (in the distal part of the nerve) or multiple axons
(in the proximal part of the nerve close to ganglia). In the ANS, it is
common for bundles of unmyelinated axons to occupy a single groove.
Because they form bundles within the Remak Schwann cell’s cytoplasm,


unmyelinated nerves are often called **Remak bundles** . An interesting
feature of unmyelinated nerve fibers has been observed in which axons may
switch their position between neighboring Remak bundles along the nerve.

### **Satellite Cells**


The neuronal cell bodies of ganglia are surrounded by a layer of small
cuboidal cells called **satellite cells** . Although they form a complete layer
around the cell body, only their nuclei are typically visible in routine H&E
preparations (Fig. 12.20a and b). In paravertebral and peripheral ganglia,
neural cell processes must penetrate between the satellite cells to establish a
synapse (there are no synapses in sensory ganglia). They help to establish
and maintain a controlled microenvironment around the neuronal body in
the ganglion, providing electrical insulation as well as a pathway for
metabolic exchanges. Thus, the functional role of the satellite cell is
analogous to that of the Schwann cell, except that it does not make myelin.


**FIGURE** **12.20.** **Photomicrograph** **of** **a** **nerve** **ganglion.** **a.**
Photomicrograph showing a ganglion stained by the Mallory–Azan method.
Note the large nerve cell bodies ( _arrows_ ) and nerve fibers ( _NF_ ) in the
ganglion. Satellite cells are represented by the very small nuclei at the
periphery of the neuronal cell bodies. The ganglion is surrounded by a dense
irregular connective tissue capsule ( _CT_ ) that is comparable to, and
continuous with, the epineurium of the nerve. ×200. **b.** Higher magnification
of the ganglion showing individual axons and a few neuronal cell bodies with


their satellite cells ( _arrows_ ). The nuclei in the region of the axons are mostly
Schwann cell’s nuclei. ×640.

### **Enteric Neuroglial Cells**


Neurons and their processes located within ganglia of the enteric division of
the ANS are associated with **enteric neuroglial cells** . These cells are
morphologically and functionally similar to **astrocytes** in the CNS (see
later). Enteric neuroglial cells share common functions with astrocytes, such
as structural, metabolic, and protective support of neurons. However, recent
studies indicate that enteric glial cells may also participate in enteric
neurotransmission and help coordinate activities of the nervous and immune
systems of the gut.

### **Central Neuroglia**


There are four types of central neuroglia:


**Astrocytes** are morphologically heterogeneous cells that provide
physical and metabolic support for neurons of the CNS.
**Oligodendrocytes** are small cells that are active in the formation and
maintenance of myelin in the CNS.
**Microglia** are inconspicuous cells with small, dark, elongated nuclei that
possess phagocytotic properties.
**Ependymal cells** are columnar cells that line the ventricles of the brain
and the central canal of the spinal cord.


Only the nuclei of glial cells are seen in routine histologic preparations
of the CNS. Heavy metal staining or immunocytochemical methods are
necessary to demonstrate the shape of the entire glial cell.

Although **glial cells** have long been described as supporting cells of
nerve tissue in the purely physical sense, current concepts emphasize the
**functional interdependence** of neuroglial cells and **neurons** . The most
obvious example of physical support occurs during development. The brain
and spinal cord develop from the **embryonic neural tube** . In the head
region, the neural tube undergoes remarkable thickening and folding,
leading ultimately to the final structure, the brain. During the early stages of
the process, embryonic glial cells extend through the entire thickness of the
neural tube in a radial manner. These **radial glial** cells serve as the physical
scaffolding that directs the migration of neurons to their appropriate position
in the brain.


**Astrocytes are closely associated with neurons to support and**
**modulate their activities.**


**Astrocytes** are the largest of the neuroglial cells. They form a network of
cells within the CNS and communicate with neurons to support and
modulate many of their activities. Some astrocytes span the entire thickness
of the brain, providing a scaffold for migrating neurons during brain
development. Other astrocytes stretch their processes from blood vessels to
neurons. The ends of the processes expand, forming end-feet that cover
large areas of the outer surface of the vessel or axolemma. Recently, it has
been shown that **reactive astrocytes** possess **phagocytic ability** and are
involved in eliminating parts of live neurons such as synapses, nerve cell
processes, as well as neuronal debris in the developing and injured brain.
During brain development, neurons generate excess synapses. Astrocytic
phagocytosis selectively eliminates these unnecessary synapses to achieve
precise neural connectivity. Although astrocytes do not form myelin, they
provide a compensatory mechanism to clear myelin debris after nerve cell
injury if microglia (the primary phagocytic cells in the brain) are unable to
execute phagocytosis (see page 413).

Two kinds of astrocytes are identified:


**Protoplasmic astrocytes** are more prevalent in the outermost covering
of the brain called _gray matter_ . These astrocytes have numerous short,
branching cytoplasmic processes (Fig. 12.21). Fine processes of a single
protoplasmic astrocyte form an extensive network interacting with up to
two million synapses in humans, allowing the gray matter to relay
information at neuronal synapses. They also contribute to
neurotransmitter, ion, and energy homeostasis.


**FIGURE 12.21.** **Protoplasmic astrocyte in the gray matter of the brain.**
**a.** This schematic drawing shows the foot processes of a protoplasmic
astrocyte terminating on a blood vessel and the axonal process of a nerve
cell. The foot processes terminating on the blood vessel contribute to the
blood–brain barrier. The bare regions of the vessel as shown in the
drawing would be covered by processes of neighboring astrocytes, thus
forming the overall barrier. **b.** This laser scanning confocal image of a
protoplasmic astrocyte in the gray matter of the dentate gyrus was
visualized by intracellular labeling method. In lightly fixed tissue slices,
selected astrocytes were impaled and iontophoretically injected with
fluorescent dye (Alexa Fluor 568) using pulses of negative current. Note
the density and spatial distribution of cell processes. ×480. (Reprinted with
permission from Bushong EA, Martone ME, Ellisman MH. Examination of
the relationship between astrocyte morphology and laminar boundaries in
the molecular layer of adult dentate gyrus. _J Comp Neurol_ . 2003;462:241–
251.)


**Fibrous astrocytes** are more common in the inner core of the brain
called _white matter_ . These astrocytes have fewer, longer, relatively
straight, and less branched processes (Fig. 12.22). In the white matter,
electrical impulses are mainly propagated along the axons (most often
myelinated), with little information processing. The processes of fibrous
astrocytes run along axons throughout the white matter and make contact
with axons only at the node of Ranvier.


**FIGURE 12.22.** **Fibrous astrocytes in the white matter of the brain. a.**
Schematic drawing of a fibrous astrocyte in the white mater of the brain. **b.**
Photomicrograph of the white matter of the brain showing the extensive
radiating cytoplasmic processes for which astrocytes are named. They are
best visualized, as shown here, with immunostaining methods that use
antibodies against glial fibrillary acidic protein (GFAP). ×220. (Reprinted
with permission from Fuller GN, Burger PC. Central nervous system. In:
Sternberg SS, ed. _Histology for Pathologists_ . Lippincott-Raven; 1997.)


Both types of astrocytes contain prominent bundles of intermediate
filaments composed of **glial fibrillary acidic protein (GFAP)** . The
filaments are much more numerous in the fibrous astrocytes, however, hence
the name. Antibodies to GFAP are used as specific stains to identify
astrocytes in sections and tissue cultures (see Fig. 12.22b). Tumors arising
from fibrous astrocytes, **fibrous astrocytomas**, account for about
80% of adult primary brain tumors. They can be identified

.
microscopically and by their **GFAP specificity**

Astrocytes play important roles in the movement of metabolites and
wastes to and from neurons. They help maintain the tight junctions of the
capillaries that form the **blood–brain barrier** (see pages 424-425). In
addition, astrocytes provide a covering for the “bare areas” of myelinated
axons—for example, at the nodes of Ranvier and synapses. They may
confine neurotransmitters to the synaptic cleft and remove excess
neurotransmitters by pinocytosis. **Protoplasmic astrocytes** on the brain
and spinal cord surfaces extend their processes (subpial feet) to the basal
lamina of the pia mater to form the **glia limitans**, a relatively impermeable
barrier surrounding the CNS (Fig. 12.23).


**FIGURE 12.23.** **Distribution of glial cells in the brain.** This diagram shows
the four types of glial cells—astrocytes, oligodendrocytes, microglial cells,
and ependymal cells—interacting with several structures and cells found in
the brain tissue. Note that the astrocytes and their processes interact with
the blood vessels as well as with axons and dendrites. Astrocytes also send
their processes toward the brain surface, where they contact the basement
membrane of the pia mater, forming the glia limitans. In addition, processes
of astrocytes extend toward the fluid-filled spaces in the central nervous
system (CNS), where they contact the ependymal lining cells.
Oligodendrocytes are involved in myelination of the nerve fibers in the CNS.
Microglia exhibit phagocytotic functions.


**Astrocytes modulate neuronal activities by buffering the K** **[+]**

**concentration in the extracellular space of the brain.**


It is now generally accepted that astrocytes **regulate K** **[+]** **concentrations** in
the brain’s extracellular compartment, thus maintaining the
microenvironment and modulating the activities of the neurons. The
astrocyte plasma membrane contains an abundance of K [+] pumps and K [+]

channels that mediate the transfer of K [+] ions from areas of high to low
concentration. Accumulation of large amounts of intracellular K [+] in
astrocytes decreases local extracellular K [+] gradients. The astrocyte
membrane becomes depolarized, and the charge is dissipated over a large


area by the extensive network of astrocyte processes. The maintenance of
the K [+] concentration in the brain’s extracellular space by astrocytes is called
**potassium spatial buffering** .


**Oligodendrocytes produce and maintain the myelin sheath in the**
**CNS.**


The **oligodendrocyte** is the cell responsible for producing CNS myelin.
The myelin sheath in the CNS is formed by concentric layers of
oligodendrocyte plasma membrane. The formation of the sheath in the CNS
is more complex, however, than the simple wrapping of Schwann cell’s
mesaxon membranes that occurs in the PNS (pages 405-407).

Oligodendrocytes appear in specially stained LM preparations as small
cells with relatively few processes compared with astrocytes. They are often
aligned in rows between the axons. Each oligodendrocyte gives off several
tongue-like processes that make contact with nearby axons. Each process
wraps itself around a portion of an axon, forming an **internodal segment**
**of myelin** . The multiple processes of a single oligodendrocyte may
myelinate one axon or several nearby axons (Fig. 12.24). The nucleuscontaining region of the oligodendrocyte may be at some distance from the
axons it myelinates.


**FIGURE 12.24.** **Three-dimensional view of an oligodendrocyte as it**
**relates to several axons.** Cytoplasmic processes from the oligodendrocyte
cell body form flattened cytoplasmic sheaths that wrap around each of the
axons. The relationship of cytoplasm and myelin is essentially the same as
that of Schwann cells.


Because a single oligodendrocyte may myelinate several nearby axons
simultaneously, the cell cannot embed multiple axons in its cytoplasm and
allow the mesaxon membrane to spiral around each axon. Instead, each
tongue-like process appears to spiral around the axon, always staying in
proximity to it, until the myelin sheath is formed.


**The myelin sheath in the CNS differs from that in the PNS.**


There are several other important differences between the myelin sheaths in
the CNS and those in the PNS. Oligodendrocytes in the CNS express
different myelin-specific proteins during myelination than those expressed
by Schwann cells in the PNS. Instead of P0 and PMP22, which are


expressed only in myelin of the PNS, other proteins, including **proteolipid**
**protein (PLP)**, **myelin oligodendrocyte glycoprotein (MOG)**, and
**oligodendrocyte myelin glycoprotein (OMgp)**, perform similar
functions in CNS myelin. Deficiencies in the expression of these
proteins appear to be important in the pathogenesis of several
autoimmune **demyelinating diseases** of the CNS.

On the microscopic level, myelin in the CNS exhibits fewer Schmidt–
Lanterman clefts because the astrocytes provide metabolic support for CNS
neurons. Unlike Schwann cells of the PNS, oligodendrocytes do not have an
external lamina. Furthermore, because of the manner in which
oligodendrocytes form CNS myelin, little or no cytoplasm may be present in
the outermost layer of the myelin sheath, and with the absence of external
lamina, the myelin of adjacent axons may come into contact. Thus, where
myelin sheaths of adjacent axons touch, they may share an intraperiod line.
Finally, the nodes of Ranvier in the CNS are larger than those in the PNS.
The larger areas of exposed axolemma thus make **saltatory conduction**
(see later) even more efficient in the CNS.

Another difference between the CNS and the PNS in regard to the
relationships between supporting cells and neurons is that unmyelinated
neurons in the CNS are often found to be bare—that is, they are not
embedded in glial cell processes. The lack of supporting cells around
unmyelinated axons as well as the absence of basal lamina material and
connective tissue within the substance of the CNS helps to distinguish the
CNS from the PNS in histologic sections and TEM specimens.


**Microglia possess phagocytotic properties.**


**Microglia** are phagocytotic cells. They normally account for about 5% of all
glial cells in the adult CNS but proliferate and become actively phagocytotic
( **reactive microglial cells** ) in regions of injury and disease. Microglial
cells are considered part of the mononuclear phagocyte system (see Folder
6.4, page 203) and originate from erythro-myeloid progenitor cells in the
yolk sac. Microglia precursor cells migrate to developing CNS during the
embryonic and perinatal stages of development (see page 415). In the past,
microglia have been regarded as the primary phagocytic cells in the brain.
However, recent evidence shows that astrocytic phagocytosis provides a
compensatory mechanism for microglial dysfunction. Similar to astrocytes,
microglial cells are involved in synaptic pruning, a process that forms the
cellular basis for learning and memory, especially during brain development
and brain injury (see page 410). Recent evidence suggests that
microglia play a critical role in **defense against invading**
**microorganisms** and neoplastic cells. They remove bacteria, injured
cells, and the debris of cells that undergo apoptosis. They also


mediate neuroimmune reactions, such as those occurring in chronic
pain conditions.

Microglia are the smallest of the neuroglial cells and have relatively
small, elongated nuclei (Fig. 12.25). When stained with heavy metals,
microglia exhibit short, twisted processes. Both the processes and the cell
body are covered with numerous spikes. The spikes may be the equivalent
of the ruffled border seen on other phagocytotic cells. The TEM reveals
numerous lysosomes, inclusions, and vesicles. However, microglia contain
little rER and few microtubules or actin filaments.


**FIGURE 12.25.** **Microglial cell in the gray matter of the brain. a.** This
diagram shows the shape and characteristics of a microglial cell. Note the
elongated nucleus and relatively few processes emanating from the body. **b.**
Photomicrograph of microglial cells ( _arrows_ ) showing their characteristic
elongated nuclei. The specimen was obtained from an individual with diffuse
microgliosis. In this condition, the microglial cells are present in large
numbers and are readily visible in a routine hematoxylin and eosin (H&E)
preparation. ×420. (Reprinted with permission from Fuller GN, Burger PC.
Central nervous system. In: Sternberg SS, ed. _Histology for Pathologists_ .
Lippincott-Raven; 1997.)


**Ependymal cells form the epithelial-like lining of the ventricles of**
**the brain and spinal canal.**


**Ependymal cells** form the epithelium-like lining of the fluid-filled cavities
of the CNS. They form a single layer of cuboidal-to-columnar cells that
have the morphologic and physiologic characteristics of fluid-transporting
cells (Fig. 12.26). They are tightly bound by junctional complexes located at
the apical surfaces. Unlike a typical epithelium, ependymal cells lack an
external lamina. At the TEM level, the basal cell surface exhibits numerous
infoldings that interdigitate with adjacent astrocyte processes. The apical


surface of the cell possesses cilia and microvilli. The latter are involved in
absorbing cerebrospinal fluid (CSF).


**FIGURE 12.26.** **Ependymal lining of the spinal canal. a.** Photomicrograph
of the central region of the spinal cord stained with toluidine blue. The _arrow_
points to the central canal. ×20. **b.** At higher magnification, ependymal cells,
which line the central canal, can be seen to consist of a single layer of
columnar cells. ×340. (Courtesy of Dr. George D. Pappas.) **c.** Transmission
electron micrograph showing a portion of the apical region of two columnar
ependymal cells. They are joined by a junctional complex ( _JC_ ) that separates
the lumen of the canal from the lateral intercellular space. The apical surface
of the ependymal cells has both cilia ( _C_ ) and microvilli ( _M_ ). Basal bodies ( _BB_ )
and a Golgi apparatus ( _G_ ) within the apical cytoplasm are also visible.
×20,000. (Courtesy of Dr. Paul Reier.)


**Tanycytes** are specialized types of ependymal cells. They are most
numerous in the floor of the third ventricle. The free surface of tanycytes is
in direct contact with CSF, but in contrast to the ependymal cells, they do
not possess cilia. The cell body of tanycytes gives rise to a long process that
projects into the brain parenchyma. Their role remains unclear; however,
they are involved in the transport of substances from the CSF to the blood
within the portal circulation of the hypothalamus. Tanycytes are sensitive to
glucose concentration; therefore, they may be involved in detecting and
responding to changes in energy balance as well as in monitoring other
circulating metabolites in the CSF.

Within the **system of brain ventricles**, the epithelium-like lining is
further modified to produce the CSF by transport and secretion of materials
derived from adjacent capillary loops. The modified ependymal cells and
associated capillaries are called the **choroid plexus** .


### **Impulse Conduction**

**An action potential is an electrochemical process triggered by**
**impulses carried to the axon hillock after other impulses are**
**received on the dendrites or the cell body itself.**


A **nerve impulse** is conducted along an axon much as a flame travels along
the fuse of a firecracker. This electrochemical process involves the
generation of an **action potential**, a wave of membrane depolarization that
is initiated at the initial segment of the axon hillock. Its membrane contains
a large number of **voltage-gated Na** **[+]** **and K** **[+]** **channels** . In response to a
stimulus, voltage-gated Na [+] channels in the initial segment of the axon
membrane open, causing an influx of Na [+] into the axoplasm. This influx of
Na [+] briefly reverses (depolarizes) the negative membrane potential of the
resting membrane (−70 mV) to positive (+30 mV). After depolarization, the
voltage-gated Na [+] channels close and voltage-gated K [+] channels open. K [+]

rapidly exits the axon, returning the membrane to its resting potential.
Depolarization of one part of the membrane sends electrical current to
neighboring portions of unstimulated membrane, which is still positively
charged. This local current stimulates adjacent portions of the axon’s
membrane and repeats depolarization along the membrane. The entire
process takes less than 1,000th of a second. After a very brief (refractory)
period, the neuron can repeat the process of generating an action potential
once again.


**Rapid conduction of the action potential is attributable to the nodes**
**of Ranvier.**


**Myelinated axons** conduct impulses more rapidly than unmyelinated
axons. Physiologists describe the nerve impulse as “jumping” from node to
node along the myelinated axon. This process is called **saltatory** _[L. saltus,_
_to jump]_ or **discontinuous conduction** . In myelinated nerves, the myelin
sheath around the nerve does not conduct an electric current and forms an
insulating layer around the axon. However, the voltage reversal can _only_
occur at the nodes of Ranvier, where the axolemma lacks a myelin sheath.
Here, the axolemma is exposed to extracellular fluids and possesses a high
concentration of voltage-gated Na [+] and K [+] channels (see Figs. 12.17 and
12.24). Thus, the voltage reversal (and thus the impulse) jumps as current
flows from one node of Ranvier to the next. The speed of saltatory
conduction is related not only to the thickness of the myelin but also to the
diameter of the axon. Conduction is more rapid along axons of greater
diameter.


In **unmyelinated axons**, Na [+] and K [+] channels are distributed
uniformly along the length of the fiber. The nerve impulse is conducted
more slowly and moves as a continuous wave of voltage reversal along the

axon.

### **ORIGIN OF NERVE TISSUE CELLS**


**CNS neurons and central glia, except microglial cells, are derived**
**from neuroectodermal cells of the neural tube.**


Neurons, oligodendrocytes, astrocytes, and ependymal cells are derived
from cells of the **neural tube** . After developing neurons have migrated to
their predestined locations in the neural tube and have differentiated into
mature neurons, they no longer divide. However, in the adult mammalian
brain, a very small number of **neural stem cells** retain the ability to divide.
These cells migrate into the sites of injury and differentiate into fully
functional nerve cells.

**Oligodendrocyte** precursors are highly migratory cells. They appear to
share a developmental lineage with motor neurons migrating from their site
of origin to developing axonal projections (tracts) in the white matter of the
brain or spinal cord. The precursors then proliferate in response to the local
expression of mitogenic signals. The matching of oligodendrocytes to axons
is accomplished through a combination of local regulation of cell
proliferation, differentiation, and apoptosis.

**Astrocytes** are also derived from cells of the neural tube. During the
embryonic and early postnatal stages, immature astrocytes migrate into the
cortex, where they differentiate and become mature astrocytes. **Ependymal**
**cells** are derived from the proliferation of neuroepithelial cells that
immediately surround the canal of the developing neural tube.

In contrast to other central neuroglia, **microglia cells** are derived from
mesodermal macrophage precursors, specifically from **erythro-myeloid**
**progenitor cells** in the yolk sac. They infiltrate the neural tube in the early
stages of its development and under the influence of growth factors such as
colony-stimulating factor 1 (CSF-1) produced by developing neural cells as
they undergo proliferation and differentiation into motile amoeboid cells.
These motile cells are commonly observed in the developing brain. As the
only glial cells of mesenchymal origin, microglia possess the **vimentin**
**class of intermediate filaments**, which can be useful in identifying these
cells with immunocytochemical methods.


**PNS ganglion cells and peripheral glia are derived from the neural**
**crest.**


The development of the **ganglion cells** of the PNS involves the
proliferation and migration of ganglion precursor cells from the **neural**
**crest** to their future ganglionic sites, where they undergo further
proliferation. Here, the cells develop processes that reach the cells’ target
tissues (e.g., glandular tissue or smooth muscle cells) and sensory territories.
Initially, more cells are produced than are needed. Those that do not make
functional contact with a target tissue undergo apoptosis.

**Schwann cells** also arise from migrating neural crest cells that become
associated with the axons of early embryonic nerves. Several genes have
been implicated in Schwann cell development. Sex-determining region Y
(SRY) box 10 ( _Sox10_ ) is required for the generation of all peripheral glia
from neural crest cells. Axon-derived neuregulin-1 ( _Nrg-1_ ) sustains the
**Schwann cell precursors** that undergo differentiation and divide along
the growing nerve processes. The fate of all immature Schwann cells is
determined by the nerve processes with which they have immediate contact.
Immature Schwann cells that associate with large-diameter axons mature
into myelinating Schwann cells, whereas those that associate with smalldiameter axons mature into nonmyelinating cells.

### **ORGANIZATION OF THE PERIPHERAL NERVOUS** **SYSTEM**


The **peripheral nervous system (PNS)** consists of peripheral nerves with
specialized nerve endings and ganglia-containing nerve cell bodies that
reside outside the CNS.

### **Peripheral Nerves**


**A peripheral nerve is a bundle of nerve fibers held together by**
**connective tissue.**


The nerves of the PNS are made up of many nerve fibers that carry sensory
and motor (effector) information between the organs and tissues of the body
and between the brain and spinal cord. The term **nerve fiber** is used in
different ways that can be confusing. It can connote the axon with all of its
coverings (myelin and Schwann cell), as used earlier, or it can connote the
axon alone. It is also used to refer to any process of a nerve cell, either
dendrite or axon, especially if insufficient information is available to
identify the process as either an axon or a dendrite.

The cell bodies of peripheral nerves may be located either within the
CNS or outside the CNS in **peripheral ganglia** . Ganglia contain clusters of


neuronal cell bodies and the nerve fibers leading to and from them (see Fig.
12.20). The cell bodies in the dorsal root ganglia as well as ganglia of
cranial nerves belong to sensory neurons ( **somatic afferents** and **visceral**
**afferents** that belong to the ANS discussed earlier), whose distribution is
restricted to specific locations (Table 12.2 and Fig. 12.3). The cell bodies in
the paravertebral, prevertebral, and terminal ganglia belong to postsynaptic
“motor” neurons ( **visceral efferents** ) of the ANS (see Table 12.1 and Fig.
12.20).









**Dorsal root ganglia of all spinal nerves**
**Sensory ganglia of cranial nerves**

Trigeminal (semilunar, Gasserian) ganglion of the trigeminal (V) nerve
Geniculate ganglion of the facial (VII) nerve
Spiral ganglion (contains bipolar neurons) of the cochlear division of
the vestibulocochlear (VIII) nerve
Vestibular ganglion (contains bipolar neurons) of the vestibular
division of the vestibulocochlear (VIII) nerve
Superior and inferior ganglia of the glossopharyngeal (IX) nerve
Superior and inferior ganglia of the vagus (X) nerve


**Ganglia that contain cell bodies of autonomic (postsynaptic)**
**neurons; these are synaptic stations**


**Sympathetic ganglia**

Sympathetic trunk (paravertebral) ganglia (the highest of these is the
superior cervical ganglion)
Prevertebral ganglia (adjacent to origins of large unpaired branches
of abdominal aorta), including celiac, superior mesenteric, inferior
mesenteric, and aorticorenal ganglia
Adrenal medulla, which may be considered a modified sympathetic
ganglion (each of the secretory cells of the medulla, as well as the
recognizable ganglion cells, is innervated by cholinergic presynaptic
sympathetic nerve fibers)
**Parasympathetic ganglia**

Head ganglia

Ciliary ganglion associated with the oculomotor (III) nerve
Submandibular ganglion associated with the facial (VII) nerve
Pterygopalatine (sphenopalatine) ganglion of the facial (VII) nerve
Otic ganglion associated with the glossopharyngeal (IX) nerve


Terminal ganglia (near or in wall of organs), including ganglia of the
submucosal (Meissner) and myenteric (Auerbach) plexuses of the
gastrointestinal tract (these are also ganglia of the enteric division of
the ANS) and isolated ganglion cells in a variety of organs


_a_ Practical note: Neuron cell bodies seen in tissue sections such as tongue, pancreas,
urinary bladder, and heart are invariably terminal ganglia or “ganglion cells” of the
parasympathetic nervous system.


To understand the PNS, it is also necessary to describe some parts of the
CNS.


**Motor neuron cell bodies of the PNS lie in the CNS.**


The cell bodies of motor neurons that innervate skeletal muscle ( **somatic**
**efferents** ) are located in the brain, brainstem, and spinal cord. The axons
leave the CNS and travel in peripheral nerves to the skeletal muscles that
they innervate. A single neuron conveys impulses from the CNS to the
effector organ.


**Sensory neuron cell bodies are located in ganglia outside, but close**
**to, the CNS.**


In the sensory system (both the **somatic afferent** and the **visceral**
**afferent** components), a single neuron connects the receptor, through a
sensory ganglion, to the spinal cord or brainstem. **Sensory ganglia** are
located in the dorsal roots of the spinal nerves and in association with
sensory components of cranial nerves V, VII, VIII, IX, and X (see Table
12.2).

### **Connective Tissue Components of a Peripheral** **Nerve**


The bulk of a **peripheral nerve** consists of nerve fibers and their
supporting Schwann cells. The individual nerve fibers and their associated
Schwann cells are held together by connective tissue organized into three
distinctive components, each with specific morphologic and functional
characteristics (Fig. 12.27; see also Fig. 12.3).


**FIGURE 12.27.** **Electron micrograph of a peripheral nerve and its**
**surrounding perineurium. a.** Electron micrograph of unmyelinated nerve
fibers and a single myelinated fiber ( _MF_ ). The perineurium ( _P_ ), consisting of
several cell layers, is seen on the _left_ of the micrograph. Perineurial cell
processes ( _arrowheads_ ) have also extended into the nerve to surround a
group of axons ( _A_ ) and their Remak Schwann cell as well as a small blood
vessel ( _BV_ ). The enclosure of this group of _A_ represents the root of a small
nerve branch that is joining or leaving the larger fascicle. ×10,000. The area
within the _circle_ encompassing the endothelium of the vessel and the
adjacent perineurial cytoplasm is shown in the _inset_ at higher magnification.
Note the basal (external) laminae of the vessel and the perineurial cell
( _arrows_ ). The junction between endothelial cells of the blood vessel is also
apparent ( _arrowheads_ ). ×46,000. **b.** Electron micrograph showing the
perineurium of a nerve. Four cellular layers of the perineurium are present.
Each layer has a basal (external) lamina ( _BL_ ) associated with it on both
surfaces. Other features of the perineurial cell include an extensive
population of actin microfilaments ( _MF_ ), pinocytotic vesicles ( _arrows_ ), and
cytoplasmic densities ( _CD_ ). These features are characteristic of smooth
muscle cells. The innermost perineurial cell layer ( _right_ ) exhibits tight
junctions ( _asterisks_ ) where one cell is overlapping a second cell in forming
the sheath. Other features seen in the cytoplasm are mitochondria ( _M_ ),


rough-surfaced endoplasmic reticulum ( _rER_ ), and free ribosomes ( _R_ ).
×27,000.


The **endoneurium** includes loose connective tissue surrounding each
individual nerve fiber.
The **perineurium** includes specialized connective tissue surrounding
each nerve fascicle.
The **epineurium** includes dense irregular connective tissue that
surrounds a peripheral nerve and fills the spaces between nerve fascicles.


**Endoneurium constitutes the loose connective tissue associated**
**with individual nerve fibers.**


The **endoneurium** is not conspicuous in routine LM preparations, but
special connective tissue stains permit its demonstration. At the electron
microscope level, collagen fibrils that constitute the endoneurium are readily
apparent (see Figs. 12.15 and 12.16). The fibrils run both parallel to and
around the nerve fibers, binding them together into a fascicle or bundle.
Because **fibroblasts** are relatively sparse in the interstices of the nerve
fibers, it is likely that most of the collagen fibrils are secreted by the
Schwann cells. This conclusion is supported by tissue culture studies in
which collagen fibrils are formed in pure cultures of Schwann cells and
dorsal root neurons.

Other than occasional fibroblasts, the only other connective tissue cells
normally found within the endoneurium are **mast cells** and **macrophages** .
Macrophages mediate immunologic surveillance and also participate in
nerve tissue repair. Following nerve injury, they proliferate and actively
phagocytose myelin debris. In general, most of the nuclei (90%) found in
cross sections of peripheral nerves belong to Schwann cells; the remaining
10% is equally distributed between the occasional fibroblasts and other
cells, such as **endothelial cells** of capillaries, macrophages, and mast cells.


**Perineurium is the specialized connective tissue surrounding a**
**nerve fascicle that contributes to the formation of the blood–nerve**

**barrier.**


Surrounding the nerve bundle is a sheath of unique connective tissue cells
that constitutes the **perineurium** . The perineurium serves as a metabolically
active diffusion barrier that contributes to the formation of a **blood–nerve**

**barrier** . This barrier maintains the ionic milieu of the ensheathed nerve
fibers. In a manner similar to the properties exhibited by the endothelial
cells of brain capillaries forming the blood–brain barrier (see pages 424

425), **perineurial cells** possess receptors, transporters, and enzymes that
provide for the active transport of substances.

The perineurium may be one or more cell layers thick, depending on the
nerve diameter. The cells that compose this layer are squamous; each layer
exhibits an external (basal) lamina on both surfaces (Fig. 12.27b and Plate
12.1, page 432). The cells are contractile and contain an appreciable number
of actin filaments, a characteristic of smooth muscle cells and other
contractile cells. Moreover, when there are two or more perineurial cell
layers (as many as five or six layers may be present in larger nerves),
collagen fibrils are present between the perineurial cell layers, but
fibroblasts are absent. **Tight junctions** provide the basis for the **blood–**
**nerve barrier** and are present between the cells located within the same
layer of the perineurium. In effect, the arrangement of these cells as a barrier
—the presence of tight junctions and external (basal) lamina material—
likens them to an epithelioid tissue. On the other hand, their contractile
nature and their apparent ability to produce collagen fibrils also liken them
to smooth muscle cells and fibroblasts.

The limited number of connective tissue cell types within the
endoneurium (page 416) undoubtedly reflects the protective role that the
perineurium plays. Typical immune system cells (i.e., lymphocytes, plasma
cells) are not found within the endoneurial and perineurial compartments.
This absence of immune cells (other than the mast cells and macrophages) is
accounted for by the protective barrier created by the perineurial cells.
Typically, only fibroblasts, a small number of resident macrophages, and
occasional mast cells are present within the nerve compartment.


**Epineurium consists of dense irregular connective tissue that**
**surrounds and binds nerve fascicles into a common bundle.**


The **epineurium** forms the outermost tissue of the peripheral nerve. It is a
typical **dense irregular connective tissue** that surrounds the fascicles
formed by the perineurium (Plate 12.2, page 434). Adipose tissue is often
associated with the epineurium in larger nerves.

The blood vessels that supply the nerves travel in the epineurium, and
their branches penetrate into the nerve and travel within the perineurium.
Tissue at the level of the endoneurium is poorly vascularized; metabolic
exchange of substrates and wastes in this tissue depends on diffusion from
and to the blood vessels through the perineurial sheath (see Fig. 12.27).

### **Afferent (Sensory) Receptors**


**Afferent receptors are specialized structures located at the distal**
**tips of the peripheral processes of sensory neurons.**


Although **receptors** may have many different structures, they have one
basic characteristic in common: They can initiate a nerve impulse in
response to a stimulus. Receptors may be classified as follows:


**Exteroceptors** react to stimuli from the external environment—for
example, temperature, touch, smell, sound, and vision.
**Enteroceptors** react to stimuli from within the body—for example, the
degree of filling or stretch of the alimentary canal, bladder, and blood
vessels.
**Proprioceptors**, which also react to stimuli from within the body,
provide sensation of body position and muscle tone and movement.


The simplest receptor is a bare axon called a **nonencapsulated (free)**
**nerve ending** . This ending is found in epithelia, connective tissue, and in
close association with hair follicles.


**Most sensory nerve endings acquire connective tissue capsules or**
**sheaths of varying complexity.**


Sensory nerve endings with connective tissue sheaths are called
**encapsulated endings** . Many encapsulated endings are mechanoreceptors
located in the skin and joint capsules (Krause end bulb, Ruffini corpuscles,
Meissner corpuscles, and Pacinian corpuscles) and are described in Chapter
15, Integumentary System (pages 555-559). **Muscle spindles** are
encapsulated sensory endings located in skeletal muscle; they are described
in Chapter 11, Muscle Tissue (pages 359-360). Functionally, related Golgi
tendon organs are encapsulated tension receptors found at musculotendinous
junctions.

### **ORGANIZATION OF THE AUTONOMIC NERVOUS** **SYSTEM**


Although the ANS was introduced early in this chapter (see page 389), it is
useful here to describe some of the salient features of its organization and
distribution. The ANS is classified into three divisions:


**Sympathetic division**
**Parasympathetic division**
**Enteric division**


**The ANS controls and regulates the body’s internal environment.**


The **ANS** is the portion of the PNS that conducts involuntary impulses to
smooth muscle, cardiac muscle, and glandular epithelium. These effectors
are the functional units in the organs that respond to regulation by nerve
tissue. The term _visceral_ is sometimes used to characterize the ANS and its
neurons, which are referred to as **visceral motor (efferent) neurons** .
However, visceral motor neurons are frequently accompanied by **visceral**
**sensory (afferent) neurons** that transmit pain and reflexes from visceral
effectors (i.e., blood vessels, mucous membrane, and glands) to the CNS.
These pseudounipolar neurons have the same arrangement as other sensory
neurons—that is, their cell bodies are located in sensory ganglia, and they
possess long peripheral and central axons, as described earlier.

The main organizational difference between the efferent flow of
impulses to skeletal muscle (somatic effectors) and the efferent flow to
smooth muscle, cardiac muscle, and glandular epithelium (visceral
effectors) is that one neuron conveys the impulses from the CNS to the
somatic effector, whereas a chain of two neurons conveys the impulses from
the CNS to the visceral effectors (Fig. 12.28). Thus, there is a synaptic
station in an autonomic ganglion outside the CNS where a presynaptic
neuron makes contact with postsynaptic neurons. Each presynaptic neuron
synapses with several postsynaptic neurons.


**FIGURE 12.28.** **Schematic diagram of somatic efferent and visceral**
**efferent neurons.** In the somatic efferent (motor) system, one neuron
conducts the impulses from the central nervous system (CNS) to the effector
(skeletal muscle). In the visceral (autonomic) efferent system (represented in
this drawing by the sympathetic division of the autonomic nervous system

[ANS]), a chain of two neurons conducts the impulses: a presynaptic neuron
located within the CNS and a postsynaptic neuron located in the
paravertebral or prevertebral ganglia. Moreover, each presynaptic neuron
makes synaptic contact with more than one postsynaptic neuron.
Postsynaptic sympathetic fibers supply smooth muscles (as in blood vessels)
or glandular epithelium (as in sweat glands). Neurons of the ANS that supply
organs of the abdomen reach these organs by way of the splanchnic nerves.
In this example, the splanchnic nerve joins with the celiac ganglion, where
most of the synapses of the two-neuron chain occur.

### **Sympathetic and Parasympathetic Divisions of the** **Autonomic Nervous System**


**The presynaptic neurons of the sympathetic division are located in**
**the thoracic and upper lumbar portions of the spinal cord.**


The **presynaptic neurons** send axons from the thoracic and upper lumbar
spinal cord to the vertebral and paravertebral ganglia. The **paravertebral**
**ganglia** in the **sympathetic trunk** contain the cell bodies of the
postsynaptic effector neurons of the **sympathetic division** (see Figs. 12.28
and 12.29).


**FIGURE 12.29.** **Schematic diagram showing the general arrangement of**
**sympathetic and parasympathetic neurons of the autonomic nervous**
**system (ANS).** The sympathetic outflow is shown on the _left_, the
parasympathetic on the _right_ . The sympathetic (thoracolumbar) outflow
leaves the central nervous system (CNS) from the thoracic and upper lumbar
segments (T1–L2) of the spinal cord. These presynaptic fibers communicate
with postsynaptic neurons in two locations: the paravertebral and


prevertebral ganglia. Paravertebral ganglia are linked together and form two
sympathetic trunks on each side of the vertebral column ( _drawn as a single_
_column on the side of the spinal cord_ ). Prevertebral ganglia are associated
with the main branches of the abdominal aorta ( _yellow ovals_ ). Note the
distribution of postsynaptic sympathetic nerve fibers to the viscera. The
parasympathetic (craniosacral) outflow leaves the CNS from the gray matter
of the brainstem within cranial nerve (CN) III, CN VII, CN IX, and CN X and
the gray matter of sacral segments (S2–S4) of the spinal cord and is
distributed to the viscera. The presynaptic fibers traveling with CN III, CN VII,
and CN IX communicate with postsynaptic neurons in various ganglia
located in the head and neck region ( _yellow ovals in front of the head_ ). The
presynaptic fibers traveling with CN X and those from sacral segments (S2–
S4) have their synapses with postsynaptic neurons in the wall of visceral
organs (terminal ganglia). The viscera thus contains both sympathetic and
parasympathetic innervation. Note that a two-neuron chain carries impulses
to all viscera, except the adrenal medulla.


**The presynaptic neurons of the parasympathetic division are**
**located in the brainstem and sacral spinal cord.**


The **presynaptic parasympathetic neurons** send axons from the
brainstem—that is, the midbrain, pons, medulla, and the sacral segments of
the spinal cord (S2–S4)—to **visceral ganglia** . The ganglia in or near the
wall of abdominal and pelvic organs and the visceral motor ganglia of
cranial nerves III, VII, IX, and X contain cell bodies of the postsynaptic
effector neurons of the **parasympathetic division** (see Figs. 12.28 and
12.29).

The sympathetic and parasympathetic divisions of the ANS often supply
the same organs. In these cases, the actions of the two are usually
antagonistic. For example, sympathetic stimulation increases the rate of
cardiac muscle contractions, whereas parasympathetic stimulation reduces
the rate.


Many functions of the SNS are similar to those of the adrenal medulla,
an endocrine gland. This functional similarity is partly explained by the
developmental relationships between the cells of the adrenal medulla and
the postsynaptic sympathetic neurons. Both are derived from the neural
crest, are innervated by presynaptic sympathetic neurons, and produce
closely related physiologically active agents, EPI and NE. A major
difference is that the sympathetic neurons deliver the agent directly to the
effector, whereas the cells of the adrenal medulla deliver the agent indirectly
through the bloodstream. The innervation of the adrenal medulla may
constitute an exception to the rule that autonomic innervation consists of a
two-neuron chain from the CNS to an effector unless the adrenal medullary


cell is considered the functional equivalent of the second neuron (in effect, a
neurosecretory neuron).

### **Enteric Division of the Autonomic Nervous System**


**The enteric division of the ANS consists of the ganglia and their**
**processes that innervate the alimentary canal.**


The **enteric division of the ANS** represents a collection of neurons and
their processes within the walls of the alimentary canal. It controls motility
(contractions of the gut wall), exocrine and endocrine secretions, and blood
flow through the gastrointestinal tract; it also regulates immunologic and
inflammatory processes.

The enteric nervous system can function independently from the CNS
and is regarded as the “ **brain of the gut** .” However, digestion requires
communication between enteric neurons and the CNS, which is provided by
parasympathetic and sympathetic nerve fibers. Enteroceptors located in the
alimentary tract provide sensory information to the CNS regarding the state
of digestive functions. The CNS then coordinates sympathetic stimulation,
which inhibits gastrointestinal secretion, motor activity, and contraction of
gastrointestinal sphincters and blood vessels as well as parasympathetic
stimuli that produce opposite actions. **Interneurons** integrate information
from sensory neurons and relay this information to enteric motor neurons in
the form of reflexes. For instance, the gastrocolic reflex is elicited when
distention of the stomach stimulates contraction of musculature of the colon,
triggering defecation.

Ganglia and postsynaptic neurons of the enteric division are located in
the lamina propria, muscularis mucosae, submucosa, muscularis externa,
and subserosa of the alimentary canal from the esophagus to the anus (Fig.
12.30). Because the enteric division does not require presynaptic input from
the vagus nerve and sacral outflow, the intestine will continue peristaltic
movements, even after the vagus nerve or pelvic splanchnic nerves are
severed.


**FIGURE 12.30.** **Enteric nervous system.** This diagram shows the
organization of the enteric system in the wall of the small intestine. Note the
location of two nerve plexuses containing ganglion cells. The more
superficial plexus, the myenteric plexus (Auerbach plexus), lies between two
muscle layers. Deeper in the region of the submucosa is a network of
unmyelinated nerve fibers and ganglion cells, forming the submucosal plexus
(Meissner plexus). Parasympathetic fibers originating from the vagus nerve
enter the mesentery of the small intestine and synapse with the ganglion
cells of both plexuses. Postsynaptic sympathetic nerve fibers also contribute
to the enteric nervous system.


Neurons of the enteric division are not supported by Schwann or satellite
cells; instead, they are supported by **enteric neuroglial cells** that resemble
astrocytes (see pages 410-411). Cells of the **enteric division** are also
affected by the same pathologic changes that can occur in neurons
of the brain. Lewy bodies associated with **Parkinson disease** (see
Folder 12.1) as well as amyloid plaques and neurofibrillary tangles
associated with **Alzheimer disease** have been found in the walls of


the large intestine. This finding may lead to the development of
routine gastrointestinal biopsies for early diagnosis of these
conditions rather than the more complex and risk-associated biopsy
of the brain for Alzheimer disease and postmortem identification of
Parkinson disease.

### **A Summarized View of Autonomic Distribution**


Figures 12.28 and 12.29 summarize the origins and distribution of the ANS.
Refer to these figures as you read the descriptive sections. Note that the
diagrams indicate both the paired innervation (parasympathetic and
sympathetic) common to the ANS and the important exceptions to this
general characteristic.

###### **Head**


**Parasympathetic presynaptic outflow** to the head leaves the brain
with the cranial nerves, as indicated in Figure 12.29, but the routes are
quite complex. Cell bodies may also be found in structures other than
head ganglia listed in Table 12.1 and Figure 12.28 (e.g., in the tongue).
These are “terminal ganglia” that contain nerve cell bodies of the
parasympathetic system.
**Sympathetic presynaptic outflow** to the head comes from the thoracic
region of the spinal cord. The _postsynaptic neurons_ have their cell bodies
in the superior cervical ganglion; the axons leave the ganglion in a nerve
network that hugs the wall of the internal and external carotid arteries to
form the periarterial plexus of nerves. The internal carotid plexus and
external carotid plexus follow the branches of the carotid arteries to reach
their destination.

###### **Thorax**


**Parasympathetic presynaptic outflow** to the thoracic viscera is via
the vagus nerve (X). The _postsynaptic neurons_ have their cell bodies in
the walls or in the parenchyma of the organs of the thorax.
**Sympathetic presynaptic outflow** to the thoracic organs is from the
upper thoracic segments of the spinal cord. _Sympathetic postsynaptic_
_neurons_ for the heart are mostly in the cervical ganglia; their axons make
up the cardiac nerves. _Postsynaptic neurons_ for the other thoracic viscera
are in ganglia of the thoracic part of the sympathetic trunk. The axons
travel via small splanchnic nerves from the sympathetic trunk to organs
within the thorax and form the pulmonary and esophageal plexuses.


###### **Abdomen and pelvis**

**Parasympathetic presynaptic outflow** to the abdominal viscera is via
the vagus (X) and pelvic splanchnic nerves. _Postsynaptic neurons_ of the
parasympathetic system to abdominopelvic organs are in terminal ganglia
that generally are in the walls of the organs, such as the ganglia of the
submucosal (Meissner) plexus and the myenteric (Auerbach) plexus in
the alimentary canal. These ganglia are part of the enteric division of the
ANS.
**Sympathetic presynaptic outflow** to the abdominopelvic organs is
from the lower thoracic and upper lumbar segments of the spinal cord.
These fibers travel to the prevertebral ganglia through abdominopelvic
splanchnic nerves consisting of the greater, lesser, and least thoracic
splanchnic and lumbar splanchnic nerves. _Postsynaptic neurons_ have their
cell bodies mostly in the prevertebral ganglia (see Fig. 12.28). Only
presynaptic fibers terminating on cells in the medulla of the suprarenal
(adrenal) gland originate from paravertebral ganglia of the sympathetic
trunk. The adrenal medullary cells function as a special type of
postsynaptic neuron that releases neurotransmitter directly into the
bloodstream instead of into the synaptic cleft.

###### **Extremities and body wall**


There is no parasympathetic outflow to the body wall and extremities.
Anatomically, the autonomic innervation in the body wall is only
sympathetic (see Fig. 12.28). Each spinal nerve contains postsynaptic
sympathetic fibers—that is, unmyelinated visceral efferents of neurons
whose cell bodies are in paravertebral ganglia of the sympathetic trunk. For
sweat glands, the neurotransmitter released by the “sympathetic” neurons is
ACh instead of NE.

### **ORGANIZATION OF THE CENTRAL NERVOUS** **SYSTEM**


The **central nervous system** consists of the **brain** located in the cranial
cavity and the **spinal cord** located in the vertebral canal. The CNS is
protected by the skull and vertebrae and is surrounded by three connective
tissue membranes called **meninges** . The brain and spinal cord essentially
float in the CSF that occupies the space between the two inner meningeal
layers. The brain is further subdivided into the **cerebrum**, **cerebellum**, and
**brainstem**, which connects with the spinal cord.


**In the brain, the gray matter forms an outer covering or cortex; the**
**white matter forms an inner core or medulla.**


The **cerebral cortex** that forms the outermost layer of the brain contains
nerve cell bodies, axons, dendrites, and central glial cells, and it is the site of
synapses. In a freshly dissected brain, the cerebral cortex has a gray color,
hence the name **gray matter** . In addition to the cortex, islands of gray
matter called **nuclei** are found in the deep portions of the cerebrum and
cerebellum.

The **white matter** contains only axons of nerve cells plus the associated
glial cells and blood vessels (axons in fresh preparations appear white).
These axons travel from one part of the nervous system to another. Whereas
many of the axons going to, or coming from, a specific location are grouped
into functionally related bundles called **tracts**, the tracts themselves do not
stand out as delineated bundles. The demonstration of a tract in the white
matter of the CNS requires a special procedure, such as the destruction of
cell bodies that contribute fibers to the tract. The damaged fibers can be
displayed by the use of appropriate staining or labeling methods and then
traced. Even in the spinal cord, where the grouping of tracts is most
pronounced, there are no sharp boundaries between adjacent tracts.

### **Cells of the Gray Matter**


The types of cell bodies found in the gray matter vary according to which
part of the brain or spinal cord is being examined.


**Each functional region of the gray matter has a characteristic**
**variety of cell bodies associated with a meshwork of axonal,**
**dendritic, and glial processes.**


The meshwork of axonal, dendritic, and glial processes associated with the
gray matter is called the **neuropil** . The organization of the neuropil is not
demonstrable in H&E-stained sections. It is necessary to use methods other
than H&E histology to decipher the cytoarchitecture of the gray matter
(Plate 12.3, page 436).

Although general histology programs usually do not deal with the actual
arrangements of the neurons in the CNS, the presentation of two examples
will add to the appreciation of H&E sections that students usually examine.
These examples present a region of the cerebral cortex (Fig. 12.31 and Plate
12.3, page 436) and the cerebellar cortex (Fig. 12.32 and Plate 12.4, page
438).


**FIGURE 12.31.** **Nerve cells in intracortical cerebral circuits.** This
simplified diagram shows the organization and connections between cells in
different layers of the cortex contributing to cortical afferent fibers ( _arrows_
_pointing up_ ) and cortical efferent fibers ( _arrows pointing down_ ). The small
interneurons are indicated in _yellow_ .


**FIGURE 12.32.** **Cytoarchitecture of the cerebellar cortex. a.** This diagram
shows a section of the folium, a narrow, leaf-like gyrus of the cerebellar
cortex. The longer cut edge is parallel to the folium. Note that the cerebellar
cortex contains white matter and gray matter. Three distinct layers of gray
matter are identified on this diagram: the superficially located molecular
layer, the middle Purkinje cell layer, and the granule cell layer adjacent to the
white matter. Mossy fibers and ascending fibers are major afferent fibers of
the cerebellum. **b.** Purkinje cell layer from rat cerebellum visualized using
double-fluorescent–labeling methods. Red DNA staining indicates the nuclei
of cells in molecular and granule cell layer thin section. Note that each
Purkinje cell exhibits an abundance of dendrites. ×380. (Courtesy of Thomas
J. Deerinck.)


Notable in the cerebellar cortex (see Fig. 12.32) is the Purkinje
cell layer. Individuals infected by **rabies virus (RABV)** have
characteristic inclusions in the cytoplasm of affected neurons called
**Negri bodies** . These eosinophilic, sharply outlined, 2–10 μm in
diameter inclusions visible in LM represent intracellular **viral**
**replication compartments** formed during viral infection. They are
easily observed in the cytoplasm of the Purkinje cells and pyramidal
cells of the hippocampus. Negri bodies have been used for decades
as primary histologic proof of RABV infection. The current approach
for postmortem diagnosis of human and animal rabies is based on
the direct fluorescent antibody (DFA) test. Recently, an LN34 panlyssavirus real-time reverse transcription-polymerase chain reaction
(RT-PCR) assay has been introduced and has improved rabies
diagnostics and surveillance.

The **brainstem** is not clearly separated into regions of gray matter and
white matter. The nuclei of the cranial nerves located in the brainstem,


however, appear as islands surrounded by more or less distinct tracts of
white matter. The nuclei contain the cell bodies of the motor neurons of the
cranial nerves and are both the morphologic and functional counterparts of
the anterior horns of the spinal cord. In other sites in the brainstem, as in the
**reticular formation**, the distinction between white matter and gray matter
is even less evident.

### **Organization of the Spinal Cord**


The **spinal cord** is a flattened cylindrical structure that is directly
continuous with the brainstem. It is divided into 31 segments (8 cervical, 12
thoracic, 5 lumbar, 5 sacral, and 1 coccygeal), and each segment is
connected to a pair of **spinal nerves** . Each spinal nerve is joined to its
segment of the cord by a number of rootlets grouped as dorsal (posterior) or
ventral (anterior) roots (Fig. 12.33; see also Fig. 12.3).


**FIGURE 12.33.** **Posterior view of the spinal cord with surrounding**
**meninges.** Each spinal nerve arises from the spinal cord by rootlets, which


merge to form dorsal (posterior) and ventral (anterior) nerve roots. These
roots unite to form a spinal nerve that, after a short course, divides into larger
ventral (anterior) and smaller dorsal (posterior) primary rami. Note the dura
mater (the outer layer of the meninges) that surrounds the spinal cord and
emerging spinal nerves. The denticulate ligament of the pia mater that
anchors the spinal cord to the wall of the spinal canal is also visible.


In cross section, the spinal cord exhibits a butterfly-shaped grayish-tan
inner substance surrounding the **central canal**, the **gray matter**, and a
whitish peripheral substance, the **white matter** (Fig. 12.34). White matter
(see Fig. 12.3) contains only tracks of myelinated and unmyelinated axons
traveling to and from other parts of the spinal cord and to and from the
brain.


**FIGURE 12.34.** **Cross section of the human spinal cord.** This
photomicrograph shows a cross section through the lower lumbar (most
likely L4–L5) level of the spinal cord stained by the Bielschowsky silver
method. The spinal cord is organized into an outer part, the white matter, and
an inner part, the gray matter, which contains nerve cell bodies and


associated nerve fibers. The gray matter of the spinal cord appears roughly
in the form of a butterfly. The anterior and posterior prongs are referred to as
_ventral horns_ ( _VH_ ) and _dorsal horns_ ( _DH_ ), respectively. They are connected
by the gray commissure ( _GC_ ). The white matter contains nerve fibers that
form ascending and descending tracts. The outer surface of the spinal cord
is surrounded by the pia mater. Blood vessels of the pia mater, the ventral
fissure ( _VF_ ), and some dorsal roots of the spinal nerves are visible in the
section. ×5.


**Gray matter** contains neuronal cell bodies and their dendrites, along
with axons and central neuroglia (Plate 12.5, page 440). Functionally related
groups of nerve cell bodies in the gray matter are called **nuclei** . In this
context, the term _nucleus_ means a cluster or group of neuronal cell bodies
plus fibers and neuroglia. Nuclei of the CNS are the morphologic and
functional equivalents of the ganglia of the PNS. Synapses occur only in the
gray matter.


**The cell bodies of motor neurons that innervate striated muscle are**
**located in the ventral (anterior) horn of the gray matter.**


**Ventral motor neurons**, also called **anterior horn cells**, are large
basophilic cells easily recognized in routine histologic preparations (see Fig.
12.34 and Plate 12.5, page 440). Because the motor neuron conducts
impulses away from the CNS, it is an efferent neuron.

The axon of a motor neuron leaves the spinal cord, passes through the
ventral (anterior) root, becomes a component of the spinal nerve of that
segment, and, as such, is conveyed to the muscle. The axon is myelinated,
except at its origin and termination. Near the muscle cell, the axon divides
into numerous terminal branches that form neuromuscular junctions with the
muscle cell (see page 357).


**The cell bodies of sensory neurons are located in ganglia that lie on**
**the dorsal root of the spinal nerve.**


Sensory neurons in the dorsal root ganglia are pseudounipolar (Plate 12.1,
page 432). They have a single process that divides into a peripheral segment
that brings information from the periphery to the cell body and a central
segment that carries information from the cell body into the gray matter of
the spinal cord. Because the sensory neuron conducts impulses to the CNS,
it is an _afferent neuron_ . Impulses are generated in the terminal receptor
arborization of the peripheral segment.

### **Connective Tissue of the Central Nervous System**


Three sequential connective tissue membranes, the **meninges**, cover the
brain and spinal cord.


The **dura mater** is the outermost layer.
The **arachnoid** layer lies beneath the dura.
The **pia mater** is a delicate layer resting directly on the surface of the
brain and spinal cord.


Meninges develop from a single layer of mesenchyme surrounding the
developing brain. This layer, called the **primary meninx**, is the primordium
for the developing meninges, bones of the skull, and dermal layer of the
skin. The primary meninx further differentiates into an outer dense layer
(that gives rise to the dermal layer of the skin and bones of the skull) and an
inner reticular layer, which is considered the **meningeal mesenchyme** .
This layer is separated into the **pachymeninx** (which develops into the dura
mater) and **leptomeninx** (which develops into the arachnoid and pia mater).
The pachymeninx contains longitudinally arranged fibroblasts that produce
collagen fibers, whereas the leptomeninx represents a meshwork of loosely
organized leptomeningeal cells. The cavitation of the leptomeninx generates
arachnoid trabeculae and the subarachnoid space. In adults, the pia mater
represents the visceral portion, and the arachnoid represents the parietal
portion of the leptomeninx. The common origin of both meninges is evident
in adults in which numerous delicate arachnoid trabeculae composed of
leptomeningeal cells and fine collagen bundles pass between the pia mater
and the arachnoid.


**The dura mater is a relatively thick sheet of dense irregular**
**connective tissue.**


In the cranial cavity, the thick layer of connective tissue that attaches to the
inner surface of the skull forms the **dura mater** _[L. tough mother]_ . It
consists of two layers:


The **periosteal (outer) layer** that serves as the periosteum of the internal
surface of the skull bones
The **meningeal (inner) layer** that is fused to the periosteal layer in most
regions


These two layers are separated only at the sites of **venous (dural)**
**sinuses**, which are lined by endothelium. Venous (dural) sinuses serve as
the principal channels for blood returning from the brain; they receive blood
from the cerebral veins and carry it to the internal jugular veins.


Sheet-like extensions of the inner (meningeal) layer of the dura mater
are called **dural reflections** . They form partitions between parts of the
brain, supporting those parts within the cranial cavity and carrying the
arachnoid to deeper parts of the brain. For example, the **falx cerebri**
separates the two cerebral hemispheres along the midline, and the
**tentorium cerebelli** separates the cerebral hemispheres posteriorly from
the cerebellum.


In the spinal canal, the periosteal layer becomes the periosteum of the
vertebrae and is separated from the inner meningeal layer by the epidural
space, which contains adipose tissue and venous plexuses. The meningeal
layer of the dura mater forms a separate tube surrounding the spinal cord
(see Fig. 12.33).


**The arachnoid is a delicate sheet of connective tissue adjacent to**
**the inner surface of the dura.**


The **arachnoid** forms a water-proof layer that abuts the inner surface of the
dura and extends delicate **arachnoid trabeculae** to the pia mater on the
surface of the brain and spinal cord. The web-like trabeculae of the
arachnoid give this tissue its name _[Gr. arachne—resembling a spider’s_
_web]_ . Trabeculae are composed of loose connective tissue fibers containing
elongated fibroblasts. The space bridged by these trabeculae is the
**subarachnoid space** ; it contains the **cerebrospinal fluid** (Fig. 12.35). In
some areas, the arachnoid mater protrudes through the meningeal layer of
the dura mater into the dural venous sinuses. These areas, called **arachnoid**
**granulations**, are involved in the transport of CSF from the subarachnoid
space into the venous sinuses (see Fig. 12.35).


**FIGURE 12.35.** **Schematic diagram of the layers of the scalp and**
**cerebral meninges.** This diagram of the frontal section of the top of the
head shows the layers of the scalp, organization of the parietal bones of the
skull, and arrangement of meninges and blood vessels within the cranial
cavity. The five layers of the scalp can be remembered with the mnemonic
SCALP: (1) Skin; (2) Connective tissue (dense irregular) located below the
skin with an embedded subcutaneous layer of the vascular network; (3)
Aponeurosis, which represents a flat tendon (dense regular connective
tissue) for the attachment of occipital and frontalis muscles; (4) Loose
connective tissue network of collagen, elastic, and reticular fibers; and (5)
Pericranium, which represents the periosteum on the outer surface of the
bone. Below the scalp, the section through the parietal bone reveals a middle
spongy bone layer called _diploë_ located between the inner and outer plates
of compact bone. Diploic veins in the diploë connect dural sinuses with the
extracranial venous systems through emissary veins. Within the cranial
cavity, the superficial, outer layer of the dura mater, called the _periosteal_
_layer_, is firmly attached to bone and serves as a periosteum (darker color).
Note the branches of meningeal arteries with accompanying veins located
between the periosteal layer of the dura mater and bone. The deeper, inner
layer of the dura mater is called the _meningeal layer_ ( _lighter color_ ). In most
regions of the cranial cavity, both layers of dura mater are fused, except at
the sites of venous (dural) sinuses; here, the layers are separated from each
other by a vascular space lined by endothelium. In a few regions of the
cranial cavity, fused meningeal layers of the dura mater project away from
the bone to form dural infoldings (reflections) that separate the different


regions of the brain. Note the falx cerebri, the largest dural infolding that
separates the right and left cerebral hemispheres. Deep to the dura mater is
the arachnoid. It is adjacent, but not attached, to the dura mater. The
arachnoid sends numerous web-like arachnoid trabeculae to the pia mater
that adheres to the brain surface and follows all its contours. The
subarachnoid space is located between the arachnoid and the pia mater; it
contains cerebrospinal fluid. The space also contains the larger blood
vessels (cerebral arteries and veins) that send branches into and receive
tributaries from the brain. Note that in some areas called _arachnoid_
_granulations_, the arachnoid mater protrudes through the meningeal layer of
the dura mater into the dural venous sinuses. Arachnoid granulations are
involved in the transport of cerebrospinal fluid from the subarachnoid space
into venous sinuses.


**The pia mater lies directly on the surface of the brain and spinal**
**cord.**


The **pia mater** _[L. tender mother]_ is also a delicate connective tissue layer.
It lies directly on the surface of the brain and spinal cord and is continuous
with the perivascular connective tissue sheath of the blood vessels of the
brain and spinal cord. Both surfaces of the arachnoid, the inner surface of
the pia mater, and the trabeculae are covered with a thin squamous epithelial
layer. Both the arachnoid and the pia mater fuse around the opening for the
cranial and spinal nerves as they exit the dura mater.

### **Blood–Brain Barrier**


**The blood–brain barrier protects the CNS from fluctuating levels of**
**electrolytes, hormones, and tissue metabolites circulating in the**
**blood vessels.**


The observation more than 100 years ago that vital dyes injected into the
bloodstream can penetrate and stain nearly all organs, except the brain,
provided the first description of the **blood–brain barrier** . More recently,
advances in microscopy and molecular biology techniques have revealed the
precise location of this unique barrier and the role of brain endothelial cells
in transporting essential substances to the brain tissue.

The blood–brain barrier maintains the optimal microenvironment in the
CNS for proper brain function. In essence, it separates the brain tissue from
circulating blood. The major functions of the blood–brain barrier are to:


protect the brain from potential blood-borne toxins,
meet the metabolic demands of the brain tissue, and
regulate the homeostatic microenvironment in the CNS.


**The blood–brain barrier resides in the single layer of uninterrupted**
**vascular endothelial cells lining continuous capillaries in the CNS.**


The blood–brain barrier develops early in the embryo through an interaction
between glial astrocytes and capillary endothelial cells. The barrier is
created largely by the elaborate **tight junctions** between the **endothelial**
**cells**, which form continuous-type capillaries. Studies with the TEM using
electron-opaque tracers show complex tight junctions between the
endothelial cells. Morphologically, these junctions more closely resemble
epithelial tight junctions than tight junctions present between other
endothelial cells. In addition, TEM studies reveal a close association of
astrocytes and their end-foot processes with the **endothelial basal lamina**
(Fig. 12.36). The tight junctions eliminate gaps between endothelial cells
and prevent simple diffusion of solutes and fluid into the neural tissue.
Evidence suggests that the integrity of blood–brain barrier tight junctions
depends on the normal functioning of the associated **astrocytes;** however,
the astrocytes themselves and their end-foot processes do not significantly
contribute to the physical barrier. Several brain diseases are
characterized by a breakdown in the **blood–brain barrier** .
Examination of brain tissue in these conditions with the TEM reveals
loss of tight junctions as well as alterations in the morphology of
astrocytes. Other experimental evidence has revealed that astrocytes
release soluble factors that increase barrier properties and tight
junction protein content.


**FIGURE 12.36.** **Schematic drawing of the blood–brain barrier.** This
drawing shows the blood–brain barrier, which consists of endothelial cells
joined together by elaborate, complex tight junctions, endothelial basal
lamina, and the end-foot processes of astrocytes.


**The blood–brain barrier restricts passage of certain ions and**
**substances from the bloodstream to tissues of the CNS.**


The presence of only a few small vesicles indicates that pinocytosis across
the brain endothelial cells is severely restricted. Substances with a molecular
weight **greater than 500 Da** generally cannot cross the blood–brain barrier.
However, some molecules leave and enter the blood capillaries through
endothelial cells. For instance, O 2, CO 2, and certain lipid-soluble molecules
(e.g., ethanol and steroid hormones) easily penetrate the endothelial cells
and pass freely between the blood and extracellular fluid of the CNS. Owing
to the high K [+] permeability of the neuronal membrane, neurons are


particularly sensitive to changes in the concentration of extracellular K [+] . As
previously discussed, astrocytes are responsible for buffering the
concentration of K [+] in the brain extracellular fluid (see pages 411-412).
They are assisted by endothelial cells of the blood–brain barrier that
effectively limit the movement of K [+] into the extracellular fluid of the CNS.


**Substances that do cross the brain capillary wall are actively**
**transported by influx and efflux transporters.**


Many molecules that are required for neuronal integrity leave and enter the
blood capillaries through endothelial cells. Brain endothelial cells use highly
polarized transmembrane transporters to regulate the influx of nutrients and
efflux of metabolic waste and toxins between the blood and the extracellular
fluid of the CNS. The major class of known **efflux transporters** is the
**ATP-binding cassette (ABC)** transporters. These efflux transporters
utilize ATP to transport molecules into the blood against their concentration
gradients. Brain endothelial cells also express specialized **influx**
**transporters** that facilitate the transport of nutrients such as glucose (which
neurons depend on almost exclusively for energy), ions, amino acids,
nucleotides, vitamins, and proteins from the blood to the extracellular fluid
of the CNS. Many of these transporters belong to the superfamily **solute**
**carrier proteins (SLCs)**, which include glucose transporters (GLUT1) and
cationic amino acid transporters (SLC7A1). The permeability of the blood–
brain barrier to these macromolecules is attributable to the level of
expression of specific transporters on the brain endothelial cell surface.

Several other proteins that reside within the plasma membrane of
endothelial cells protect the brain by metabolizing certain molecules, such
as drugs and foreign proteins, thus preventing them from crossing the
barrier. The restrictive nature of the blood–brain barrier hinders the
delivery of therapeutics for many neurologic disorders. For example,
**L** **-dopa (levodopa)**, the precursor of the neuromediators dopamine
and noradrenaline, easily crosses the blood–brain barrier. However,
the **dopamine** formed from the decarboxylation of L -dopa in
endothelial cells cannot cross the barrier and is restricted from the
CNS. In this case, the blood–brain barrier regulates the concentration
of L -dopa in the brain. Clinically, this restriction explains why L -dopa
is administered for the treatment of **dopamine deficiency** (e.g.,
Parkinson disease) rather than dopamine.

Recent studies indicate that the end-feet of astrocytes also play an
important role in maintaining **water homeostasis** in brain tissue. **Water**
**channels** (aquaporin AQP4) are found in end-foot processes in which
water crosses the blood–brain barrier. In pathologic conditions, such as brain


edema, these channels play a key role in reestablishing osmotic equilibrium
in the brain.


**The midline structures bordering the third and fourth ventricles are**
**unique areas of the brain that are outside the blood–brain barrier.**


Some parts of the CNS, however, are not isolated from substances carried in
the bloodstream. The barrier is ineffective or absent in the sites located
along the third and fourth ventricles of the brain, which are collectively
called **circumventricular organs** . Circumventricular organs include the
pineal gland, median eminence, subfornical organ, area postrema,
subcommissural organ, organum vasculosum of the lamina terminalis, and
posterior lobe of the pituitary gland. These barrier-deficient areas are most
likely involved in the sampling of materials circulating in the blood that are
normally excluded by the blood–brain barrier and then conveying
information about these substances to the CNS. Circumventricular organs
are important in regulating body fluid homeostasis and controlling
neurosecretory activity of the nervous system. Some researchers describe
them as “windows of the brain” within the central neurohumoral system.

### **RESPONSE OF NEURONS TO INJURY**


Neuronal injury induces a complex sequence of events termed **axonal**
**degeneration** and **neural regeneration** . Neurons, Schwann cells,
oligodendrocytes, macrophages, and microglia are involved in these
responses. In contrast to the PNS, in which injured axons rapidly regenerate,
axons severed in the CNS usually cannot regenerate. This striking difference
is most likely related to the inability of oligodendrocytes and microglia cells
to phagocytose myelin debris quickly and the restriction of large numbers of
migrating macrophages by the blood–brain barrier. Because myelin debris
contains several inhibitors of axon regeneration, its removal is essential to
the regeneration progress.

### **Degeneration**


**The portion of a nerve fiber distal to a site of injury degenerates**
**because of interrupted axonal transport.**


Degeneration of an axon distal to a site of injury is called **anterograde**
**(Wallerian) degeneration** (Fig. 12.37a and b). The first sign of injury,
which occurs 8–24 hours after the axon is damaged, is axonal swelling. The
axon then disintegrates, and the components of the cytoskeleton, including
microtubules and neurofilaments, are disassembled, resulting in


fragmentation of the axon. Myelin is also destroyed. This process is known
as **granular disintegration of the axonal cytoskeleton** . In the PNS, loss
of axon contact induces several changes in myelinating Schwann cells. After
injury, Schwann cells lose their characteristic gene expression pattern and
undergo dedifferentiation and reprogramming into **repair Schwann cells** .
This reprogramming involves the activation of a set of repair-related
transcription factors and reexpression of molecules characteristic of
immature Schwann cells during their early stages of development. Schwann
cells undergoing reprogramming downregulate promyelin transcription
factors and expression of myelin-specific proteins (see pages 405-407).
Genes associated with epithelial-to-mesenchymal transition (EMT) are
upregulated, triggering myelin autophagy that breaks down the myelin
sheath enclosing the axon. At the same time, transformed repair Schwann
cells upregulate and secrete several **glial growth factors (GGFs)**,
members of a family of axon-associated neuregulins and potent stimulators
of axonal proliferation. Increased secretion of cytokines allows repair
Schwann cells to interact with immune cells and recruit **macrophages** to
the site of nerve injury. Under the influence of GGFs, repair Schwann cells
divide and arrange themselves in a line along their external laminae.
Because axonal processes distal to the site of injury have been removed by
phagocytosis, the linear arrangement of the repair Schwann cells’ external
laminae resembles a long tube with an empty lumen (Fig. 12.37b). In the
CNS, oligodendrocyte survival is dependent on signals from axons. In
contrast to Schwann cells, if oligodendrocytes lose contact with axons, they
respond by initiating apoptotic programmed cell death.


**FIGURE 12.37.** **Response of a nerve fiber to injury. a.** A normal nerve
fiber at the time of injury, with its nerve cell body and the effector cell (striated
skeletal muscle). Note the position of the neuron nucleus and the number
and distribution of Nissl bodies. **b.** When the fiber is injured, the neuronal
nucleus moves to the cell periphery, and the number of Nissl bodies is
greatly reduced. The nerve fiber distal to the injury degenerates along with its
myelin sheath. Schwann cells dedifferentiate into repair Schwann cell; myelin
debris is phagocytosed by macrophages. **c.** Proliferating repair Schwann
cells form cellular bands (of Büngner) that are penetrated by the growing
axonal sprout. The axon grows at a rate of 0.5–3 mm/d. Note that the muscle
fibers show a pronounced atrophy. **d.** If the growing axonal sprout reaches
the muscle fiber, the regeneration is successful and new neuromuscular
junctions are developed; thus, the function of skeletal muscle is restored.
**Inset.** A confocal immunofluorescent image showing reinnervated skeletal
muscle of the mouse. Regenerating motor axons are stained _green_ for
neurofilaments; reestablished connections with two neuromuscular junctions
are visualized in _pink_, which reflects specific staining for postsynaptic
acetylcholine receptors; repair Schwann cells are stained _blue_ for S100,
which represents a Schwann cell–specific calcium-binding protein.
Regenerating axons have extended along repair Schwann cells, which has
led them to the original synaptic sites of the muscle fibers. ×640. (Courtesy
of Dr. Young-Jin Son.)


**The most important cells in clearing myelin debris from the site of**
**nerve injury are monocyte-derived macrophages.**


In the PNS, even before the arrival of phagocytotic cells at the site of nerve
injury, **repair Schwann cells** initiate the removal of myelin debris. It is
estimated that during the first 5–7 days after nerve injury, about 50% of the
myelin is degraded by repair Schwann cells. The rest of myelin clearance is
performed by macrophages, which migrate to the site of injury and
phagocytose myelin debris. Several cytokines, such as interleukin-6 (IL-6),
leukemia inhibitory factor (LIF), and monocyte chemotactic protein 1
(MCP-1), are secreted by repair Schwann cells. These cytokines activate
**resident macrophages** (normally present in small numbers in the
peripheral nerves) to migrate to the site of nerve injury, proliferate, and then
phagocytize remaining myelin debris.

The efficient clearance of myelin debris in the PNS is attributed to the
massive recruitment of **monocyte-derived macrophages** that migrate
from blood vessels and infiltrate the vicinity of the nerve injury (Fig. 12.38).
When an axon is injured, the blood–nerve barrier (see pages 424-425) is
disrupted along the entire length of the injured axon, which allows for the
influx of these cells into the site of injury. The presence of large numbers of


monocyte-derived macrophages speeds up the process of myelin removal,
which, in peripheral nerves, is usually completed within 2 weeks.


**FIGURE 12.38.** **Schematic diagram of response to neuronal injury within**
**peripheral and central nervous systems.** Injuries of nerve processes
(axons and dendrites) in both the peripheral nervous system (PNS) and the
central nervous system (CNS) induce axonal degeneration and neural
regeneration. These processes involve not only neurons but also supportive
cells such as Schwann cells and oligodendrocytes as well as phagocytic
cells such as macrophages and microglia. Injuries to axons in the PNS lead
to their degeneration, which triggers the reprogramming and dedifferentiation
of Schwann cells into repair Schwan cells and disruption of the blood–nerve
barrier along the entire length of the injured axon. Repair Schwann cells play
a major part in the initial phase of myelin degradation and clearance. About
50% of the myelin is degraded during this phase. Dismantling of the blood–
nerve barrier allows massive infiltration of monocyte-derived macrophages,
which phagocytose myelin debris. Rapid clearance of myelin debris allows
for axon regeneration and subsequent restoration of the blood–nerve barrier.
In the CNS, limited disruption of the blood–brain barrier restricts infiltration of
monocyte-derived macrophages, dramatically slowing the process of myelin


removal. Myelin is primarily removed by reactive microglia and secondarily
by reactive astrocytes. In addition, apoptosis of oligodendrocytes, inefficient
phagocytic activity of microglia, and the formation of an astrocyte-derived
scar lead to failure of nerve regeneration in the CNS.


**In the CNS, inefficient clearance of myelin debris due to limited**
**access** **of** **monocyte-derived** **macrophages,** **the** **inefficient**
**phagocytic activity of microglia, and the formation of an astrocyte-**
**derived scar severely restricts nerve regeneration.**


A key difference in the **CNS response to axonal injury** relates to the fact
that the blood–brain barrier (see pages 424-425) is disrupted only at the site
of injury and not along the entire length of the injured axon (see Fig. 12.38).
This limits infiltration of monocyte-derived macrophages to the CNS and
dramatically slows the process of myelin removal, which can take months or
even years. Although the number of microglial cells increases at the sites of
CNS injury, these **reactive microglia cells** do not possess the full
phagocytotic capabilities of migrating macrophages. As discussed earlier
(see page 410), astrocytic phagocytosis also plays a role in nerve tissue
remodeling after brain injury. The inefficient **clearance of myelin debris**
is a major factor in the failure of nerve regeneration in the CNS. Another
factor that affects nerve regeneration is the formation of a **glial (astrocyte-**
**derived) scar** that fills the empty space left by degenerated axons. Scar
formation is discussed in Folder 12.3; cognitive impairments after COVID19 infection are discussed in Folder 12.4.


When a region of the central nervous system (CNS) is injured,
astrocytes near the lesion become activated. They divide and undergo
marked hypertrophy with a visible increase in the number of their
cytoplasmic processes. In time, the processes become densely packed
with **glial fibrillary acidic protein (GFAP) intermediate filaments** .
Eventually, scar tissue is formed. This process is referred to as **reactive**
**gliosis**, whereas the resulting permanent scar is most often called a
**plaque** . Reactive gliosis varies widely in duration, degree of
hyperplasia, and time course of expression of GFAP immunostaining.

Several biological mechanisms for induction and maintenance of
reactive gliosis have been proposed. The type of glial cell that responds
during reactive gliosis depends on the brain structure that is damaged.
In addition, activation of the microglial cell population occurs almost


immediately after any kind of injury to the CNS. These reactive
microglial cells migrate toward the site of injury and exhibit marked
phagocytic activity. However, their phagocytic activity and ability to
remove myelin debris are much less than that of monocyte-derived
macrophages. Gliosis is a prominent feature of many diseases of the
CNS, including stroke, neurotoxic damage, genetic diseases,
inflammatory demyelination, and neurodegenerative disorders, such as
multiple sclerosis. Much of the research in CNS regeneration is focused
on preventing or inhibiting glial scar formation.


The **COVID-19** (coronavirus disease 2019) pandemic caused by severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in
over 550 million documented COVID cases worldwide and 6.3 million
deaths (mid-2022 data). Individuals with COVID-19 experience
symptoms ranging from mild respiratory symptoms to severe multiorgan
illnesses. Recent studies indicate that in both humans and animal
models, even mild COVID infection can result in detrimental
**neuroinflammatory responses** . These are marked by elevation of
neurotoxic cytokines and chemokines such as IFN-γ, IL6, TNF-α,
CXCL10, CCL7, CCL2, CCL11, GMCSF, BAFF, and others that
characteristically react against **white matter microglial cells** . In a
mouse model of mild respiratory COVID-19 infection, researchers
discovered hippocampal changes that included a decreased number of
oligodendrocytes with subsequent myelin loss. These changes were
accompanied by elevated levels of cerebrospinal fluid (CSF)
chemokines, including **CCL11** (also known as _eosinophil chemotactic_
_protein_ or _eotaxin-1_ ), which is associated with the cognitive impairments
seen in aging. Similarly, individuals that recovered from COVID-19
experience persistent neurologic symptoms resembling **cancer**
**therapy–related cognitive impairment (CRCI)** . Certain drugs used
in chemotherapy treatment (e.g., methotrexate) activate a distinct
subpopulation of microglia that reside in white matter. Activated
(reactive) microglia impair the ongoing differentiation of myelin-forming
oligodendrocytes (loss of myelin), inhibit new neuron formation
(neurogenesis) in the hippocampus, and cause elevation of CCL11. The
cognitive impairments experienced by individuals with CRCI syndrome
are often referred to as “ **chemo fog** .” Recent studies indicate that
COVID-19 survivors experience similar neurologic symptoms called
“ **COVID fog**,” which represent post-COVID cognitive impairments.
These include **impaired attention, decreased concentration,**


**slowed information processing speed, memory problems**, as well
as other impairments of executive function. As a result of these
impairments, individuals who recovered from COVID-19 may present in
the clinic with increased rates of **anxiety, depression, disordered**
**sleep**, and **fatigue** . These symptoms of post–COVID-19 cognitive
impairments represent a major public health crisis preventing people
from returning to their previous level of occupational activity.


**Traumatic degeneration occurs in the proximal part of the injured**

**nerve.**


Some retrograde degeneration also occurs in the proximal axon and is called
**traumatic degeneration** . This process appears to be histologically similar
to anterograde (Wallerian) degeneration. The extent of traumatic
degeneration depends on the severity of the injury and usually extends to
only one or a few internodal segments. Sometimes, traumatic degeneration
extends more proximally than one or a few nodes of Ranvier and may result
in death of the cell body. When a motor fiber is cut, the muscle innervated
by that fiber undergoes atrophy (Fig. 12.37c).


**Retrograde signaling to the cell body of an injured nerve causes a**
**change in gene expression that initiates reorganization of the**
**perinuclear cytoplasm.**


Axonal injury also initiates retrograde signaling to the nerve cell body,
leading to the upregulation of a gene called **c-jun** . C-jun transcription factor
is involved in the early as well as later stages of nerve regeneration.
Reorganization of the perinuclear cytoplasm and organelles starts within a
few days. The cell body of the injured nerve swells, and its nucleus moves
peripherally. Initially, Nissl bodies disappear from the center of the neuron
and move to the periphery of the neuron in a process called **chromatolysis** .
Chromatolysis is first observed within 1–2 days after injury and reaches a
peak at about 2 weeks (see Fig. 12.37b). The changes in the cell body are
proportional to the amount of axoplasm destroyed by the injury; extensive
loss of axoplasm can lead to the death of the cell.

Before the development of modern dyes and radioisotope tracer
techniques, Wallerian degeneration and chromatolysis were used as
research tools. These tools allowed researchers to trace the
pathways and destination of axons and the localization of the cell
bodies of experimentally injured nerves.

### **Regeneration**


**In the PNS, repair Schwann cells divide and develop cellular bands**
**that bridge a newly formed scar and direct growth of new nerve**

**processes.**


As mentioned previously, at the site of the injury, cells are reprogrammed to
generate specialized **repair Schwann cells** to promote tissue repair.
Division of repair Schwann cells is the first step in the regeneration of a
severed or crushed peripheral nerve. Initially, these cells arrange themselves
in a series of cylinders called **endoneurial tubes** . Removal of myelin and
axonal debris inside the tubes eventually causes them to collapse.
Proliferating repair Schwann cells elongate, extending long, parallel
processes, and organize themselves into cellular bands resembling
longitudinal columns called regeneration tracks or **bands of Büngner** (Fig.
12.39). These cellular bands guide the growth of new nerve processes
( **neurites** or **sprouts** ) of regenerating axons. Once the bands are in place,
large numbers of sprouts begin to grow from the proximal stump (see Fig.
12.37c). A **growth cone** develops in the distal portion of each sprout that
consists of filopodia rich in actin filaments. The tips of the filopodia
establish a direction for the advancement of the growth cone. They
preferentially interact with proteins of the extracellular matrix such as
fibronectin and laminin found within the external lamina of the repair
Schwann cell. Thus, if a sprout associates itself with a band of Büngner, it
regenerates between the layers of external lamina of the repair Schwann
cell. This sprout will grow along the band at a rate of about **3 mm/day** .
Although many new sprouts do not make contact with cellular bands and
degenerate, their large number increases the probability of reestablishing
sensory and motor connections. After crossing the site of injury, sprouts
enter the surviving cellular bands in the distal stump. These bands then
guide the neurites to their destination as well as provide a suitable
microenvironment for continued growth (Fig. 12.37d). Axonal regeneration
leads to Schwann cell redifferentiation, which occurs in a proximal-to-distal
direction. In addition, redifferentiated Schwann cells upregulate genes for
myelin-specific proteins and downregulate **c-Jun transcription factor**,
which is central to the reprogramming of myelinating and nonmyelinating
Remak Schwann cells to repair Schwann cells after injury.


**FIGURE 12.39.** **Electron micrograph of a distal stump of regenerating**
**nerve.** This image shows a cross section through the distal stump of the
mouse tibial nerve 4 weeks after transection. A repair Schwan cell with a
large nucleus and a thin rim of cytoplasm is enclosed by the basal (external)
lamina ( _BL_ ). Several cross sections of Büngner bands ( _BB_ ) are embedded in
the endoneurial connective tissue ( _eCT_ ). They contain elongated parts of
repair Schwann cells and their parallel processes. Note that every band and
their components are also surrounded by the basal laminae. The cell in the
_right upper corner_ represents connective tissue cell (lack of basal lamina),
and it may represent part of fibroblast or macrophage. × 65,000. (Courtesy of
Dr. Kristjan R. Jessen, University College London, London, UK).


**If physical contact is reestablished between a motor neuron and its**
**muscle, function is usually reestablished.**


Microsurgical techniques that rapidly reestablish intimate apposition of
severed nerve and vessel ends have made reattachment of severed limbs and
digits, with subsequent reestablishment of function, a relatively common
procedure. If the axonal sprouts do not reestablish contact with the
appropriate Schwann cells, then the sprouts grow in a disorganized


manner, resulting in a mass of tangled axonal processes known as a
**traumatic neuroma** or **amputation neuroma** . Clinically, a traumatic
neuroma usually appears as a freely movable nodule at the site of
nerve injury and is characterized by pain, particularly on palpation.
Formation of a traumatic neuroma of the injured motor nerve
prevents reinnervation of the affected muscle.

## NERVE TISSUE


**OVERVIEW OF THE NERVOUS SYSTEM**


The **nervous system** enables the body to respond to changes in its
external environment and controls the functions of internal organs and
systems.
Anatomically, the nervous system is divided into the **central nervous**
**system** (CNS; (brain and spinal cord) and the **peripheral nervous**
**system** (PNS; peripheral and cranial nerves and ganglia).
Functionally, the nervous system is divided into the **somatic nervous**
**system** (SNS; under conscious voluntary control) and the **autonomic**
**nervous system** (ANS; under involuntary control).
The ANS is further subdivided into **sympathetic**, **parasympathetic**,
and **enteric divisions** . The enteric division serves the alimentary
canal and regulates the function of internal organs by innervating
smooth and cardiac muscle cells as well as glandular epithelium.


**SUPPORTING CELLS OF THE NERVOUS SYSTEM:**

**NEUROGLIA**


**Peripheral neuroglia** includes Schwann cells and satellite cells.
In **myelinated** nerves, **Schwann cells** produce the **myelin sheath**
from compacted layers of their own cell membranes that are wrapped
concentrically around the nerve cell process.
The junction between two adjacent Schwann cells, the **node of**
**Ranvier**, is the site where the electrical impulse is regenerated for


high-speed propagation along the axon.
In **unmyelinated** nerves, nerve processes are enveloped in the
cytoplasm of **Remak Schwann cells** .
**Satellite cells** maintain a controlled microenvironment around the

nerve cell bodies in ganglia of the PNS.
There are four types of **central neuroglia** : **astrocytes** (provide
physical and metabolic support for neurons of the CNS),
**oligodendrocytes** (produce and maintain the myelin sheath in the
CNS), **microglia** (possess phagocytotic properties and mediate
neuroimmune reactions), and **ependymal cells** (form the epitheliallike lining of the ventricles of the brain and spinal canal).


**NEURONS**


**Nerve tissue** consists of two principal types of cells: **neurons**
(specialized cells that conduct impulses) and **supporting cells**
(nonconducting cells in close proximity to nerve cells and their
processes).
The neuron is the structural and functional unit of the nervous system.
**Neurons** do not divide; however, in certain regions of the brain,
**neural stem cells** may divide and differentiate into new neurons.
Neurons are grouped into three categories: **sensory neurons** (carry
impulses from receptors to the CNS), **motor neurons** (carry impulses
from the CNS or ganglia to effector cells), and **interneurons**
(communicate between sensory and motor neurons).
Each neuron consists of a **cell body** or **perikaryon** (contains the
nucleus, Nissl bodies, and other organelles), an **axon** (usually the
longest process of the cell body; transmits impulses away from the cell
body), and several **dendrites** (shorter processes that transmit impulses
toward the cell body).
Neurons communicate with other neurons and with effector cells by
specialized junctions called **synapses** .
**Chemical synapses** are the most common type of synapse. Each has
a **presynaptic** **element** containing vesicles filled with
neurotransmitter, a **synaptic cleft** into which neurotransmitter is
released from the presynaptic vesicles, and a **postsynaptic**
**membrane** containing receptors to which the neurotransmitter binds.
**Electrical synapses** are less common and are represented by **gap**
**junctions** .
The chemical structure of a **neurotransmitter** determines either an
**excitatory** (e.g., acetylcholine, glutamine) or **inhibitory** (e.g., GABA,
glycine) response from the postsynaptic membrane.


**ORIGIN OF NERVE TISSUE CELLS**


CNS neurons and central glia (except microglial cells) are derived from
neuroectodermal cells of the **neural tube** . Microglial cells represent
population of resident macrophages derived from erythro-myeloid
progenitor cells in the **yolk sac** .
PNS ganglion cells and peripheral glia are derived from the **neural**
**crest** .


**ORGANIZATION OF THE PERIPHERAL NERVOUS**

**SYSTEM**


The PNS consists of **peripheral nerves** with specialized nerve
endings (synapses) and **ganglia** -containing nerve cell bodies.
**Motor neuron cell bodies** of the PNS lie in the CNS, and **sensory**
**neuron cell bodies** are located in the dorsal root ganglia.
Individual nerve fibers are held together by connective tissue organized
into **endoneurium** (surrounds each individual nerve fiber and
associated Schwann cell), **perineurium** (surrounds each nerve
fascicle), and **epineurium** (surrounds a peripheral nerve and fills the
spaces between nerve fascicles).
**Perineurial cells** are connected by tight junctions and contribute to
the formation of the **blood–nerve barrier** .


**ORGANIZATION OF THE CENTRAL NERVOUS SYSTEM**


The CNS consists of the **brain** and **spinal cord** . It is protected by the
skull and vertebrae and is surrounded by three connective tissue
membranes called **meninges** ( **dura matter**, **arachnoid**, and **pia**
**matter** ).
The **cerebrospinal fluid (CSF)** produced by the choroid plexus in the
brain ventricles occupies the **subarachnoid space** located between
arachnoid and pia matter. CSF surrounds and protects the CNS within
the cranial cavity and the vertebral column.
In the brain, the **gray matter** forms an outer layer of the cerebral
cortex, whereas the **white matter** forms the inner core that is
composed of axons, associated glial cells, and blood vessels.


In the **spinal cord**, gray matter exhibits a butterfly-shaped inner
substance, whereas the white matter occupies the periphery.
The **cerebral cortex** contains nerve cell bodies, axons, dendrites, and
central glial cells.
The **blood–brain barrier** protects the CNS from fluctuating levels of
electrolytes, hormones, and tissue metabolites circulating in the blood.


**ORGANIZATION OF THE AUTONOMIC NERVOUS**

**SYSTEM**


The **ANS** controls and regulates the body’s internal environment. Its
neural pathways are organized in a chain of two neurons ( **presynaptic**
and **postsynaptic neurons** ) that convey impulses from the CNS to
the visceral effectors.

The ANS is subdivided into sympathetic, parasympathetic, and enteric
divisions.

**Presynaptic neurons** of the **sympathetic division** are located in the
thoracolumbar portion of the spinal cord, whereas the **presynaptic**
**neurons** of the **parasympathetic division** are located in the
brainstem and sacral spinal cord.
The **enteric division** of the ANS consists of ganglia and their
processes that innervate the alimentary canal.


**RESPONSE OF NEURONS TO INJURY**


Injured axons in the PNS usually regenerate, whereas axons severed in
the CNS do not regenerate. This difference is related to the inability of
microglial cells and astrocytes to efficiently phagocytose myelin debris.
In the PNS, neuronal injury initially induces complete degeneration of
an axon distal to the site of injury ( **Wallerian degeneration** ).
**Traumatic degeneration** occurs in the proximal part of the injured
nerve, followed by **neural regeneration**, in which repair Schwann
cells divide and develop cellular bands that guide the growing axonal
sprouts to the effector site.

#### **PLATE 12.1 SYMPATHETIC AND DORSAL ROOT** **GANGLIA**


##### Sympathetic ganglion, human, silver and
###### hematoxylin and eosin (H&E) stains ×160.

This micrograph shows a sympathetic ganglion stained with
silver and counterstained with H&E is illustrated here. Shown to
advantage are several discrete bundles of nerve fibers ( _NF_ ) and
numerous large circular structures, namely, the cell bodies ( _CB_ ) of
the postsynaptic neurons. Random patterns of nerve fibers are also
seen. Moreover, careful examination of the cell bodies shows that some display
several processes joined to them. Thus, these are multipolar neurons (one contained
within the _rectangle_ is shown at higher magnification). Generally, the connective
tissue is not conspicuous in a silver preparation, although it can be identified by
virtue of its location around the larger blood vessels ( _BV_ ), particularly in the _upper_
_part_ of this figure.

##### Sympathetic ganglion, human, silver and H&E
###### stains ×500.


The cell bodies of the sympathetic ganglion are typically large,
and the one labeled here shows several processes ( _P_ ). In addition,
the cell body contains a large, pale-staining spherical nucleus ( _N_ );
this, in turn, contains a spherical, intensely staining nucleolus
( _NL_ ). These features, namely, a large pale-staining nucleus
(indicating much-extended chromatin) and a large nucleolus, reflect a cell active in


protein synthesis. Also shown in the cell body are accumulations of lipofuscin ( _L_ ), a
yellow pigment that is darkened by silver. Because of the large size of the cell body,
the nucleus is not always included in the section; in that case, the cell body appears
as a rounded cytoplasmic mass.

##### Dorsal root ganglion, cat, H&E ×160.


Dorsal root ganglia differ from autonomic ganglia in a number
of ways. Whereas the latter contain multipolar neurons and have
synaptic connections, dorsal root ganglia contain pseudounipolar
sensory neurons and have no synaptic connections in the ganglion.


Part of a dorsal root ganglion stained with H&E is shown in
this figure. The specimen includes the edge of the ganglion, where
it is covered with connective tissue ( _CT_ ). The dorsal root ganglion contains large cell
bodies ( _CB_ ) that are typically arranged as closely packed clusters. Also, between and
around the cell clusters, there are bundles of nerve fibers ( _NF_ ). Most of the fiber
bundles indicated by the label have been sectioned longitudinally.

##### Dorsal root ganglion, cat, H&E ×350.


At higher magnification of the same ganglion, the constituents
of the nerve fiber show their characteristic structure, namely, a
centrally located axon ( _A_ ) surrounded by an empty space after
myelin was washed out during slide preparation (not labeled),
which, in turn, is bounded on its outer border by the thin
cytoplasmic strand of the neurilemma ( _arrowheads_ ).

The cell bodies of the sensory neurons display large, pale-staining spherical
nuclei ( _N_ ) and intensely staining nucleoli ( _NL_ ). Also seen in this H&E preparation
are the nuclei of satellite cells ( _Sat C_ ) that completely surround the cell body and are
continuous with the Schwann cells that invest the axon. Note how much smaller

these cells are compared with the neurons. Clusters of cells ( _asterisks_ ) within the
ganglion that have an epithelioid appearance are en-face views of satellite cells
where the section tangentially includes the satellite cells but barely grazes the
adjacent cell body.


**A,** axon
**BV,** blood vessels
**CB,** cell body of neuron
**CT,** connective tissue
**L,** lipofuscin
**N,** nucleus of nerve cell


**NF,** nerve fibers
**NL,** nucleolus
**P,** processes of nerve cell body
**Sat C,** satellite cells
**arrowheads,** neurilemma
**asterisks,** clusters of satellite cells


#### **PLATE 12.2 PERIPHERAL NERVE**


##### Peripheral nerve, cross section, femoral nerve,
###### hematoxylin and eosin (H&E) ×200 and ×640.

This cross section shows several bundles of nerve fibers
( _BNF_ ). The external cover for the entire nerve is the **epineurium**
( _Epn_ ), the layer of dense connective tissue that one touches when
a nerve has been exposed during a dissection. The epineurium may
also serve as part of the outermost cover of individual bundles. It
contains blood vessels ( _BV_ ) and may contain some fat cells. Typically, adipose tissue
( _AT_ ) surrounds the nerve.


The figure on the _right_ shows, at higher magnification, the perineurial septum
(marked with _arrows_ on the _left_ image, which is now rotated and vertically
disposed).


The layer beneath the epineurium that directly surrounds the bundle of nerve
fibers is the **perineurium** ( _Pn_ ). As seen in the cross section through the nerve, the
nuclei of the perineurial cells appear flat and elongated; they are actually being
viewed on edge and belong to flat cells that are also being viewed on edge. Again, as
noted by the distribution of nuclei, it can be ascertained that the perineurium is only
a few cells thick. The perineurium is a specialized layer of cells and extracellular
material whose arrangement is not evident in H&E sections. The perineurium ( _Pn_ )
and epineurium ( _Epn_ ) are readily distinguished in the _triangular area_ formed by the
diverging perineurium of the two adjacent nerve bundles.

The nerve fibers included in the figure on the _right_ are mostly myelinated, and
because the nerve is cross-sectioned, the nerve fibers are also seen in this plane.
They have a characteristic cross-sectional profile. Each nerve fiber shows a centrally
placed axon ( _A)_ ; this is surrounded by a myelin space ( _M_ ) in which some radially
disposed precipitate may be retained, as in this specimen. External to the myelin
space is a thin cytoplasmic rim representing the **neurilemma** . On occasion, a
Schwann cell’s nucleus ( _SS_ ) appears to be perched on the neurilemma. The _upper_


edge of the nuclear crescent appears to occupy the same plane as that occupied by
the neurilemma ( _NI_ ). These features enable one to identify the nucleus as belonging
to a Schwann (neurilemma) cell. Other nuclei are not related to the neurilemma but,
rather, appear to be located between the nerve fibers. Such nuclei belong to the rare
fibroblasts ( _F_ ) of the endoneurium. The latter is the delicate connective tissue
between the individual nerve fibers; it is extremely sparse and contains the
capillaries ( _C_ ) of the nerve bundle.

##### Peripheral nerve, longitudinal section, femoral
###### nerve, H&E ×200 and ×640.


The edge of a longitudinally sectioned nerve bundle is shown
on the _left_ ; a portion of the same nerve bundle is shown at higher
magnification on the _right_ . The boundary between the epineurium
( _Epn_ ) and perineurium is ill-defined. Within the nerve bundle, the
nerve fibers show a characteristic wavy pattern. Included among
the wavy nerve fibers are nuclei belonging to **Schwann cells** and cells within the
endoneurium. Higher magnification allows one to identify certain specific
components of the nerve. Note that the nerve fibers ( _NF_ ) are now shown in
longitudinal profile. Moreover, each myelinated nerve fiber shows a centrally
positioned axon ( _A_ ) surrounded by a myelin space ( _M_ ), which, in turn, is bordered on
its outer edge by the thin cytoplasmic band of the neurilemma ( _NI_ ). Another
diagnostic feature of myelinated nerve fibers is also seen in longitudinal section,
namely, the **node of Ranvier** ( _NR_ ). This is the site at which the ends of the two
Schwann cells meet. Histologically, the node appears as a constriction of the
neurilemma, and sometimes, the constriction is marked by a cross-band, as in the
figure on the _right_ . It is difficult to determine whether the nuclei ( _N_ ) shown here
belong to Schwann cells or endoneurial fibroblasts.


**A,** axon
**AT,** adipose tissue
**BNF,** bundle of nerve fibers
**BV,** blood vessels
**C,** capillary
**Epn,** epineurium
**F,** fibroblast
**M,** myelin
**N,** nucleus of Schwann cell
**NF,** nerve fiber
**Nl,** neurilemma
**NR,** node of Ranvier


**Pn,** perineurium
**SS,** Schwann cell nucleus
**arrows,** septum formed by perineurium


##### Cerebral cortex, brain, human, Luxol fast blue—
###### (Periodic acid–Schiff) PAS ×65.

This micrograph shows a low-magnification view of the
cerebral cortex ( _CC_ ). It includes the full thickness of the gray
matter and a small amount of white matter at the bottom of the

micrograph ( _WM_ ). The white matter contains considerably fewer
cells per unit area; these are neuroglial cells rather than nerve cell
bodies that are present in the cortex. Covering the cortex is the pia mater ( _PM_ ). A
vein ( _V_ ) can be seen enclosed by the pia mater. Also, a smaller blood vessel ( _BV_ ) can
be seen entering the substance of the cortex. The six layers of the cortex are marked
by _dashed lines_, which represent only an approximation of the boundaries. Each
layer is distinguished on the basis of predominant cell types and fiber (axon and
dendrite) arrangement. Unless the fibers are specifically stained, they cannot be
utilized to further aid in the identification of the layers. Rather, the delineation of the
layers, as they are identified here, is based on cell types and more specifically, the
shape and appearance of the cells.


The six layers of the cortex are named and described as follows:


I. The **plexiform layer** (or molecular layer) consists largely of fibers, most of

which travel parallel to the surface, and relatively few cells, mostly neuroglial
cells and occasional horizontal cells of Cajal.
II. The **small pyramidal cell layer** (or outer granular layer) consists mainly of

small pyramidal cells and granule cells, also called _stellate cells_ .
III. The **layer of medium pyramidal cells** (or layer of outer pyramidal cells)

is not sharply demarcated from layer II. However, the pyramidal cells are
somewhat larger and possess a typical pyramidal shape.
IV. The **granular layer** (or inner granular layer) is characterized by the presence

of many small granule cells (stellate cells).
V. The **layer of large pyramidal cells** (or inner layer of pyramidal cells)

contains pyramidal cells that, in many parts of the cerebrum, are smaller than


the pyramidal cells of layer III but, in the motor area, are extremely large and
are called _Betz cells_ .
VI. The **layer of polymorphic cells** contains cells with diverse shapes, many

of which have a spindle of fusiform shape. These cells are called _fusiform cells_ .


In addition to pyramidal cells, granule cells, and fusiform cells, two other cell
types are also present in the cerebral cortex but are not recognizable in this
preparation: the horizontal cells of Cajal, which are present only in layer I and send
their processes laterally, and the cells of Martinotti, which send their axons toward
the surface (opposite to that of pyramidal cells).

##### Layer I of cerebral cortex, brain, human, Luxol
###### fast blue—PAS ×350.


This higher power micrograph shows layer I, the **plexiform**
**layer** . It consists of nerve fibers, numerous neuroglial cells ( _NN_ ),
and occasional horizontal cells of Cajal. The neuroglial cells
appear as naked nuclei, with the cytoplasm being indistinguishable
from the nerve fibers that make up the bulk of this layer. Also
present is a small capillary ( _Cap_ ). The _pink_ outline of the vessel is due to the PASstaining reaction of its basement membrane.

##### Layer II of cerebral cortex, brain, human, Luxol
###### fast blue—PAS ×350.


This micrograph shows layer II, the **small pyramidal cell**
**layer** . Many small pyramidal cells ( _PC_ ) are present. Granule cells
( _GC_ ) are also numerous, although difficult to identify here.

##### Layer IV of cerebral cortex, brain, human, Luxol
###### fast blue—PAS ×350.


This micrograph shows layer IV, the **granular layer** . Many
of the cells here are granule cells, but neuroglial cells are also
prominent. The micrograph also reveals a number of capillaries.
Note how they travel in various directions.


##### Layer VI of cerebral cortex, brain, human, Luxol
###### fast blue—PAS ×350.

This micrograph shows layer VI, the **layer of polymorphic**
**cells**, so named because of the diverse shape of the cells in this
region. Pyramidal cells ( _PC_ ) are readily recognized. Other cell
types present include fusiform cells ( _FC_ ), granule cells, and
Martinotti cells.

##### White matter, brain, human, Luxol fast blue—PAS

###### ×350.


This micrograph shows the outer portion of the **white**
**matter** . The small round nuclei ( _NN_ ) belong to neuroglial cells.
As in the cortex, the cytoplasm of the cell is not distinguishable.
Thus, they appear as naked nuclei in the bed of nerve processes.
The neuropil is essentially a densely packed aggregation of nerve
fibers and neuroglial cells.


**BV,** blood vessel
**Cap,** capillary
**CC,** cerebral cortex
**FC,** fusiform cells
**GC,** granule cells
**NN,** neuroglial nuclei
**PC,** pyramidal cells
**PM,** pia mater
**V,** vein
**WM,** white matter


#### **PLATE 12.4 CEREBELLUM**


##### Cerebellum, brain, human, hematoxylin and eosin
###### (H&E) ×40.

The **cerebellar cortex** has the same appearance regardless
of which region is examined. In this low-magnification view of the
cerebellum, the outermost layer, the **molecular layer** ( _Mol_ ), is
lightly stained with eosin. Beneath this layer is the **granule cell**
**layer** ( _Gr_ ), which stains intensely with hematoxylin. Together,
these two layers constitute the cortex of the cerebellum. Deep in the granule cell
layer is another region that stains lightly with H&E and, except for location, shows
no distinctive histologic features. This is the white matter ( _WM_ ). As in the cerebrum,
it contains nerve fibers, supporting neuroglial cells, and small blood vessels but no
neuronal cell bodies. The fibrous cover on the cerebellar surface is the pia mater
( _Pia_ ). Cerebellar blood vessels ( _BV_ ) travel in this layer. (Shrinkage artifact has
separated the pia mater from the cerebellar surface.) The _rectangular area_ is shown
at higher magnification in the figure on the _right_ .

##### Cerebellum, brain, human, H&E ×400.


At the junction between the molecular and granule cell layers
are the extremely large flask-shaped cell bodies of the **Purkinje**
**cells** ( _Pkj_ ). These cells are characteristic of the cerebellum. Each
possesses numerous dendrites ( _D_ ) that arborize in the molecular
layer. The Purkinje cell has a single axon that is not usually
evident in H&E sections. This nerve fiber represents the beginning
of the outflow from the cerebellum.

The figure shows relatively few neuron cell bodies, those of the basket cells
( _BC_ ), in the molecular layer; they are widely removed from each other and, at best,
show only a small amount of cytoplasm surrounding the nucleus. In contrast, the
granule cell layer presents an overall spotted-blue appearance due to the staining of
numerous small nuclei with hematoxylin. These small neurons, called **granule**
**cells**, receive incoming impulses from other parts of the CNS and send axons into
the molecular layer, where they branch in the form of a T, so that the axons contact
the dendrites of several Purkinje cells and basket cells. Incoming (mossy) fibers
contact granule cells in the lightly stained areas called _glomeruli_ ( _arrows_ ). Careful
examination of the granule cell layer where it meets the molecular layer will reveal a


group of nuclei ( _G_ ) that are larger than the nuclei of granule cells. These belong to
Golgi type II cells.

##### Cerebellum, brain, human, silver stain ×40.


The specimen in this figure has been stained with a silver
procedure. Such procedures do not always color the specimen
evenly, as does H&E. Note that the part of the molecular layer on
the _right_ is much darker than that on the _left_ . A _rectangular area_
on the _left_ has been selected for examination at higher
magnification in the _lower right_ figure. Even at the relatively low
magnification shown here, however, the Purkinje cells can be recognized in the silver
preparation because of their large size, characteristic shape, and location between an
outer molecular layer ( _Mol_ ) and an inner granule cell layer ( _Gr_ ). The main advantage
of this silver preparation is that the **white matter** ( _WM_ ) can be recognized as being
composed of fibers; they have been blackened by the silver-staining procedure. The
pia mater ( _Pia_ ) and cerebellar blood vessels ( _BV_ ) are also evident in the preparation.

##### Cerebellum, brain, human, silver stain ×400.


At higher magnification, the **Purkinje cell** bodies ( _Pkj_ ) stand
out as the most distinctive and conspicuous neuronal cell type of
the cerebellum, and numerous dendritic branches ( _D_ ) can be seen.
Note, also, the blackened fibers within the granule cell layer ( _Gr_ ),
about the Purkinje cell bodies, and in the molecular layer ( _Mol_ )
disposed in a horizontal direction (relative to the cerebellar
surface). Basket cells ( _BC_ ) are the most common neurons that are visible in the
molecular layer. The _arrow_ indicates a T-turn characteristic of the turn made by
axons of granule cells. As these axonal branches travel horizontally, they make
synaptic contact with numerous Purkinje cells.


**BC,** basket cells
**BV,** blood vessels
**D,** dendrites
**G,** Golgi type II cells
**Gr,** granule cell layer
**Mol,** molecular layer
**Pia,** pia mater
**Pkj,** Purkinje cells
**WM,** white matter


**arrows,** upper right figure, glomeruli; lower right figure, T branching of

axon in molecular layer
**rectangular area,** areas shown at higher magnification


##### Spinal cord, human, silver stain ×16.

A cross section through the lower lumbar region of the spinal
cord is shown here. The preparation is designed to stain the gray
matter that is surrounded by the ascending and descending nerve
fibers. Although the fibers that have common origins and
destinations in the physiologic sense are arranged in tracts, these
tracts cannot be distinguished unless they have been marked by
special techniques, such as causing injury to the cell bodies from which they arise or
by using special dyes or radioisotopes to label the axons.


The **gray matter** of the spinal cord appears roughly in the form of a butterfly.
The anterior and posterior prongs are referred to as _ventral horns_ ( _VH_ ) and _dorsal_
_horns_ ( _DH_ ), respectively. The connecting bar is called the _gray commissure_ ( _GC_ ).
The neuron cell bodies that are within the ventral horns (ventral horn cells) are so
large that they can be seen even at this extremely low magnification ( _arrows_ ). The
pale-staining fibrous material that surrounds the spinal cord is the **pia mater** ( _Pia_ ).
It follows the surface of the spinal cord intimately and dips into the large ventral
fissure ( _VF_ ) and the shallower sulci. Blood vessels ( _BV_ ) are present in the pia mater.
Some dorsal roots ( _DR_ ) of the spinal nerves are included in the section.

##### Ventral horn, spinal cord, human, silver stain ×640.


This preparation shows a region of a ventral horn. The nucleus
( _N_ ) of the **ventral horn cell** (ventral motor neuron) is the large,
spherical, pale-staining structure within the cell body. The ventral
horn cell has many obvious processes. A number of other nuclei
belong to neuroglial cells. The cytoplasm of these cells is not
evident. The remainder of the field consists of nerve fibers and
neuroglial cells whose organization is hard to interpret. This is
called the neuropil ( _Np_ ).

##### Ventral horn, spinal cord, human, toluidine blue
###### ×640.


This preparation of the spinal cord is from an area comparable
to the _left_ image. Three ventral horn cells (ventral motor neurons)
are visible. Owing to the plane of section, only two of them
exhibit large pale-staining nuclei ( _N_ ) with dark-staining nucleoli in
the center. The toluidine blue reveals the **Nissl bodies** ( _NB_ ) that
appear as the large, dark-staining bodies in the cytoplasm. Nissl bodies do not extend
into the axon hillock. The axon leaves the cell body at the axon hillock. The nuclei
of neuroglial cells ( _NN_ ) are also evident here.


**BV,** blood vessels
**DH,** dorsal horn
**DR,** dorsal root
**GC,** gray commissure
**N,** nucleus of ventral horn cell
**NB,** Nissl bodies
**NN,** nucleus of neuroglial cell
**Np,** neuropil
**Pia,** pia mater
**VF,** ventral fissure
**VH,** ventral horn
**arrows,** cell bodies of ventral horn cell