Knowledge of the structural organization of the nervous system is
essential to the proper understanding of its normal, as well as
For didactic purposes, the nervous system is generally divided
into central and peripheral components. The central nervous system
includes the brain and the spinal cord. The peripheral nervous system
includes cranial and peripheral nerves and associated ganglia. The
autonomic nervous system includes parts of the central and peripheral
The brain includes the cerebral hemispheres, the cerebellum, and
the brain stem. The latter includes the diencephalon; mesencephalon,
or midbrain; pons; and medulla oblongata. Each of these components is
made up of cell groups and fibers, arranged in a manner that
characterizes the particular component. Bundles of nerve fibers
serving a common function and sharing a common origin and destination
are grouped together in tracts or fasciculi. A group of neurons
serving a common function forms a nucleus.
Knowledge of the existence and location of tracts has been gained
through years of clinical observation and experimentation in both
animals and man. Some of the methods used in the tracing of neural
Study of normal preparations: Many aspects of fiber
connectivity of the nervous system have been elucidated by early
studies using normal material and methods that demonstrate myelin
sheaths (Weigert and Weil methods) or that impregnate cell bodies
and their processes (Golgi method). The disadvantage of these
methods is the difficulty of determining the site of termination
of these fibers.
Myelinogenesis: This method, introduced by Flechsig,
makes use of the fact that different fiber tracts become
myelinated at different times in their development. Thus, study of
the nervous system in embryos and in early neonatal life often
affords information about the existence and locality of the
different fiber tracts. This method is infrequently used
Study of pathological conditions in man and experimental
lesions in animals: This method accounts for most of our
current knowledge of neural connectivity. Although human material
has been of use, experimentally produced lesions in animals have
the major advantage of selectivity of site and size. Caution
should be exercised, however, in applying to humans results
achieved in experimental animals.
After a lesion has been produced in animals or man and sufficient
time has elapsed for anterograde degeneration to set in, the
brains and spinal cords can be studied, and degenerated tracts can
be localized by one of the following three methods:
Methods that stain normal myelin (Weigert,
Weil): In such preparations, normal myelin appears dark
blue or black, and the degenerated tracts will be conspicuous
by their failure to pick up the stain.
Methods that stain degenerating myelin (Marchi): In such
preparations, only degenerating myelinated tracts pick up the
stain and can be followed from origin to termination. Normal
myelinated tracts remain unstained. A major advantage of the
Marchi method is that positive results may be obtained years
after degeneration has occurred, making it particularly useful
in the study of human material postmortem. One disadvantage of
this method is that thinly myelinated or unmyelinated tracts
will not stain. Another disadvantage is that it does not stain
degenerating terminals; hence, the exact site of termination of
a tract cannot be determined with certainty.
Methods that stain degenerating axons (Nauta-Gygax,
Fink-Heimer, De Olmos): These are silver impregnation
techniques that stain degenerating axons and pre-terminals
(Nauta-Gygax) or terminals (Fink-Heimer, De Olmos). These
methods have a distinct advantage over myelin methods, since
they are capable of revealing poorly myelinated as well as
unmyelinated nerve fibers, because the axon, and not the
myelin, is stained by these methods.
A neuroanatomist is interested not only in the location and
course of fiber tracts but also in their site of termination.
To determine the latter, methods that stain the terminal
boutons (Glees, Bodian) are used. Electron microscopy can also
be used for this purpose.
Retrograde cell changes: By this method, the position
of neurons giving rise to the tract is determined. Such neurons
undergo chromatolytic changes of their Nissl substance or
disappear completely (retrograde degeneration) if their axon is
severed. These changes can be demonstrated by any of the methods
that stain ribonucleic acids (Nissl material), the Nissl
Autoradiography: This is a relatively recent pathway
tracing technique used in brain research. it utilizes the
principle that radioactive amino acids injected in the vicinity of
neuronal perikarya will be taken up by the neuron, incorporated
into its macromolecules, and transported anterograde along the
axon to its terminal. After a finite time following injection, the
radioactive amino acid can be demonstrated by autoradiography. By
this method, the path of a neural tract can be traced from its
origin to its termination.
Enzymatic method: When the enzyme horseradish
peroxidase (HRP) is injected at the site of termination of nerve
fibers, it is taken up by the nerve terminals and transported
retrograde to the perikaryon where it is visualized by an enzyme
histochernical technique as brown granules in the soma and
Fluorescence method: This method, introduced in the
early 1960s, is used to trace the fiber pathways of adrenergic and
monaminergic neural systems. It relies on the observation that
primary amines form fluorescent condensation products when treated
with formaldehyde in the presence of protein. Fluorescent
condensation products are demonstrated in cells, axons, and
terminals by fluorescence microscopy.
Physiological exploration: By this method, stimulation
and recording techniques are used to establish the presence or
absence of structural and/or functional relationships between two
or more loci in the nervous system. The stimulation and recording
of evoked potentials may be orthodromic (recording of activity in
the terminal projection site of a fiber system) or antidromic
(recording of activity in the cells of origin when their axon
terminals or axons are stimulated). Gross stimulation and
recording techniques reflect the relationship between groups of
neurons; intracellular recordings reflect the relationship between
pairs of neurons.
These methods used to study neural connectivity are based on the
principle of the neuron as a trophic unit. If an axon is transected,
its peripheral parts, including its termination, undergo
degeneration. This is referred to as anterograde degeneration. The
methods described in 3 above are used to show this type of
degeneration. Simultaneously with anterograde degeneration, changes
occur in the proximal components of the neuron, namely in the
proximal axon, the cell body, and dendrites. These changes are known
as retrograde changes.
When considered together, anterograde and retrograde methods allow
a detailed mapping of neural connectivity.
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