Униполярный нейрон имеет аксон

Gross Anatomy

Despite being larger in humans than in most other species (Johnston, 1914), its characteristic thinness and close proximity to the olfactory bulb and tract makes the NT difficult to distinguish from these structures. Moreover, its relationship to trigeminal nerve endings within the nasal cavity is not clear, as its terminations are difficult to identify by electron microscopy. The NT is frequently extracted along with other parts of the brain during human autopsies and dissections, making it nearly impossible to subsequently locate (Bordoni and Zanier, 2013). Adding to this difficulty, the ganglion terminale, the central ganglion of the NT complex, is inconsistent in size and shape (Jennes, 1986). This ganglion has been suggested to be homologous in mammals to the nucleus olfactoretinalis found in fish (Demski and Schwanzel-Fukuda, 1987), a nucleus associated with interactions between the olfactory and visual systems. However, the general association between the NT and both the visual and olfactory systems is enigmatic in most forms. It is noteworthy that the NT is present in whales and dolphins—animals that lack olfactory bulbs and a functioning olfactory system (Buhl and Oelschlager, 1986).

In most forms, a defining element of the NT is its immunoreactivity to GnRH. Schwanzel-Fukuda and Silverman (1980) demonstrated the presence of GnRH within the NT of the guinea pig (Cavia porcellus). GnRH was absent from the olfactory and vomeronasal nerves, implying that the GnRH-secreting fibers are unique to the NT. In the rat, the NT likely supplies the main and accessory olfactory systems with GnRH fibers (Witkin and Silverman, 1983). Uptake studies in the mouse using horseradish peroxidase (HRP) suggest that the GnRH neurons of the NT have access to fenestrated capillaries within the subarachnoid space, the subepithelial connective tissue of the nasal mucosa, and the nasal epithelium proper (Jennes, 1986).

That being said, it should be emphasized that not all NT fibers are GnRH reactive (Schwanzel-Fukuda et al., 1986; Koza and Wirsig-Wiechmann, 2001). Moreover, GnRH does not appear to be present in the NT of some species, such as the lamprey (Northcutt and Puzdrowski, 1988), although a number of GnRH peptides, some of which are yet to be identified, may not be labeled by extant antibodies (Sherwood et al., 1993). Importantly, cell populations within the NT of various organisms have been shown to immunologically label a wide range of antibodies, including substance P (Kyle et al., 1995), choline acetyltransferase (Schwanzel-Fukuda et al., 1986), vasoactive intestinal polypeptide (Schwanzel-Fukuda et al., 1986), acetylcholinesterase (AChE) (White and Meredith, 1995), OMP (Valverde et al., 1993), calbindin (Abe et al., 1992), GABA (Fischer and Stell, 1997), tyrosine hydroxylase (White and Meredith, 1995), FMRF-amide (Wirsig-Wiechmann, 1990; Eisthen and Northcutt, 1996; Fiorentino et al., 2002), and neural cell adhesion molecule (NCAM) (Schwanzel-Fukuda and Pfaff, 2002). Nitric oxide synthase (NOS) coexists with AChE in the NT in some species, presumably related to a role in modulating the function of nitric oxide (Fuller and Burger, 1990).

The cells of the NT complex can be divided into two types: Type I, which are large cells immunoreactive to GnRH, and Type II, which are small cells not immunoreactive to GnRH (Oka and Ichikawa, 1991) (Fig. 9.2). In some chondrichthyes, as well as in lung fish, distinct divisions of the NT have been identified. In the lungfish, for example, an anterior division enters the brain via the olfactory bulb, whereas a posterior division enters into the diencephalon at the level of the optic nerve. While there is debate as to whether these divisions should be considered separate nerves (Schober et al., 1994), it appears likely that these primitive divisions were somehow incorporated into what is now considered the more unitary NT found in more advanced forms (Von Bartheld et al., 1988).

Dendrites and Axons

Chemical synapses transmit signals very rapidly to the adjacent postsynaptic site with a synaptic delay of about 0.3–5 ms. However, a second family of synapses exists that uses electrical current to transmit information. These are the electrical synapses or gap junctions; they can transmit a signal almost instantaneously without any delay by passing current directly from one cell to the adjacent cell and, in contrast to chemical synapse, they can act in a bidirectional fashion. Electrical synapses are formed by connexin integral membrane proteins, six monomers of which assemble into a hemi-channel that is called “connexon.” This hemi-channel spans the neuronal plasma membrane and aligns with a connexon of an adjacent neuronal membrane to form a hydrophilic, intercellular channel. The channel has a pore of about 1.5 nm and allows small organic molecules, Ca²⁺ and cyclic adenosine monophosphate (cAMP) to freely move between the two cells. Usually, a large number of connexons concentrates in patches that can greatly vary in size. At these patches, the plasma membranes of adjacent neurons are separated by only 4 nm, which is much smaller than a 20 nm space of a synaptic cleft. Connexins are members of a large gene family that has about 20 members and are expressed in a tissue-specific manner.

Definition and markers

Neurons are excitable cells which play a role in the reception of stimuli and information through a highly specific interconnection. Accordingly, neurons are cells which transfer information intra- and intercellularly. Neurons need glucose and blood supply and show prominent protein synthesis. Three structural elements, helping the information transfer, are unique to most of the neurons: the axons, dendrites, and synapses. Anaxonic cells are found, for example, in the retina and the olfactory bulb. For neuropathology practice, neurons can be recognized based on identification of the cell body (perikaryon), the nucleus with nucleolus, and cell processes. Visualization of neuronal processes needs special staining. Neurons are various shapes (multipolar, unipolar, and bipolar) and size. Small interneurons can be around the size of an oligodendroctye (5 μm), while motor neurons are up to 100–130 μm. Although unipolar and bipolar neurons are present in the nervous system, most neurons are multipolar. Neurons have a long cell process called an axon. This can extend for many centimeters. Axons transmit impulses to other neurons. The numerous short neuronal processes are called dendrites. They connect with axons through synapses. Based on the dendritic branching pattern neurons can be further classified (e.g., stellate, pyramidal, fusiform, Purkinje, and glomerular). Axons and dendrites together are called neurites. In disease, neurons show selective vulnerability: not all react similarly to equivalent harmful events.

Traditional staining like hematoxylin and eosin (H&E) and particularly Nissl (or cresyl violet) staining combined with luxol for myelin allows recognition of major neuronal groups. Some of the silver stainings such as Bielschowsky, Golgi, or Bodian are also used to delineate neurons or their processes. For a more specific distinction of neurons and their parts, immunohistochemical staining is recommended, in particular that silver staining may show high variability between different laboratories. Antibodies used in the diagnostic practice comprise phosphorylated neurofilaments (e.g., SMI-31), labeling mostly the axons; nonphosphorylated neurofilaments (e.g., SMI-32), labeling neuronal body and occasional dendrites and thick axons; and further markers labeling dendrites and neuronal body and only occasional axons (e.g., microtubule-associated protein-2). A further marker NeuN labels mostly the nuclei of neurons and can be used particularly for the diagnostics of CNS tumors of neuronal origin. They are sensitive for long formalin fixation and less reliable in autopsy material. For tumor classification chromogranin can be used. The most widely used synaptic marker in tumor diagnostics is synaptophysin (presynaptic marker), but α-synuclein or synapsin antibodies are also used. Electric synapse-related gap junctions can be labeled by connexin-32.

Dorsal Root Ganglia

Dorsal root ganglion cells develop from the neural crest migration at about 4 weeks pc and immediately begin to migrate ventrally. Ascent of the conus medullaris relative to the vertebral column occurs progressively from 13 to 40 weeks pc, elongating the cauda equina of the lumbosacral spinal nerves (Zalel et al., 2006). In 6–7 weeks pc embryos, dorsal root ganglia are composed of loosely packed and randomly oriented cells with wide intercellular spaces and scattered processes (Olszewska et al., 1979). Early bipolar neurons begin to appear during the 7^th and 8^th weeks pc. Evidence of apoptosis in the form of oval cells with electron-dense pyknotic nuclei is seen in dorsal root ganglia at about the 8^th week. Intermediate bipolar neurons, with prominent development of rough endoplasmic reticulum, begin to appear at 9–10 weeks pc, while unipolar neurons, which have well-developed organelles and a single broad process arising from one pole, appear at about 11 weeks pc (Olszewska et al., 1979). The appearance of (pseudo)unipolar neurons correlates with the onset of reflex responsiveness from the skin of the upper limb (Hooker, 1942) signifying that both central and peripheral processes of a significant proportion of these cells have reached their appropriate target structures. In the developing human cervical spinal cord, central processes of muscle spindle afferents cross the dorsal horn by 7.5 weeks pc, perhaps guided by radial glia cell processes (McDermott et al., 2005) and make contact with motoneurons by 9 weeks pc (Clowry et al., 2005).

Both high-molecular-weight neurofilament protein and vimentin are present within dorsal root ganglion cells at 6 weeks pc (Lukás et al., 1993; Almqvist et al., 1994). Immunoreactivity for vimentin declines in ganglion cells, but increases in differentiating satellite cells, with increasing age. Immunoreactivity for neuron-specific enolase, a neuron-specific enzyme that is useful as a marker of neuronal differentiation, develops in dorsal root ganglion cells at about the same time (7 weeks pc) as its appearance in the spinal cord (Kato and Takashima, 1994). Immunoreactivity for somatostatin begins to appear in a few dorsal root ganglion cells at 9 weeks pc (Charnay et al., 1987; Marti et al., 1987) and remains stable in terms of number of immunoreactive neurons throughout fetal life. Somatostatin-immunoreactive processes in the dorsal horn of the spinal cord appear at 9 weeks pc, increase in number and density during the period from 12 to 28 weeks pc, and remain stable from 36 weeks pc to 4 months after birth (Charnay et al., 1987). Immunoreactivity for the low-affinity nerve growth factor receptor (NGFr) also appears at about 9 weeks pc in larger ganglion cells and immunoreactive fibers appear in the medial dorsal horn between 12 and 20 weeks pc (Suburo et al., 1992). Both of these immunoreactivities are absent in the adult. Immunoreactivity for enkephalin and CGRP appears in dorsal root ganglia somata at 14 weeks pc, whereas galanin and substance P immunoreactivity do not appear in dorsal root ganglia somata until 24 weeks pc (Marti et al., 1987).

VI.F.6. Polarity of Neurons

Unipolar neurons are not found in vertebrate nervous systems, although young neurons have but one process at certain developmental stages and look like them. But in invertebrates, they represent the dominant population and, hence, the largest number of nerve cells on earth.

Bipolar neurons are simple modifications, with fusiform cell bodies, of the columnar epithelial cells from which they evolved. In humans, they form primary sensory neurons in the olfactory epithelium, retina, and vestibulocochlear ganglia. Terminal ramifications in the periphery (e.g., in the organ of Corti) respond fractionately to stimuli and may be considered distant dendrites. By contrast, the long process leading to the soma, like the other process departing, is by all criteria axonal, even having a myelin sheath for increased speed of impulse conduction. By the interposition of an axonal cable between the receptive region and the cell body, spikes triggered peripherally pass swiftly to the soma, over which they flow to the other process and on to the CNS, wherein their central ramifications distribute impulses to secondary sensory neurons.

Pseudounipolar neurons are modified bipolar cells. The opposing processes shift around the soma during development and combine into one, at least proximally. This process takes a short, often convoluted course and then branches like the letter T: one branch going to the periphery and the other to the CNS (Fig. 21I), as in bipolar neurons. Nerve impulses in these cells pass from one branch to the other, subsequently “backfiring” the single process and soma. Pseudounipolar and bipolar cells make up all primary sensory neurons in the PNS. Both have limited integrative domains in distant dendritic tufts and no input on their somata, which are limited to trophic and housekeeping duties. Their central terminals, however, receive presynaptic endings, providing efferent modulation of their transmission to secondary sensory neurons. This arrangement is important in suppressing the receipt of painful stimuli. It is an enkephalinergic component of a complex brain stem analgesia system.

Multipolar neurons have many variably branched processes projecting in many directions. The most common type of vertebrate neuron, they comprise virtually all neurons of the human CNS. With their diversified input (from 10⁴ to 3×10⁵ apiece), they have tremendous integrative capacity. In the shape, size, and position of their somata, in the number, length, and branching pattern of axons and dendrites, and in neuroactive substances synthesized and released, a panoply of multipolar neurons is found in the CNS (Fig. 27). This variety is so extraordinary that neurobiologist Pasko Rakic has said, “I believe it is safe to estimate that there are more forms of cells in the brain of a mammal than in all the rest of the entire body.” Functionally, their vast number (100 billion, maybe 1 trillion) falls into two groups: a small number of motor neurons (about 2 million), sending axons to muscles and glands, and the remainder a host of interneurons.

As stated, the dendrites of multipolar neurons are the most intriguing variables, expressing their integrative power. They vary from few to profuse, from straight and smooth to curving and spiny, and from meagre shrubbery to magnificent arboreal extravaganzas. The axon comes next, being short or long, unbranched or rectilinearly, almost obsessively collateralized, and ruler-straight and departing the locale or sinuous and wandering through the local neuropil. Then the soma: ovoid, spherical, pyriform, fusiform, fat, skinny, big, small: miniscule (4 μm, half the size of a red blood cell) in dwarf neurons to huge (150 μm) in giants. Teased out in a tissue preparation, the Betz cells in the human cerebral cortex can be seen with the naked eye.

Histology and Pathophysiology

Hypothalamic hamartoma is thought to be a developmental aberration, but its origin is unclear. Remnants of brain tissue left along the floor of the third ventricle when chorda withdraws may account for its origin in the central nervous system (CNS). Histologically, it consists mainly of normal brain elements: neurons, glial cells, and fiber bundles that are frequently myelinated and connected to surrounding hypothalamic structures. Frequently, however, hamartomas do not reproduce the normal architecture of neighbouring tissue.

The hypothalamic hamartoma functions as an ectopic luteinizing hormone-releasing hormone (LHRH) pulse generator that escapes the intrinsic CNS inhibitory mechanism. In the mouse, monkey and human, LHRH neurons originate in the medial olfactory placode of the developing nose, migrate across the nasal septum, and enter the forebrain with the nervus terminalis, arching into the septal-preoptic area and hypothalamus. In hypothalamic hamartoma a significant number of LHRH neurons migrate beyond the medial basal hypothalamus to the region of the mammillary bodies and tuber cinereum and form one of the constituents of the heterotopic mass of CNS tissue. The defect in migration could be related to an imbalance of diffusible chemotrophic factors that are secreted by restricted cell populations within the brain or to neural cell adhesion molecules, which play an important role in axonal pathfinding.

Since the number of LHRH neurons is limited, it is possible that a majority of the LHRH neurosecretory neurons may migrate into the hamartomas during CNS development. On the other hand, hypothalamic hamartoma may be related to aberrant differentiation among other cell types of neural primordia, including progenitor cells with the capacity to form LHRH neurosecretory neurons.

Histological specimens observed after surgery reveal hamartomas of low cell density containing irregularly structured groups of ganglionoid cells with variably sized unipolar and bipolar neurons interspersed among glial cells with myelinated and unmyelinated fibres connected to sorrounding hypothalamic structures. The tissue is highly vascular and many of the vessels have fenestrated endothelium and double basement membranes. Each vessel is almost totally sorrounded by axons. There is no or very little tendency to proliferation.

Immunohistochemical studies confirm the neuronal origin of hypothalamic hamartoma showing positive staining for neuron-specific enolase, synaptophysin and neurofilament protein.

Different immunohystochemical studies demonstrate the presence of membrane-bound, electron-dense granules (100 nm in diameter) which contain LHRH within the perikarya, the axons and the axons terminals and which are the elements of an independent neuroendocrine unit.

The examination of two hypothalamic hamartomas associated with sexual precocity revealed that they contained astroglial cells expressing TGFα, but not LHRH neurons. These findings imply that some hypothalamic hamartomas induce sexual precocious puberty by activating endogenous LHRH secretion via astroglial-derived factors such as TGFα and/or TGFβ. This activation appears to require a close proximity of hypothalamic hamartoma to either LHRH neurons or their axonal processes in the median eminence. In some cases, the hamartoma itself does not initiate precocious sexual maturation due to its location, but rather a lesion of the adjacent hypothalamic tissue resulting from surgery may cause activation of astroglial cells which may then lead to increased LHRH secretion from hypothalamic LHRH neurons.

A number of findings suggest that hamartomas are themselves epileptogenic. Electroencephalography (EEG) recordings revealed focal spikes arising from the depth contacts within hypothalamic hamartomas, while electrical stimulation studies reliably reproduce gelastic episodes, suggesting a close relationship between hamartomas and the generation of laughing attacks. The most fascinating studies based on ictal single-photon emission-computed-tomography demonstrated marked blood flow in the hypothalamus and thalamic structures during gelastic events. Improvement in intractable epilepsy has been reported in some cases after the resection of hamartoma.

Clinical and experimental evidence suggest that the hypothalamus and adjacent structures, in particular the mamillary bodies and its immediate connections, may comprise an important sub-cortical pathway for seizure propagation. Sessile hypothalamic hamartomas with displacement of the hypothalamus are associated with seizures.

Recent evidence shows that, unlike laughing and focal seizures, slow spike-and-wave discharges and associated tonic and atonic seizures do not arise directly from hamartoma. Indeed, postoperatively, these seizures may progressively “run down” after removal of the hamartoma, suggesting that they are the result of secondary epileptogenesis. Most HH cases are sporadic. Approximately 5% of HH cases are associated with Pallister-Hall syndrome, which is caused by haploinsufficiency of GLI3. Craig et al have identified somatic GLI3 mutations in sporadic HH cases, suggesting a role in the etiology of HH lesions.

Metabolic Compartmentalization of the Brain

The central nervous system (CNS) is part of the whole nervous system consisting primarily of the brain and spinal cord. The cortical tissue of the brain is comprised of three types of cells: highly heterogeneous populations of neuronal cells, large astroglial cells, and numerous small microglial cells. The ratio of astrocytes to neurons in the brain cortex is typically between 1:2 and 1:3 (Suzana, 2014). Neuronal cells, which have axons and numerous dendrites, fulfill the specific functions of the brain. Each neuron communicates with thousands of other neurons by establishing synaptic junctions (Poritsky, 1969; Holtzman et al., 2006). According to Abeles (1991), the synaptic density of the cerebral cortex is approximately the same in all mammalian species 8 × 10⁸ per 1 mm³. Thus, in mice with 100,000 neurons per 1 mm³, each neuron receives 8000 synapses, whereas in humans with 20,000 neurons per 1 mm³, each neuron receives 40,000 synapses. Accordingly, more than 90% of all brain mitochondria are located at the synaptic junctions (Abeles, 1991).

Mitochondria are located at the parts of the cell with the most functional activity. More than 90% of mitochondria are concentrated at the synaptic junctions of axons and dendrites in neuronal cells. In astrocytes, mitochondria are concentrated at the ends of the processes, which are close to synapses. The mitochondrial activity in soma correlates with the spontaneous and synaptic activations and functionally is different from those at the synapses (Wong-Riley, 1989).

Based on physiological interactions, neurons may be classified as excitatory or inhibitory (Abeles, 1991). The excitatory nerve cells release neurotransmitters, most often glutamate, which, when they come in contact with the membrane of the postsynaptic terminal of a synapse, activate ion fluxes that cause depolarization of the postsynaptic membrane of the recipient cell. The inhibitory neurons release neurotransmitter γ-aminobutyric acid (GABA), which causes hyperpolarization of the postsynaptic cell, diminishing the depolarizing ion fluxes caused by the excitatory neurons. Therefore these sites possess a low level of mitochondrial markers because repolarization of the membrane after depolarization is a passive process and does not require much ATP (Wong-Riley, 1989). The excitatory glutamatergic signals significantly predominate over the inhibitory ones comprising about 80% of the cortical synapses׳ signals (Belanger et al., 2011).

Studies on the distribution of energy for different brain functions have shown that neurons spend approximately 90% of ATP for the synaptic transport of Na⁺, K⁺, Cl⁻, and Ca²⁺ ions, and less than 10% for the reutilization of neuromediators and metabotropic responses (Abeles, 1991; Attwell and Laughlin, 2001). Thus, neurons have very little energy and metabolic capacity for housekeeping. The most important consequence is that more than 90% of brain mitochondria are localized at synaptic junctions, which have no space for glycolytic enzymes to utilize glucose as the energy source or enzymatic systems for maintaining and repairing synapses and synaptic mitochondria. For these reasons, synapses have a short life and must continuously be replaced with new ones. Moreover, increased neuronal functional activity stimulates new synapses, whereas decreased functional activity results in diminished synaptic junctions (Genoud et al., 2006). Neurons have a particular transport system to deliver new mitochondria to synapses from the soma where they are made. A critical feature of isolated synaptic mitochondria is that they do not contain any endogenous substrates, unlike isolated mitochondria from other tissues. This unique feature makes synaptic mitochondria depend on the external supply of substrates from astroglia (Panov et al., 2014).

A large number of synaptic contacts also has an essential metabolic significance for both neurons and astrocytes. Neurotransmitters not only have signaling roles but also serve as substrates for mitochondrial respiration. Different types of neurons have different neurotransmitters, and there are variations in the number, type, and activity of glutamate transporters and catabolism of neurotransmitters such as GABA or dopamine. These contribute to the local variations in the neuronal mitochondrial activity in energy and reactive oxygen species production. Astrocytes must replenish the glutamate pool, which is also the precursor of GABA and glutamine (the transport and storage form for glutamate). For these reasons, astroglia play a crucial role in providing synaptic mitochondria with substrates and replenishing the pool of neuromediators, which undergo catabolism.

1.4 Cells of the nervous system

There are two main cell types in the nervous system: neurons and supporting cells. While the neuron is the main functional unit, the remaining cells (glial and ependymal) have been classically viewed as secondary, mainly supporting neuronal function. However, new data has shown that this neuron-glial interaction is far more complex. The idea that neurons and glia coexist in a 1:10 relation has been highly propelled in the literature but it is now clear that they exist in similar proportions [135].

Dorsal Root Ganglion

A dorsal root ganglion is a collection of primary sensory neurons. The central and peripheral processes of these cell bodies form the sensory connection between the nervous system and the periphery. The generally held vision that one spinal DRG is related to one dermatome is difficult to attain. Each DRG entry area in the spinal cord has overlap with its upper and lower DRG entry zone and the peripheral fields tend to overlap. A sharp demarcation therefore is not present. Sense of pain is more sharply demarcated than sense of touch, complicating matters. Destruction of one DRG is hardly noticed due to the overlap of peripheral innervation and cord projection entries.

In the need to develop a somatosensory neural interface that is relevant for the function of prosthetic control, focus has been laid on the dorsal root ganglion. Microstimulation of primary afferents in the L7 DRG of the cat showed the possibility to recruit more of the same fibers by simply increasing the stimulus (Gaunt et al., 2009). Grouping of nerve fibers in so-called “microbundles” originating in adjacent skin areas (Wall, 1960) should explain such behavior, expressing a topographical or group organization in the inside fibers of the DRG.

Within the mature DRG all diameters of neurons between 10 and over 100 μm are present but unorganized. In C8 ganglion in humans 40,000–50,000 neurons were counted (Pearson et al., 1978). Light and dark neurons (called A cells and B cells respectively; medium and small cells are also subdivided in B and C cells, see Devor, 1999) are discerned using different classical stainings, showing a comparable unorganized pattern. However, dark cells are generally small unipolar neurons, while light cells are always large unipolar cells. Using electron microscopy a further subdivision into three subtypes is possible (A1–3 and B1–3) based on the endoplasmic reticulum and Golgi apparatus.

Histochemistry brought forward a peculiar property of DRGs. It showed glycogen present in several mammalian DRG neurons and glycogen is observed in around 60% of the neurons mainly, but not exclusively, in large cells. Such a great neuronal variation, also in the presence of acetylcholinesterase activity, was noted in the spinal DRG neurons of different vertebrates, including humans, established with both biochemical and histochemical techniques (Friede, 1966; see also Feirabend and Marani, 2003). This strong variance in content of DRG neurons, present in nearly all vertebrate species, has been recorded for neurotransmitters (glutamate, aspartate, GABA, serotonin), neuropeptides (CGRP, substance P, cholecystokin, somatostatin, neuropeptide Y, VIP, syntaxin, peripherin, dynorphin, trkA), neurotrophic factors like BDNF, NGF (e.g. Michael et al., 1997, also for CGRP), lectins (Streit et al., 1985), carbohydrates (e.g. Dodd and Jessel, 1985; Marani et al., 1992), receptors (e.g. neurotropin, Mu et al., 1993) and enzymes, except for some enzymes of the metabolic cycle. Pain-related substances are mainly found in small cells (substance P, galanin, neuropeptides Y and FF, CGRP, stomatin) with a comparable strong variance in neuronal content. It is unfeasible to reference all these substances, since ganglion results are strongly dispersed also as small fractions over many publications (for early overview see Lawson, 1992).

Generally no organized or topographical pattern can be recognized in the DRG for its neurons. Subsets of neurons, sometimes in groups, but nevertheless scattered at random throughout the whole DRG, occasionally can be discerned.

This could also be proven for the rat brachial DRGs (Wessels and Marani, 1993). Labeling of single intercostal nerves always resulted in a whole labeled DRG. This typical half DRG labeling was absent in mature rats. It goes without saying that this rostro-caudal pattern of half DRGs in both lumbosacral and brachial plexus has been related to plexus formation. Moreover the rostro-caudal organization is maintained in the spinal nerves. “Fibers of a spinal nerve which will eventually make up a forelimb (or a hind limb) nerve stick together, while finding their way through the plexus (Wessels and Marani, 1993, see also Wessels et al., 1994, for a review).” Support comes from Hirano and Fuse (1989), where in the quail one DRG was constituted by two cranio-caudally arranged groups of neurons, from Puigdellıvol-Sanchez et al. (1998) who found a rostro-ventral subdivision in L4 of the rat for femoral and sciatic DRG neurons, from Prats-Galinoa et al. (1999) where digit representation in ganglion L5 of the rat showed a rostro-caudal organization also among hindlimb digit DRGs (see also Wessels 1990a,b), and from Burton and McFarlane (1973) who found electrophysiologically a medio-lateral somatotopic organization in DRG L7 of the cat.

The disappearance of the pattern at maturity is explained by intermingling of DRG neurons during late development, generation of new DRG-cells during postnatal life (Devor and Govrin-Lippman, 1985), or the outgrowth of a second axon by each DRG-cell (Langford and Coggeshall, 1981).

The rat DRGs L4 and L5 together increase their amount of neurons with 18 per day throughout life, which is responsible for an increase in the amount of neurons: 150% higher in aged rats as compared to young ones (Devor et al., 1985). Rat DRGs therefore should be considered a dynamic structure during life time.

Human DRGs on the contrary were already early in aging research reported to be reduced in amount of neurons, having a strong decrease of nucleoli staining, increase of pigmentation, and augmentation of necrosis (see e.g. Hodge, 1894).

• Cell types

Cells of the CNS can be divided into two categories based on their embryonic origin. Cells arising from the neuroectodermal layer include neurons, astrocytes, oligodendrocytes, and ependymal cells. Cells of mesenchymal origin include the meninges, blood vessels, and microglia. The catchall term “glia” refers to astrocytes, oligodendrocytes, ependyma, and choroid plexus. Microglia are sometimes included in this category as well, but they are not true “glia” because they are thought to arise from yolk sac progenitors and/or circulating precursors of the macrophage lineage. In the CNS, each neuron is sustained by approximately 10–50 glial cells. More detailed descriptions of CNS histology and cytoarchitecture, including common lesions and artifacts, may be found in standard histology and neuropathology texts and also reviews listed in Further Reading and Relevant Websites.