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HISTORY

In the 1870s, the Italian anatomist Camillo Golgi developed such a special staining technique, and he and other scientists were then able to observe, under the microscope, the fine structures of the cells of the nervous system. Yet Golgi may not have fully appreciated that what seemed to be an extended network of nerve tissue, in reality, were millions of distinct neurons with fine fibrils touching each other. It was the Spanish scientist, Santiago Ramón y Cajal, who was credited with expounding the neuron theory. In 1906, Golgi and Ramón y Cajal shared the Nobel prize in physiology/medicine for their discoveries on the nature of the nervous system.

Even after the concept of separate neurons was generally accepted, there was controversy for many years about how the separate neurons communicated with each other. At the end of the nineteenth century, many scientists believed they did so by means of electric impulses. Others believed there was a chemical messenger that allowed neurons to influence each other. Around 1920, ACETYLCHOLINE was discovered, the first of many nerve messengers that would be discovered during the subsequent decades.

FUNCTION

The neuron is the basic functional cellular unit of nervous system operations; it is the principal investigational target of research into the actions of addictive drugs and ALCOHOL. An essential feature of the cellular composition of the brain is the high density of extremely varied, heterogeneously shaped neuron groups (see Figure 1). To understand the specialized aspects of neurons and their function, therefore, requires a discussion of the general structural and functional features characteristic to all neurons and the degree to which unique variations form consistent subsets of neurons.

Neurons share many cellular properties that distinguish them significantly from other cell types in other tissues; those changes within the cell's regulatory processes of greatest interest to researchers of addictive drugs, however, depend on features that form distinctions within the class of cells called neurons. Furthermore, the assembly of individual neurons into functional systems, through highly precise circuitry employing highly specified forms of chemical interneuronal transmission, allows for the sensitivity of a brain to addictive drugs.

In some organs of the body—such as the liver, kidney, or muscle—each cell of the tissue is generally similar in shape and function. Within that tissue, all perform in highly redundant fashion to convert their incoming raw material into, respectively, nutrients, urine, or contractions, which establishes the function of the specific tissue. In the nervous system, the variously (heterogeneously) shaped neurons (see Figure 2), supported by an even larger class of similarly (homogeneously) shaped non-neuronal cells, termed neuroglia, convert information from external, or from internal, sources into information ultimately integrated into programs for the initiation and regulation of behavior.

This integrative conversion of sensory information into behavioral programs results from the rich interconnections between neurons, and it depends on the extremely differentiated features of neurons—their size and shape; their extended cell-surface cytoplasmic processes (dendrites and axons); and their resultant interconnections that establish the sources of their incoming (afferent) information and the targets of their outgoing (efferent) communication (see also Figure 4).

COMMON FEATURES

As cells, neurons share some features in common with cells in all other organ systems (see Figure 3). They have a plasma membrane acting as an external cell wall to form a distinct boundary between the environment inside (intracellular) and outside (extracellular) the cells. The intracellular material enclosed by the plasma membrane is termed the cytoplasm. Like all other cells (except red blood cells), neurons have numerous specialized intracellular organelles, which permit them to maintain their vitality while performing their specialized functions.

Thus, neurons have mitochondria (singular, mitochondrion), by which they convert sugar and oxygen into intracellular energy molecules, which then fuel other metabolic reactions. Neurons have abundant microtubules, thin intracellular tubular struts, by which they form and maintain their often highly irregular cell structure. Neurons are also rich in a network of intracellular membranous channels, the endoplasmic reticulum, through which they distribute the energy molecules, membrane components, and other synthesized products required for functioning. Like other cells that must secrete some of their synthesized products for functioning, as neurons do with their neurotransmitters, some parts of the endoplasmic reticulum, the smooth endoplasmic reticulum, are specialized for the packaging of secretion products into storage particles, which in neurons are termed synaptic vesicles. At the center of the pool of cell material, the cytoplasm, neurons possess a nucleus, which, as in other nucleated cells, contains the full array of the genetic information characteristic of the individual organism. From this nucleus, selected subsets of genetic information are expressed to provide for the general shared and the specific unshared features of the cell. The nucleus of the neuron cell is enclosed within a membranous envelope that, as in many other types of cells, exhibits multiple nuclear pores through which information can be conveyed to and from the nucleus.

UNIQUE FEATURES

The plasma membrane of neurons differs from that of non-neuronal cells in that it contains special proteins, termed voltage-sensitive ion channels. Such channels are conceptually small tubular proteins embedded in the membrane of the neuron, which, when activated under specific conditions, allow positively charged ions of sodium, potassium, and calcium to enter the neuron. The existence of such electrically sensitive channels permits the neuron to become electrically excitable. The expression and selective distribution (compartmentalization) of such electrically excitable channels along its efferent processes, the axons, permit neurons to conduct signals efficiently for long distances; this also accounts for the bioelectrical activity of the brain assessed by electroencephalography (EEG). Similarly, the distribution of such electrically excitable ion channels along the receptive surfaces of the neurons (its dendrites and cell body [soma]) allows them to conduct and integrate signals from all over the extended shape of the neuron.

The smooth endoplasmic reticulum of the neuron is somewhat more elaborate and extensive than other cells that secrete their products; this specialized and extensive smooth endoplasmic system is termed the Golgi complex (or Golgi apparatus). Discovered accidentally, it was a useful marker for staining the nervous system to distinguish neurons from other cells of the brain when under inspection by microscope.

The nucleus of neurons is often highly elaborated, with multiple creases or infoldings, exhibiting complex configurations, within which are typically dense accumulations of cytoplasmic organelles, and almost always a very distinctive intranuclear clustering of genetic material, the nucleolus. Differentiated neurons—neurons whose developmental stage is past the step at which celltype dedication has occurred—are unable to undergo cell division, in distinct contrast to comparably metabolically active cells in such complex tissues as liver, kidney, muscle, or skin. As a result, mature neurons can repair themselves, up to a point, but are unable to regenerate themselves or respond to their growth factors in a manner that would in other tissues lead to cell division and replacement.

The most distinctive cellular feature of neurons is the degree to which they express unique patterns of size and shape. In mammals, all neurons have highly irregular shapes; such shape variations are categorized in terms of the number of cell surface extensions, or neuronal processes, that the neuronal subset expresses, as in Figure 2.

Some neurons have only one cellular process extending from the surface of a round or nearly round cell body; this form of neuron, a unipolar neuron, is typical of invertebrate nervous systems. Typical unipolar neurons are the cells of the dorsal root ganglia, in which a single efferent axon conducts information toward or away from the cell body through a branched axon.

Most neurons of the central nervous system of mammals are multipolar. That is, in addition to the efferent axon, which may also have many subsets of secondary axons, called collateral branches, that stem from the main efferent process axon, elaborations may also be expressed from the cell body surface. The latter elaborations are termed dendrites, because their shape resembles the limbs of trees. Dendrites protrude from the cell body, and they, as well as the cell body, constitute the receptive surfaces of the target neuron onto which the afferent connections make their synaptic connections.

DISTINGUISHING NEURONS

Since neurons come in so many shapes and sizes, early investigators of the brain sought to make distinctions among them, based in part on their locations, their sizes and shapes, and the connections they could be shown to receive or emit. Every scientist who worked in the formative era of brain research sought to describe a unique subset of neurons that were forever after named for their initial describer or the unique property defined. Thus, we have Betz neurons, large layer V-VI neurons of the motor cortex, and Purkinje neurons, the major output neurons of the cerebellar cortex, as well as neurons named for their shapes and appearance—pyramidal neurons of the cerebral and hippocampal cortices, mitral and tufted neurons of the olfactory bulb, and granule cell neurons of the cerebellar, hippocampal, and olfactory cortices. The last mentioned have relatively compact cell bodies, densely packed together, giving the brain a granular appearance by optical microscopy.

Dendrites and axons exhibit highly distinctive morphological patterns. The surfaces of dendrites and axons can be distinctive in the shapes of their branches. This permits fine discrimination among neurons (stellar, or star-shaped, neurons; chandelier neurons; or mossy or climbing axon fibers). Some neurons exhibit dendrites whose surfaces are smooth (aspiny); others are highly elaborated (spiny), which may serve to enlarge the receptive surfaces and enhance the degree to which such neurons may integrate afferent information.

Similarly, the morphology and stability of the axons may also be highly variable. Some neurons direct their axons to highly constrained targets in a more or less direct route; others may be highly branched, with multiple collateral branches to integrate communications from one cell cluster to many divergent targets. To provide the essential support of anabolic and secretory materials within these highly elaborated cellular structures, neurons have evolved an efficient form of intracellular transport, an energy-dependent, microtubule-guided, centripetal and centrifugal process by which organelles are dispensed to and returned from the distal processes (as well as probable macromolecular signals sensed by pinocytotic-like [fluid uptake] incorporation of such signals by distal dendrites and axons). Such signals may serve as local growth-regulatory factors, allowing even the nondividing neurons to alter their shape and connections in response to activity and signals received from their afferent sources.

NEURONAL IDENTITY

An individual neuron may be referred to on the basis of its size (magnocellular, parvicellular). A layer or "nuclear" cluster of neurons may be referred to by shape (pyramidal, mitral), the morphology of its axon terminals (i.e., basket cells, whose axon terminals make basket-shaped terminations on their targets), and its position in a sensory or motor circuit. In the latter classification scheme, those neurons closest to the incoming sensory event or to the outgoing motor-control event are termed primary sensory or motor neurons, respectively, whereas neurons at more distal positions of circuitry from the primary incoming or outgoing event are termed secondary, tertiary, and so on, depending on their position in that hierarchy.

In addition to these morphological qualities, neurons may also be separately distinguished on the basis of the functional systems to which they are connected (visual, auditory, somatosensory, proprioceptive, attentional, reinforcing, etc.) and on the basis of the neurotransmitters they employ to communicate with the neurons to which they are connected (cholinergic, adrenergic, GABA-ergic, etc.). Each of those features provides for a multidimensional definition of virtually every neuron in the brain.

(SEE ALSO: Brain Structures and Drugs; Neurotransmission; Neurotransmitters; ; Drug; Reward Pathways and Drugs)

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