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The brain stem contains extensive fields of intermingled neuronal cell bodies and nerve fibres, which are collectively termed the reticular formation. The reticular regions are often regarded as phylogenetically ancient, representing a primitive nerve network upon which more anatomically organized, functionally selective, connections have developed during evolution.

Reticular regions tend to be ill-defined collections of neurones with diffuse connections. Their conduction paths are difficult to define, often complex and polysynaptic, and they have ascending and descending components that are partly crossed and uncrossed. Their components subserve somatic and visceral functions. They also include some distinct and important cell groups, which are distinguished on the basis of their neurotransmitter substances. These include dopaminergic and noradrenergic neurones (group A), serotoninergic (group B) adrenergic (group C) and cholinergic (group Ch) neurones.

Studies with the Golgi technique show that few brain stem reticular neurones are classic Golgi type II neurones (i.e. with short axons that branch locally). In contrast, they have long dendrites that spread across the long axis of the brain stem in transverse sheets. These radiating dendrites may spread into 50% of the cross-sectional area of their half of the brain stem, and they are intersected by, and may synapse with, a complex of ascending and descending fibres. Many axons of reticular neurones ascend or descend, or bifurcate to do both. They often travel far, perhaps through the whole brain stem and even beyond. As an example, a bifurcating axon from a cell in the magnocellular medullary nucleus may project rostrally into the upper medulla, pons, midbrain tegmentum, subthalamus, hypothalamus, dorsal thalamus, septum, limbic system and neocortex, while its descending branch innervates the reticular core of the lower medulla and may reach the cervical spinal intermediate grey matter (laminae V and VI). Many reticular neurones have unidirectional, shorter axons which synapse with the radiating dendrites of numerous other neurones en route, and give off collaterals which synapse with cells in ‘specific’ brain stem nuclei or cortical formations, such as the cerebellum. Multitudes of afferent fibres converging on individual neurones, and the myriad destinations of efferent fibres, provide the structural basis for considering the reticular formation to be ‘polymodal’, ‘diffuse’ or ‘non-specific’ in function.

A contrasting dendritic form is also found, in which dendrites are short, sinuous or curved, branch profusely and pursue re-entrant courses at the perimeter of a nuclear group, defining a boundary between it and its environs. Neurones with an intermediate dendritic complexity occur in and near such nuclei and vary in density in much of the remaining reticular formation. In different zones, the proportion of different sizes of neuronal somata varies. Some regions contain only small to intermediate multipolar cells (‘parvocellular’ regions). However, there are a few areas where these mingle with large multipolar neurones in ‘gigantocellular’ or ‘magnocellular’ nuclei.

In general terms, the reticular formation is a continuous core that traverses the whole brain stem, and is continuous below with the reticular intermediate spinal grey laminae. It is divisible, on the basis of cytoarchitectonic, chemoarchitectonic and functional criteria, into three bilateral longitudinal columns: median; medial, containing mostly large reticular neurones; and lateral, containing mostly small to intermediate neurones (Fig. 19.20).


Fig. 19.20  Dorsal aspect of the brain stem showing the approximate location of nuclei of the reticular formation. Nuclei of the median and paramedian nuclear column: magenta; medial column nuclei: purple, lateral column nuclei: blue.


The median column of reticular nuclei extends throughout the medulla, pons and midbrain and contains neurones that are largely aggregated in bilateral, vertical sheets, blended in the midline and occupying the paramedian zones. Collectively they are called the nuclei of the raphe, or raphe nuclei. Many neurones in raphe nuclei are serotoninergic and are grouped into nine clusters, B1–9. The raphe pallidus nucleus and associated raphe obscurus nucleus lie in the upper two-thirds of the medulla and cross the pontomedullary junction. The raphe magnus nucleus, corresponding to many B3 neurones, partly overlaps them, and ascends into the pons. Above it is the pontine raphe nucleus, which is formed by the cell group B5. Also located in the pons is the central superior raphe nucleus, which contains parts of cell groups B6 and B8. The dorsal (rostral) raphe nucleus, approximating to cell group B7, extends through much of the midbrain.

Axons originating from the serotoninergic raphe neurones ramify extensively throughout the CNS. Although many of these fibres are diffusely distributed, others have more specific connections. For example, whereas the central superior raphe nucleus projects divergently to all areas of the cerebral cortex, different neurones in the dorsal raphe nucleus not only project specifically to circumscribed regions of the frontal, parietal and occipital cortices, but also to functionally related regions of the cerebellar cortex. Similarly, the caudate nucleus and putamen receive a preferential input from the dorsal raphe nucleus, whereas the hippocampus, septum and hypothalamus are innervated mainly by cells in the central superior mesencephalic raphe nucleus.

All raphe nuclei provide mainly serotoninergic descending projections, which terminate in the brain stem and spinal cord. Brain stem connections are multiple and complex. For example, the dorsal raphe nucleus, in addition to sending a large number of fibres to the locus coeruleus, projects to the dorsal tegmental nucleus and most of the rhombencephalic reticular formation, together with the central superior, pontine raphe and raphe magnus nuclei.

Raphe spinal serotoninergic axons originate mainly from neurones in the raphe magnus, pallidus and obscurus nuclei. They project as ventral, dorsal and intermediate spinal tracts in the ventral and lateral funiculi, and terminate respectively in the ventral horns and laminae I, II and V of the dorsal horns of all segments, and in the thoracolumbar intermediolateral sympathetic and sacral parasympathetic preganglionic cell columns. The dorsal raphe spinal projections function as a pain control pathway that descends from a mesencephalic pain control centre located in the periaqueductal grey matter, dorsal raphe and cuneiform nuclei (Ch. 18). The intermediate raphe-spinal projection is inhibitory, and, in part, modulates central sympathetic control of cardiovascular function. The ventral raphe spinal system excites ventral horn cells and could function to enhance motor responses to nociceptive stimuli.

Principally, the mesencephalic serotoninergic raphe system is reciprocally interconnected rostrally with the limbic system, septum, prefrontal cortex and hypothalamus. Efferents ascend and form a large ventral and a diminutive dorsal pathway. Both originate from neurones in the dorsal and central superior raphe nuclei. The raphe magnus nucleus also contributes to the dorsal ascending serotoninergic pathway, which is at first incorporated into the dorsal longitudinal fasciculus (of Schütz). A few fibres terminate in the central mesencephalic grey matter and posterior hypothalamus, but most continue into the medial forebrain bundle and merge with the axons of the ventral pathway, which are distributed to the same targets. The fibres of the ventral ascending serotoninergic pathway exit the ventral aspect of the mesencephalic raphe nuclei, and then course rostrally through the ventral tegmentum from where fibres pass to the ventral tegmental area, substantia nigra and interpeduncular nucleus. A large number of fibres then enter the habenulointerpeduncular tract and run rostrally to innervate the habenular nucleus, intralaminar, midline, anterior, ventral and lateral dorsal thalamic nuclei, and the lateral geniculate body. The ventral ascending serotoninergic pathway enters the medial forebrain bundle in the lateral hypothalamic area and splits to pass medially and laterally. The fibres in the medial tract terminate in the mammillary body, dorsomedial, ventromedial, infundibular, anterior and lateral hypothalamic, medial and lateral preoptic and suprachiasmatic nuclei. Those in the lateral tract take the ansa peduncularis–ventral amygdalofugal path to the amygdala, striatum and caudal neocortex. The medial forebrain bundle carries the remaining ventral ascending serotoninergic axons into the medullary stria, stria terminalis, fornix, diagonal band, external capsule, cingulate fasciculus and medial olfactory stria, to terminate in all the structures that these systems interconnect.

Major afferents into the mesencephalic raphe nuclei include those from the interpeduncular nucleus, linking the limbic and serotoninergic systems; from the lateral habenular nucleus, linking the septum, preoptic hypothalamus and prefrontal cortex via the habenulointerpeduncular tract and the medial forebrain bundle; and from the pontine central grey matter.

The ascending raphe system probably functions to moderate forebrain activities, particularly limbic, septal and hypothalamic activities. A degree of region-specific connectivity suggest that it exerts precise, as well as tonal, control.

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