Monoamine distribution in primate brain. V. Monoaminergic nuclei: anatomy, pathways, and local organization.

Abstract The noradrenergic, dopaminergic, and serotonergic cell groups of the brain stem and caudal diencephalon, and their projections, were examined in neonatal and adult squirrel monkeys, rhesus monkeys, and stump-tail monkeys utilizing the Falck-Hillarp formaldehyde condensation reaction. The axonal pathways fluoresced in neonatal monkeys and permitted direct visualization of the major bundles. Cell groups in the ventral and dorsal tegmentum of the medulla and pons (A1, A2, A3, A7) gave rise to a ventral ascending catecholamine pathway which coursed through the ventral tegmentum of the brain stem. The locus coeruleus (A4, A6) gave rise to a dorsal ascending catecholamine pathway which coursed through the medial region of the tegmentum above the ventral pathway. Prominent catecholamine cell bodies (Acg) in the central gray of the midbrain, rostral to the locus coeruleus, gave rise to an ascending dorsal periventricular pathway which ran dorsally in the tegmentum; some fibers then rapidly coursed ventrally to join a confluence with other ascending brain stem catecholamine axonal projections. The catecholamine axons ran through the medial forebrain bundle in the lateral hypothalamus, and sent further projections into limbic forebrain and cortical structures. Dopaminergic cells of the ventral tegmental area gave rise to an ascending ventral periventricular system which coursed through the most ventromedial region of the tegmentum, entered the medial forebrain bundle, and further coursed into regions of frontal and cingulate cortex, and limbic forebrain regions. The substantia nigra and some lateral cells of the lateral ventral tegmental area sent axons through the most ventral regions of the tegmentum above, and within the substantia nigra. These axons coursed into the lateral hypothalamus adjacent to the other monoaminergic axons, and proceeded to move further lateral as they ascended rostrally. They ran through the internal capsule and projected into the caudate nucleus and putamen. A major descending periventricular catecholamine system was found in the dorsal and medial region of the tegmentum of the lower brain stem, projecting into the medulla and spinal cord. Only scattered fluorescent axons were found descending to the spinal cord through the ventral tegmentum. Other catecholamine cell groups were noted in one or more primate species; they were found within the solitary tract (i.e. group Ast), and directly beneath the aqueduct (i.e. group Aaq). The hypothalamic cell groups A11–A14 were found in the caudal hypothalamus. Except for the short projection of the arcuate nucleus (A 12) to the contact zone of the median eminence, these cells gave rise to scattered axons which formed no prominent bundles visible with fluorescence histochemistry. The serotonergic cell bodies were found in the raphe nuclei of the brain stem and adjacent tegmental fields, and gave rise to both ascending and descending pathways. Nuclei raphe obscurus (B2), pallidus (B1), and magnus (B3) gave rise to dorsal and ventral descending pathways which descended to the caudal brain stem and spinal cord in a paramedian position alongside the nuclei. Nuclei raphe ponds (B5) and dorsalis (B6, B7) gave rise to a dorsal ascending serotonergic pathway, while nucleus centralis superior (B8,B9) and associated serotonergic tegmental cells gave rise to a ventral ascending serotonergic pathway. The ascending pathways coursed through the medial forebrain bundle and further projected to numerous diencephalic and telencephalic nuclei and regions. The monoamine pathways are represented in coronal, sagittal, and horizontal sections. Although differences were noted among the species examined, the general outline of the cell groups and pathways was similar. However, the primate patterns differed in several ways from comparable systems in the rat. The local organization of primate and monoaminergic nuclei demonstrated several unique characteristics. All monoaminergic nuclei demonstrated transmitter histofluorescence in primary dendrites, and sometimes in secondary or even tertiary dendrites. Some of these dendrites formed large dendrite bundles (e.g. nuclei raphe obscurus and pallidus in the caudal medulla, nuclei raphe dorsalis and centralis superior in the rostral pons and caudal mesencephalon) which possessed dendrites from both fluorescent and non-fluorescent neurons. Smaller bundles of fluorescent dendrites also were found in the locus coeruleus (coursing across the tract of the mesencephalic nucleus of V) and in the pars reticulata of substantia nigra. Further characteristics of the dendritic arborizations of the major monoaminergic nuclei are described utilizing Golgi-Cox impregnanted material. Electron microscopic observations of the locus coeruleus, substantia nigra, and raphe nuclei revealed a direct apposition of the basement membrane of some capillaries with the plasma membrane of somas and dendrites. Golgi-Cox observations revealed tanycytes on the floor of the fourth ventricle whose shafts projected into the two major raphe dendrite bundles, locus coeruleus, and the A2 region. These observations suggest that local dendritic modulation may play an important role in the regulation of neuronal excitability of some of the monoamine cell groups, and that blood-borne or CSF-borne ligands may have ready access to receptor surfaces on some monoamine cells through the unique neuronal-vascular and tanycyte shaft relationships, respectively. Electron microscopy of the medullary and dorsal raphe nuclei, locus coeruleus, substantia nigra, and ventral tegmental area revealed the presence of numerous dendro-dendritic synapses, sometimes demonstrating membrane specializations or vesicles, but not both. Each nucleus possessed a significant population (50% or more) of cells with absent or extemely sparse axo-somatic synapses. Theses somas were invested with astrocytic processes or with extended regions of the somatic membranes of oligodendroglia. Most of the synapses on these cells were axo-dendritic or dendro-dendritic. The axo-dendritic synapses terminated on both spines and parent dendrites. Some of these neurons in the raphe nuclei were tentatively identified at the ultrastructural level as serotonergic, and in locus coeruleus as catecholaminergic, utilizing x-ray analytical electron microscopic examination of chromium-tagged, glutaraldehyde-condensed monoamines. These ultrastructural observations reinforce the important role of dendrites in these major monoaminergic nuclei for the integration of afferent information from incoming axons and from dendrites of both monoaminergic and non-monoaminergic cells.