The objective is to characterize monoaminergic (MA) projections to cerebral cortex in terms of anatomic and chemical features that are important determinants of function. This study will provide a definitive account of the neurotransmitters and the cortical distribution of projections from the raphe nuclei and locus coeruleus. A central theme of this project is to test a new hypothesis that the raphe nuclei send multifocal projections to small patches of cortex; thus, clusters of adjacent neurons may selectively influence specific sets of cortical areas. Four sets of inter-related experiments are proposed. 1) Anterograde axonal transport of a lectin (PHA-L) will be employed to characterize and compare the terminal distribution of raphe-cortical and of coeruleo-cortical axons. 2) The transmitters and projections of non-5-HT neurons in the raphe nuclei will be determined. To this end, anterograde and retrograde transport methods will be combined with transmitter immunocytochemistry in order to identify the neurotransmitters of cortically projecting raphe neurons and their axon terminals. 3) The preliminary finding that 5-HT cells in different raphe nuclei give rise to highly distinctive axon terminals will be verified, and electron microscopy will be used to determine whether the specialized varicosities reflect differences in synaptic morphology and organization. 4) The intracortical localization of 5-HT receptors will be mapped and correlated with regional and laminar patterns of 5-HT innervation. [The project employs highly sensitive neuroanatomic methods for anterograde and retrograde axonal transport in combination with transmitter immunocytochemistry, receptor autoradiography and electron microscopy.] This study should provide new information of clinical importance concerning the functional organization of MA neurons. These neuronal projections are thought to regulate cortical excitability and to be involved in several neuro-psychiatric disorders, particularly the dementias and affective disorders. Moreover, these experiments should help to elucidate the effects of particular drugs of abuse recently shown to be selectively cytotoxic to 5-HT axons.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurology B Subcommittee 1 (NEUB)
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Johns Hopkins University
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Wilson, M A; Molliver, M E (1994) Microglial response to degeneration of serotonergic axon terminals. Glia 11:18-34
Series, H G; Molliver, M E (1994) Immunocytochemical evidence for serotonergic neurotoxicity of N-ethyl-methylenedioxyamphetamine (MDE). Exp Neurol 128:50-8
Wilson, M A; Mamounas, L A; Fasman, K H et al. (1993) Reactions of 5-HT neurons to drugs of abuse: neurotoxicity and plasticity. NIDA Res Monogr 136:155-78;discussion 178-87
Mamounas, L A; Mullen, C A; O'Hearn, E et al. (1991) Dual serotoninergic projections to forebrain in the rat: morphologically distinct 5-HT axon terminals exhibit differential vulnerability to neurotoxic amphetamine derivatives. J Comp Neurol 314:558-86
Wilson, M A; Molliver, M E (1991) The organization of serotonergic projections to cerebral cortex in primates: retrograde transport studies. Neuroscience 44:555-70
Molliver, M E; Berger, U V; Mamounas, L A et al. (1990) Neurotoxicity of MDMA and related compounds: anatomic studies. Ann N Y Acad Sci 600:649-61;discussion 661-4
Molliver, M E; Mamounas, L A; Wilson, M A (1989) Effects of neurotoxic amphetamines on serotonergic neurons: immunocytochemical studies. NIDA Res Monogr 94:270-305
Blue, M E; Yagaloff, K A; Mamounas, L A et al. (1988) Correspondence between 5-HT2 receptors and serotonergic axons in rat neocortex. Brain Res 453:315-28
Mamounas, L A; Molliver, M E (1988) Evidence for dual serotonergic projections to neocortex: axons from the dorsal and median raphe nuclei are differentially vulnerable to the neurotoxin p-chloroamphetamine (PCA). Exp Neurol 102:23-36
Lyons, W E; Grzanna, R (1988) Noradrenergic neurons with divergent projections to the motor trigeminal nucleus and the spinal cord: a double retrograde neuronal labeling study. Neuroscience 26:681-93

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