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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS015199-07
Application #
3396049
Study Section
Neurology B Subcommittee 1 (NEUB)
Project Start
1979-03-01
Project End
1989-08-31
Budget Start
1986-09-01
Budget End
1987-08-31
Support Year
7
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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
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
O'Hearn, E; Battaglia, G; De Souza, E B et al. (1988) Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity. J Neurosci 8:2788-803
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

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