The widespread efferent projections of serotonergic (5HT) neurons of the brain stem raphe nuclei suggest that this nuclear complex is capable of influencing the activity of extensive regions of the central nervous system (CNS). Inasmuch as alterations in 5HT function have been hypothesized as a major factor in a variety of psychiatric illnesses, it is important to form a more comprehensive view of the functional role of 5HT in the CNS. The area dentata of the hippocampal formation offers a promising model for the study of 5HT function because of its stereotypic structure and relatively simple synaptic organization. Moreover, previous studies have demonstrated a lesion-induced proliferation and migration of 5HT afferents to the area dentata which could prove valuable for the study of the normal role of 5HT in the CNS and as a unique model of 5HT dysfunction. The long term goal of this laboratory is to utilize this modified 5HT innervation of the area dentata in studies to broaden the understanding of the physiological role of 5HT in the transmission of neural signals. Moreover, this model will be used to study possible interactions of 5HT with other transmitters. Since the lesion-induced proliferation and migration of 5HT afferents must be well characterized before it becomes a valuable experimental tool, the present study is designed to define the nature of this modified 5HT projection at various stages during its evolution. The proposed experiments will examine the area dentata to determine regional changes in the 5HT plexus of normal rats and in rats studied 2, 6, 8, 12, and 20 weeks after lesions of the median raphe nucleus with 5,7 dihydroxytryptamine. The role of the hilar neurons in the induction and guidance of the proliferation of 5HT axons will be evaluated by the selective removal of the polymorphic neurons by kainic acid prior to the median raphe lesion. Anatomical experiments will be performed using 5HT immunocytochemistry alone and in combination with GAD immunocytochemistry. Qualitative and quantitative light and electron microscopy will be used to analyze the results of neuroanatomical experiments. High pressure liquid chromatography and 5HT uptake analysis will also be used to provide data regarding 5HT and 5 hydroxylindoleacetic acid concentrations and terminal membrane density, respectively.
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