The long-term objective of the proposed work is to identify and characterize at high resolution the structure and chemistry of neural circuits in the mammalian brain that underlie the basic drives and emotions keeping individuals alive and assuring survival of the species associated with hunger and thirst, defensive (fight or flight) behavior, reproductive (sexual and parental) behavior, and the sleep/wake cycle. Previous work identified the hypothalamus as a critical node in this circuitry, and characterized in detail axonal input/output relationships of its medial half with the pituitary gland, cerebral hemispheres, and brainstem/spinal cord. The proposed work is designed to complete in a systematic way, and to extend, a similar analysis of the lateral hypothalamus, and is based on the hypothesis that the lateral hypothalamus consists of two fundamentally different components, a dorsal region with widespread, diffuse projections to much of the central nervous system, and a surrounding compartmentalized region divided into some two dozen parts with very specific projection patterns to specific functional systems. The three specific aims are, a) to complete a phase one, regional analysis of the surrounding compartmentalized region; b) to begin a phase two, neuronal cell type analysis, starting with certain lateral hypothalamic regions apparently involved critically in food appetite regulation; and c) to facilitate the entry of neuroanatomical data into neuroinformatics workbenches on the web. The research is based on the combined use in rats of experimental intra-axonal pathway tracing methods, and hybridization histochemistry for the cell type-specific expression of neurotransmitter-related genes. There is a rich clinical and experimental history, dating back over a century, that disturbances of the hypothalamus, and parts of the brain interacting with the hypothalamus, produce depending on localization either obesity or anorexia, profound effects on cardiovascular and endocrine (for example, blood glucose) measures, anxiety and mood, aggressive behavior, sexual behavior and physiology (for example, the menstrual cycle), and disturbances of normal sleep and wakefulness patterns. The proposed research is designed to clarify very poorly understood neural circuits that mediate normal ingestive, defensive, reproductive, and sleep/wake behaviors; understanding their pathology will follow. ? ? ?
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