The influence of steroid hormones on basic mechanisms of neuronal development will be studied in a unique model system, the Sexually Dimorphic Nucleus of the Preoptic Area (SDN-POA) of the rat hypothalamus. Although the SDN-POA of the male rat contains more neurons and is about five times larger in overall volume than the corresponding nucleus of the female, the key to the proposed studies is that this morphological sex difference is influenced by the perinatal hormone environment. In fact, prolonged treatment of the female with testosterone propionate perinatally actually sex-reverses the brain of the female in terms of SDN-POA volume and neuronal number. This ability to determine the development of the SDN-POA by manipulating the hormone environment provides a novel opportunity to study the regulation of neurogenesis, neuronal migration and neuronal survival during a perinatal period of neuronal death. This proposal will be focused on the latter parameter which currently is considered the most likely mechanism by which steroids influence neuronal development. We will identify the specific period of cell death during perinatal development and quantify differences in this process in males, females and the female in which the SDN-POA is sex-reversed by steroids. We will also determine the anatomical sites of cell death by comparing its incidence in the SDN-POA, a control region, and along the pathway of migration the neurons of the SDN-POA take from their ependymal origin to the nucleus. During this specific perinatal period we will evaluate the ultrastructure of neurons, glia and neuropil in those areas where cell death occurs. Parameters of intracellular (e.g., number of organelles, membrane surfaces) and intercellular (e.g., synapse number and type, fraction of neuronal surface occupied by synaptic contacts, neuropil volume and characteristics) maturation will be measured by quantitative morphometrics in males, females and the sex-reversed female to describe the ultrastructural changes which precede cell death and identify the morphological correlates of steroid action which promotes neuronal survival. Since hormones may serve as critical growth factors for neurons, the proposed studies should contribute new information which will lead to greater understanding of the interaction between genomic and environmental factors during normal brain development and serve as the foundation for an understanding of abnormal brain development and function.
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