The sexual differentiation of the brain is of fundamental significance yet the mechanisms of gonadal hormone action are unknown. A recent advance has been the discovery that structural sex differences exist in the brain, which are dependent upon hormones perinatally, and may underlie the functional sexual differentiation of the brain. The research continues to be focused on the most marked structural sex difference, the Sexually Dimorphic Nucleus of the Preoptic Area (SDN-POA).
Four Specific Aims are proposed. 1. Characterize the development of the SDN-POA and its modification by the hormonal and neurochemical environment. Temporal windows and dose requirements for steroid action in modifying SDN-POA volume will be determined in several preparations in which SND-POA volume is predictably altered. In addition, the influence of the hormonal environment on characteristics of individual neurons will be determined, including size, the number of neurons specifically and permanently labeled autoradiographically by exposure to tritiated thymidine on embryonic day 18, and the development of receptors for cholecystokinin and selective opiates as determined by the autoradiographic analysis of in vitro binding. 2. Elucidate the mechanisms of steroid action. Two approaches are proposed: to verify the pathway of migration taken by SDN-POA neurons and determine the influence of the hormonal environment, and an analysis of the development of the ability of neuroblasts, migrating or postmitotic neurons to take up and retain estrogen. Both approaches will utilize autoradiography: the first will focus on neurons permanently labeled by tritiated thymidine, and the second, the uptake of tritiated moxestrol. 3. Establish the functional role of the SDN-POA in reproduction by utilizing both the destruction and stimulation of the SDN-POA. 4. Compare and contrast the development of the anteroventral periventricular nucleus (AVPV). Available data suggest that the AVPV is structurally sexually dimorphic in a direction opposite to that of the SDN-POA. Moreover, steroids may be inhibitory to the development and differentiation of this nucleus. Since the AVPV is just rostral to the SDN-POA, both nuclei can be studied in the same animal under the same conditions to challenge the universality of the hypothesis that gonadal steroids are neuronotrophic during the process of sexual differentiation. Collectively, the proposed research represents a multifaceted study of the influence of gonadal hormones on the development, structure and reproductive function of the rat hypothalamus.
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