Objectives of the project are as follows: first to identify sexual dimorphisms and the role of gonadal steroids in the regulation of neural and glial signal transduction, proliferation, and survival and in the ontogeny of brain neurotransmitter systems; second, to resolve the mechanisms of both the acute (e.g. enhanced apoptosis) and subacute (e.g. altered neurotransmitter receptor message) neural effects of gonadal steroids; third, to determine the developmental-stage dependent neural consequences of gonadal steroids; and fourth, to identify the subsequent behavioral consequences of perinatal gonadal steroid manipulations. Exposure of the brain to gonadal steroids during critical periods of development appears responsible for sexual dimorphisms in the structure and function of the brain. In the past year, we have obtained evidence for sexual dimorphisms in both basal and stimulated levels of second messengers. Thus the same hormonal signal may elicit markedly different responses in brain cells from male and female rats. Findings include the following: 1) estradiol stimulates Maxi potassium channel activity in neurons from females but not males; 2) progesterone effects on cortical neurons are sexually dimorphic (increased neurites and neuritic outgrowth in males vs. neuritic regression in females); 3) progesterone increases neuronal GABA alpha-4 subunit expression in association with increased MAP kinase in cortical neurons in females but not in males; 4) the neurosteroids DHEA and DHEA-S have oppositve effects on AKt phosphorylation and cell survival (due to the presence of a negative substituent at C3). These data suggest that gonadal steroids are significant regulators of cell survival and differentiation in the developing brain, where they undoubtedly play a major role in the formation of gonadal steroid sensitive circuitry. Further, these data complement our demonstrations of sexually dimorphic, gonadal steroid-dependent, neurotransmitter receptor modulation, effects which may underlie the ability of perinatal manipulations of gonadal steroids to alter subsequent behavior (sex and aggression) and neuroendocrine function (e.g. the capacity to express cyclic gonadotropin secretion). Finally, studies of estrogen and progesterone receptors have been undertaken in human post-mortem studies to help define possible relevant circuitry for the expression of gonadal steroid-regulated behaviors.
