Objectives of the project are as follows: first to identify sexual dimorphisms and the role of gonadal steroids 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. By performing in situ hybridization studies in rats during different stages of development, we have been able to demonstrate that gonadal steroids regulate the transcription of the GABA and serotonin receptor genes and, additionally that the effects of gonadal steroids differ as a function of developmental stage and receptor system: GABA receptor message is altered by prenatal androgen blockade, while serotonin receptor subtype message is altered by postnatal androgen (and metabolite) deprivation. Hormonal manipulations in these studies include castration and use of gonadal steroid receptor blocking agents (e.g. flutamide, the androgen receptor blocker). Since both serotonin and GABA systems have been described as playing a major role in directing brain development, perinatal alterations in gonadal steroids could influence brain development in general and gonadal steroid sensitive circuits in particular. The sexual dimorphisms and effects of gonadal steroids that we identified 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).
