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 neurotransmitter (GABA, serotonin) specific and developmental stage (last prenatal week vs. third postnatal week) dependent effects of androgen deprivation. Further, as part of an effort to identify the mechanisms by which gonadal steroids influence brain development, we have performed studies of cell survival and intracellular signaling. We have observed the following: 1) rapid, estrogen-induced non-genomic reduction of levels of activated mitogen-activated protein kinases (MAPKs)in P3 astrocytes, associated with decreased DNA synthesis (decreased thymidine incorporation and decreased S phase entry) and decreased cell proliferation; 2) sexual dimorphisms in the signal response to estrogen, with females showing greater sensitivity to estrogen (greater inhibition of MAPK) and greater decrease in cell proliferation than males; 3) DHEA-induced increases in the serine-threonine kinase AkT (protein kinase B) associated with increased cell survival and occurring through non-androgen receptor or estrogen receptor mediated mechanisms in cultured neuronal precursors from embryonic forebrain; 4) gender-related, brain region specific, and developmental stage specific expression of cell survival proteins Bcl-2 and BAX in rat brain. 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). - dimorphism, serotonin, GABA, gonadal steroids, brain development
