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) sexual dimorphisms in the distribution (cortex), concentration (hippocampus), and timing of appearance (hypothalamus) of cell survival regulators BAX and Bcl-2; 2) differential effects of estradiol and testosterone on cultured E14 cortical neurons, with estradiol increasing and testosterone decreasing both the differentiation and number of neurons (with no effects on proliferation); 3) rapid (10 minutes) reduction by estradiol of phosphorylated mitogen-activated protein kinases (MAPKs) p42 and p44 in both male and female astrocytes; 4) gradual (24 and 48 hours) reduction by estradiol of dATP levels in female but not male astrocytes. 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).
