A large number of sex differences in the central nervous systems (CNS) of vertebrates have now been described. Such morphological dimorphisms may underlie well documented sex differences in behavior, in susceptibility to certain drugs, and in the incidence of some human mental disorders including autism, depression and schizophrenia. In many cases, neural sex differences have been shown to be due to differential exposure to gonadal steroid hormones in males and females. However, the cellular and molecular mechanisms governed by hormones in the nervous system are not well understood. The identification and cloning of several new neurotrophic molecules has fueled an explosion of research into the actions of trophic molecules in the CNS, and recent findings indicate a role for neurotrophic factors in sexually dimorphic development. Experiments in the first half of this proposal will test the idea that effects of gonadal steroids are mediated by trophic factors in a well-characterized model system. The spinal nucleus of the bulbocavernosus (SNB) and its target muscles constitute an anatomically simple system that is sexually dimorphic in many mammals. SNB motoneurons reside in the lumbar spinal cord and innervate striated perineal muscles attached to the phallus. Androgens regulate SNB motoneuron survival during perinatal development, and SNB cell size in adulthood. Recent observations suggest that some effects of androgens on this system are mediated by protein neurotrophic factors. Trophic factor antagonists will be administered to developing and adult rats in order to identify endogenously produced factors controlling SNB cell survival and morphological plasticity. In the second half of this proposal, the intracellular events regulated by hormones and neurotrophic factors will be explored. Specifically, a role for the death-regulatory protein, Bcl-2, in sexually dimorphic cell death will be tested in the SNB and in the anteroventral periventricular nucleus (AVPV) of the hypothalamus. Because the neurotrophic factors and death-regulatory proteins to be examined are expressed throughout the nervous systems of many vertebrates, including humans, information gained from this work will be relevant to our overall understanding of the extracellular and intracellular molecules mediating hormone regulated development and plasticity in neural tissues.
