Progesterone & Sexual Differentiation of the Brain

This proposal addresses an issue critically important to the study of mental health: the effect of the maternal/fetal interaction on the development of sex differences in the brain. Sex differences in brain structure and function presumably underlie behavioral differences between males and females. Fetal testosterone directs the sexual differentiation of the brain and subsequent behavior. However, fetuses are also exposed to maternal progesterone which readily crosses the placenta and is presumably present in mother's milk. Progestin receptor expression in the medial preoptic nucleus (MPN) of fetal and neonatal rats is high in males but virtually absent in females. The MPN is one of the most sexually dimorphic structures in the rat brain and mediates several sexually differentiated behaviors. This suggests that maternal progesterone may play a previously overlooked role in the sexual differentiation of the CNS. The main objective of this proposal is to elucidate the role of progesterone and its receptor in the development of sex differences in the brain. Specific Aims I and II will address previously unanswered questions regarding the ontogeny and hormonal regulation of the progestin receptor in the fetal and neonatal brain. Specific Aim III will determine the relationship between circulating progesterone in fetuses/neonates and their mothers and will empirically determine whether progesterone in maternal circulation can cross the placenta and bind to nuclear receptors within the neurons of the fetal brain. Specific Aim IV will examine if the sex difference in PR in the MPN regulates sex differences known to exist in the expression of other steroid receptors. Specific Aim V will test the hypothesis that progesterone plays an important role in prevention of programmed neuronal death, a cellular/molecular mechanism critical to the sexual differentiation of the MPN. The experiments proposed in this application have clinical implications for mental health as well. The children of women in the U.S. treated with progestins during pregnancy for the prevention of miscarriage, exhibit a variety of psychological and behavioral effects. Yet, the developmental effects of perinatal exposure to maternal progesterone remains grossly understudied. Results from these studies could dramatically change our thinking about how sex differences in the brain are formed. Through this work an influential role of the mother in the sexual differentiation of the brain and behavior may be revealed.