This proposal addresses an issue critically important to the study of mental health: the effects of the maternal/fetal interaction on the development of the brain and subsequent adult behavior. Exposure to gonadal steroid hormones during prenatal life has dramatic consequences on the development of the brain and behavior. While the effects of exposure to estrogen and androgens during development are well documented, almost no information exists on the role of progesterone on neural development and behavior. Fetuses are normally exposed to maternal circulating hormones, including progesterone, the levels of which undergo rapid and extreme changes prior to parturition and during lactation. The children of millions of women in the U.S. who were treated with progesterone during pregnancy to prevent miscarriage show a variety of physical, psychological and behavioral effects.Yet, the developmental effects of perinatal exposure to maternal progesterone remains grossly understudied. The main objective of this proposal is to determine whether the uniquely high levels of progesterone in the maternal-circulation during pregnancy and postpartum can alter the steroid sensitivity of the brain of the offspring during development and/or adult life and thereby alter subsequent hormone- dependent behaviors in adulthood.
Specific Aim I will examine when during prenatal life the fetal brain first becomes sensitive to progesterone. Using immunocytochemistry it will be determined when neurons in the fetal brain first begin to express nuclear receptors for progesterone and whether progesterone receptor levels are regulated during neural development.
Specific Aim II will use steroid hormone autoradiography to verity that radiolabelled progesterone in maternal circulation can cross the placenta and the fetal blood/brain barrier to bind to nuclear steroid receptors within the fetal brain. In addition, the circulating levels of progesterone in fetuses and the source of the progesterone will be examined.
Specific Aim III will examine the effects of pre-and postnatal exposure to progesterone from maternal circulation on the display of steroid hormone dependent behaviors in the adult offspring.
Specific Aim I V will examine whether perinatal exposure to progesterone can alter the brains sensitivity to steroid hormones during either neural development or adulthood by altering the expression of progesterone and/or estrogen receptors in brain regions known to be the neural targets for progesterone and estrogen action in the display of hormone-dependent behaviors. The results from these experiments will provide insight as to the role of maternal progesterone in the development of the fetal brain and the expression of critical reproductive behaviors in adulthood.
