The events of pregnancy and lactation exert long-lasting changes on neurobiological processes in female mammals. These neuroplastic changes include shifts in neurochemical sensitivity, anatomical substrates, hormonal regulation, and behaviors such as anxiety and maternal behavior. The purpose of this exploratory proposal is to examine how prior reproductive experience, i.e. parity, may alter both central responsiveness to estrogenic regulation of maternal behavior and neural connectivity. It is hypothesized that prior reproductive experience consisting of pregnancy and lactation enhances estrogen receptor alpha (ER-?) activities in key neural sites that contribute to the long-term expression of maternal responsiveness and likely other estrogen-mediated processes later in adulthood. The project employs a combination of genetic (knockout), pharmacological, behavioral, and neuroimaging approaches to elucidate how parity alters neural responsiveness in the adult female rat. In addition to examination of the roles of pregnancy and lactation using this parity model, the neural status of females with only offspring care, but no reproductive experience, will be evaluated using fMRI. This combined innovative approach using gene knockouts, fMRI, and behavioral testing is critical because it will identify central changes and neural modifications produced by prior reproductive experience and provide a foundation for possible interventions in cases of inadequate mothering. These studies are important because the purported neuroplastic changes induced by the events of pregnancy and lactation can impact estrogen responsivity and related neural processes associated not only with the specific expression of normal and maladaptive maternal care, but more broadly in the ensuing emotional regulation throughout the lifetime of the adult female.
The focus of this proposal is on the possible long-term increase in neural sensitivity to estrogens induced by pregnancy and lactation and how reproductive experience, possibly through an estrogenic mechanism, affects brain connectivity and activity. The project uses the rat as an animal model to delineate potential causal relationships among these factors. Approaches include the use of estrogen receptor-alpha knockout rats, estrogen antagonists, fMRI, and behavioral testing. These studies will allow us to test the hypothesis that prior pregnancy and lactation enhance estrogen receptor (alpha)-regulated maternal care on a permanent basis. Moreover, shifts in neural activation and connectivity induced by prior parity and maternal care itself will be identified using neuroimaging (fMRI). Identification of neuroplastic changes in hormone- regulated responses will enhance our understanding of neural mechanisms that mediate normative maternal care as well as behavioral disorders, notably depression, across the female's lifespan.
