Postpartum regulation of CRFR1 and CRFR2 expression in oxytocin neurons

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Project Summary Psychological stress can profoundly impact maternal care and is associated with mental illnesses including postpartum depression and anxiety. Approximately 900,000 women suffer from postpartum depression and anxiety annually, resulting in devastating effects on the mother and developing child. Both oxytocin (OT) and corticotropin releasing factor (CRF) have been implicated in stress-related behavioral changes during the postpartum period. However, the precise mechanisms that control these changes, and the mechanisms through which the OT and CRF systems might interact to control behavioral changes, are largely unknown. We recently discovered that OT neurons of the mouse hypothalamus initiate expression of a receptor for CRF (CRFR1) during the postpartum period, whereas CRFR1 is absent from OT neurons in virgin mice. Our preliminary studies indicate the postpartum expression of CRFR1 in OT neurons modifies maternal care behaviors under conditions of stress. Our recent findings further suggest that the other primary receptor for CRF (CRFR2) also increases in OT neurons during the postpartum period. One critical issue that remains unknown is the factors that cause OT neurons to express CRF receptors. Therefore, the primary goal of this proposal (Aim 1) will be to determine the precise hormones and/or maternal experiences that induce this change. Specifically, we will treat virgin mice with pregnancy/postpartum period specific cocktails of estrogen/progesterone, prolactin, and glucocorticoids to determine the critical hormones that initiate CRFR1/CRFR2 expression in OT neurons. We will also determine whether specific experiences, including nursing and maternal care, can induce CRF receptor expression in OT neurons. Overall, experiments in Aim 1 will generate new hypotheses regarding the mechanisms through which dramatic maternal fluctuations in hormones and maternal experiences might impact the maternal brain and ultimately affect behaviors related to stress. In the second (smaller) aim we will perform a study to determine how expression of CRFR2 in OT neurons changes during the postpartum period. We recently found CRFR2 levels increase within OT neurons at a single timepoint (postpartum day 7) but how CRFR2 changes across the maternal period and whether these changes coincide temporally with alterations in CRFR1 is unknown. Therefore, this study will allow us to determine how (a) CRFR2 levels change across the postpartum period in mice and (b) whether CRFR2 and CRFR1 are present within the same OT neurons or in different subpopulations of OT neurons. These findings will be critical given that CRFR1 and CRFR2 commonly have opposing roles in regulation of stress responses and maternal behaviors. Thus, a shift in the balance of these two receptors could have profound impacts. Overall, experiments in this R03 proposal will aid in our understanding of neurobiological changes that occur during the maternal period and are associated human disorders including postpartum depression, anxiety, and poor parental care.