Postpartum regulation of CRFR1 and CRFR2 expression in oxytocin neurons

项目摘要 心理压力会深刻影响孕产妇护理，并与精神疾病有关， 产后抑郁和焦虑大约90万妇女患有产后抑郁症， 每年都有焦虑，对母亲和发育中的孩子造成毁灭性的影响。催产素（OT）和 促肾上腺皮质激素释放因子（CRF）与应激相关的行为变化有关， 产后时期然而，控制这些变化的精确机制以及通过这些变化的机制 OT和CRF系统可能相互作用以控制行为变化，这在很大程度上是未知的。我们最近 发现小鼠下丘脑的OT神经元启动CRF受体（CRFR 1）的表达， 在产后期间，而CRFR 1是缺乏的OT神经元在处女小鼠。我们的初步研究 这表明，在一定条件下，OT神经元中CRFR 1的产后表达会改变产妇的护理行为。 压力我们最近的研究结果进一步表明，CRF的另一种主要受体（CRFR 2）也在慢性肾功能衰竭中增加。 催产素神经元在产后期间。一个仍然未知的关键问题是导致OT的因素 神经元表达CRF受体。因此，本提案的主要目标（目标1）将是确定 精确的荷尔蒙和/或母亲的经验，诱导这种变化。具体来说，我们将对待处女小鼠 妊娠/产后期雌激素/孕激素、催乳素和糖皮质激素的特定混合物， 确定在OT神经元中启动CRFR 1/CRFR 2表达的关键激素。我们还将确定 是否特定的经验，包括护理和产妇护理，可以诱导CRF受体表达在OT 神经元总的来说，目标1中的实验将产生关于机制的新假设， 母亲荷尔蒙和母亲经历的剧烈波动可能会影响母亲的大脑， 最终影响与压力有关的行为。在第二个（较小的）目标中，我们将进行研究，以确定 CRFR 2在OT神经元中的表达在产后期间如何变化。我们最近发现CRFR 2 水平增加OT神经元在一个单一的时间点（产后7天），但如何CRFR 2的变化在整个 尚不清楚这些变化是否与CRFR 1的改变在时间上一致。 因此，这项研究将使我们能够确定（a）产后期间CRFR 2水平如何变化， 和（B）CRFR 2和CRFR 1是否存在于相同的OT神经元内或不同的亚群中 OT神经元这些发现将是至关重要的，因为CRFR 1和CRFR 2通常具有相反的作用， 压力反应和母性行为的调节。因此，这两种受体平衡的变化可能 影响深远。总的来说，R 03提案中的实验将有助于我们理解神经生物学。 发生在母亲时期的变化，与人类疾病相关，包括产后 抑郁焦虑和父母照顾不周

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.