Postpartum regulation of CRFR1 and CRFR2 expression in oxytocin neurons

催产素神经元 CRFR1 和 CRFR2 表达的产后调节

• 批准号: 10740490
• 负责人: Damian Gabriel Zuloaga
• 金额: $ 15.65万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT ALBANY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740490
• 关键词: Affect; Anxiety; Anxiety Disorders; Behavior; Behavior Control; Behavioral; Birth; Brain; CRF receptor type 1; CRF receptor type 2; Caring; Child; Collection; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Data; Discipline of Nursing; Disease; Equilibrium; Estrogens; FOS gene; Female; Glucocorticoids; Goals; Hormones; Human; Hypothalamic structure; Maternal Behavior; Mental disorders; Modification; Mothers; Mus; Neurobiology; Neurons; Neuropeptides; Neurosecretory Systems; Oxytocin; Pattern; Phase; Pilot Projects; Play; Postpartum Depression; Postpartum Period; Pregnancy; Process; Progesterone; Prolactin; Psychological Stress; Regulation; Rodent; Role; Signal Transduction; Stress; System; Woman; behavior change; biological adaptation to stress; design; experience; experimental study; neurobiological mechanism; receptor; receptor expression; reproductive; restraint stress

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.

项目摘要 心理压力会对孕产妇护理产生深远的影响，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和 每年焦虑，对母亲和成长中的孩子造成毁灭性影响。催产素（OT）和 皮质激素释放因子（CRF）与压力相关的行为变化有关 产后期。但是，控制这些变化的确切机制以及通过 OT和CRF系统可能会相互作用以控制行为变化，这在很大程度上未知。我们最近 发现小鼠下丘脑的OT神经元引发了CRF受体的表达（CRFR1） 在产后期间，维尔京小鼠的OT神经元不存在CRFR1。我们的初步研究 指示OT神经元中CRFR1的产后表达在条件下修饰孕妇护理行为 压力。我们最近的发现进一步表明，CRF的其他主要受体（CRFR2）也增加了 产后神经元。尚不清楚的一个关键问题是导致ot的因素 神经元表达CRF受体。因此，该提案的主要目标（AIM 1）将是确定 精确的激素和/或产妇体验会引起这种变化。具体来说，我们将对待维尔京老鼠 雌激素/孕酮，催乳素和糖皮质激素的怀孕/产后特定鸡尾酒 确定在OT神经元中启动CRFR1/CRFR2表达的临界激素。我们还将确定 特定的经验（包括护理和孕产妇护理）是否可以在OT中诱导CRF受体表达 神经元。总体而言，AIM 1中的实验将产生有关机制的新假设 激素和母性体验中产妇的戏剧性波动可能会影响母亲的大脑和 最终影响与压力有关的行为。在第二个（较小）的目标中，我们将进行一项研究以确定 OT神经元中CRFR2在产后时期的表达如何变化。我们最近发现CRFR2 在单个时间点（产后第7天），OT神经元内的水平增加 产妇时期以及这些变化是否与CRFR1的变化相吻合是未知的。 因此，这项研究将使我们能够确定（a）在产后整个产后的CRFR2水平在 小鼠和（b）CRFR2和CRFR1是否存在于相同的OT神经元内还是在不同的亚群中 OT神经元。考虑到CRFR1和CRFR2通常在 调节压力反应和孕产妇行为。因此，这两个受体的平衡可以转移 产生深远的影响。总体而言，该R03提案中的实验将有助于我们理解神经生物学 在母亲时期发生的变化，与包括产后在内的人类疾病有关 抑郁，焦虑和父母不良护理。