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.

项目概要 心理压力会深刻影响孕产妇护理，并与精神疾病相关，包括 产后抑郁和焦虑。大约90万女性患有产后抑郁症 每年都会产生焦虑，对母亲和发育中的孩子造成毁灭性影响。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，目前尚不清楚。我们最近 发现小鼠下丘脑的 OT 神经元启动 CRF 受体 (CRFR1) 的表达 产后期间，而原始小鼠的 OT 神经元中不存在 CRFR1。我们的初步研究 表明产后 OT 神经元中 CRFR1 的表达改变了产妇护理行为 的压力。我们最近的研究结果进一步表明，CRF 的另一个主要受体 (CRFR2) 在 产后期间的 OT 神经元。导致 OT 的因素仍然是未知的一个关键问题 神经元表达 CRF 受体。因此，本提案的主要目标（目标 1）是确定 导致这种变化的精确激素和/或母亲经历。具体来说，我们将治疗处女小鼠 怀孕/产后期特定的雌激素/黄体酮、催乳素和糖皮质激素混合物 确定在 OT 神经元中启动 CRFR1/CRFR2 表达的关键激素。我们还将确定 特定的经历，包括护理和产妇护理，是否可以诱导 OT 中的 CRF 受体表达 神经元。总体而言，目标 1 中的实验将产生关于其机制的新假设 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和 最终影响与压力相关的行为。在第二个（较小的）目标中，我们将进行一项研究以确定 产后期间 OT 神经元中 CRFR2 的表达如何变化。我们最近发现了 CRFR2 OT 神经元内的水平在单个时间点（产后第 7 天）增加，但 CRFR2 在整个过程中如何变化 产期的变化以及这些变化是否与 CRFR1 的变化在时间上一致尚不清楚。 因此，这项研究将使我们能够确定 (a) CRFR2 水平在产后期间如何变化 小鼠以及 (b) CRFR2 和 CRFR1 是否存在于相同 OT 神经元中或不同亚群中 OT 神经元。鉴于 CRFR1 和 CRFR2 通常在 压力反应和母亲行为的调节。因此，这两种受体平衡的转变可能 产生深远的影响。总的来说，R03 提案中的实验将有助于我们理解神经生物学 产妇期间发生的变化，与人类疾病相关，包括产后 抑郁、焦虑和父母照顾不佳。