Modulation of the neuroendocrine control of reproduction by early-life and adult stress and their interactions

项目摘要 不良童年经历(ACE)对生理发育有深远的影响， 健康的一个重要的社会决定因素。ACE可以改变生育结果，包括月经初潮年龄， 参与危险的性行为和生育。早年的压力也会塑造一个人 对成年后的压力做出反应，提高对以后压力的适应能力或易感性。成人的压力有 已经被独立证明会扰乱生育。两个神经内分泌轴在调节两者中起着关键作用 应激反应(下丘脑-垂体-肾上腺[HPA]轴)和生殖(下丘脑-垂体-肾上腺轴) 性腺[HPG]轴)。促肾上腺皮质激素释放激素(CRH)是高血压的主要中枢神经激素。 HPA轴的下丘脑组成部分，由室旁核(PVN)中的神经元释放。CRH还 作为下丘脑室旁核外的信号神经肽，调节应激反应的其他成分 包括情感和行为方面。促性腺激素释放激素(GnRH)神经元 下丘脑是生殖中枢控制的最终共同途径。促性腺激素释放激素神经元接收 来自许多传入群体的输入，包括前腹侧脑室周围核中的Kispeptin神经元 (AVPV)。促性腺激素释放激素(GnRH)导致黄体生成素(LH)和卵泡刺激素(FSH)从 脑下垂体，从而刺激性类固醇的合成。在女性中，雌二醇从负值转换为 排卵前阶段的正反馈作用，导致促性腺激素释放激素和促黄体生成素释放激增 促进排卵。关键的是，急性应激可以扰乱这种促黄体生成素的激增，这种扰乱可能涉及CRH。 神经元。探讨急性应激扰乱黄体生成素峰值的神经机制，并确定 如果ACEs的历史调整了这一现象，我们必须转向动物模型。啮齿动物模型共享核心 人类生殖系统的组成部分，它们允许使用遗传工具来审问 生物回路。在这里，我们将使用有限床上用品和筑巢(LBN)模型来应对早期生活压力和 成人压力的急性、分层、心理社会压力(ALPS)范例。在目标1中，我们将调查这些 应激源改变GnRH神经元的固有电生理特性和快速突触输入 发情前期的下午，与黄体生成素高峰的时间相对应。这一目标也将检验这样一个假设： LBN模型的早期生活应激对成年后急性应激对生殖的影响具有韧性。 在目标2中，将使用通道视紫红质辅助电路映射(CRACM)来询问功能 促肾上腺皮质激素释放激素和促性腺激素释放激素神经元与动静脉曲张蛋白神经元的联系。体内化学发生工具将 讨论投射到AVPV的CRH神经元的激活是否足以扰乱LH峰和 这是压力扰乱发情前期激增所必需的。拟议的研究将提供对 应激和生殖轴之间的神经生物学相互作用，增强了我们对 应激导致负面生殖结果的机制和指导未来治疗目标。

Project Summary Adverse childhood experiences (ACEs) have profound consequences for physiological development and are an important social determinant of health. ACEs can alter reproductive outcomes including age at menarche, engagement in risky sexual behaviors, and fertility. Early-life stress can also shape the way an individual responds to stress in adulthood, promoting either resiliency or susceptibility to later stress. Adult stress has been independently demonstrated to disrupt fertility. Two neuroendocrine axes play key roles regulating both the stress response (hypothalamo-pituitary-adrenal [HPA] axis) and reproduction (hypothalamo-pituitary- gonadal [HPG] axis). Corticotropin-releasing hormone (CRH) is the main central neurohormone for the hypothalamic component of the HPA axis, released by neurons in the paraventricular nucleus (PVN). CRH also serves as a signaling neuropeptide outside of the PVN, regulating other components of the stress response including emotional and behavioral aspects. Gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus are the final common pathway for the central control of reproduction. GnRH neurons receive input from many afferent populations, including kisspeptin neurons in the anteroventral periventricular nucleus (AVPV). GnRH leads to the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland, thus stimulating synthesis of sex steroids. In females, estradiol switches from a negative to positive feedback action during the preovulatory stage, leading to a surge in GnRH and LH release that promotes ovulation. Critically, acute stress can disrupt this LH surge, and this disruption may involve CRH neurons. To investigate the neural mechanisms by which acute stress disrupts the LH surge, and to determine if a history of ACEs modulates this phenomenon, we must turn to animal models. Rodent models share core components of the reproductive system with humans, and they permit the use of genetic tools to interrogate biological circuits. Here, we will use a limited bedding and nesting (LBN) model for early-life stress and an acute, layered, psychosocial stress (ALPS) paradigm for adult stress. In Aim 1, we will investigate how these stressors alter the intrinsic electrophysiological properties of and fast-synaptic input to GnRH neurons on the afternoon of proestrus, corresponding to the timing of the LH surge. This aim will also test the hypothesis that early-life stress of the LBN model confers resilience to the effects of acute stress on reproduction in adulthood. In Aim 2, channelrhodopsin-assisted circuit mapping (CRACM) will be employed to interrogate the functional connection between CRH and GnRH neurons and AVPV kisspeptin neurons. In vivo chemogenetic tools will address if activation of CRH neurons that project to the AVPV is sufficient to disrupt the LH surge and necessary for stress to disrupt the surge on proestrus. The proposed studies will provide key insights into the neurobiological interactions between the stress and reproductive axes, enhancing our understanding of the mechanisms by which stress leads to negative reproductive outcomes and guiding future therapeutic targets.