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

生命早期和成年应激及其相互作用对生殖神经内分泌控制的调节

• 批准号: 10588132
• 负责人: Amanda Gail Gibson
• 金额: $ 4.09万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588132
• 关键词: Acute; Adrenal Cortex; Adult; Affect; Age at Menarche; Animal Model; Beds; Behavioral; Biological; Brain; Cell Nucleus; Cell physiology; Cells; Conceptions; Corticosterone; Corticotropin; Corticotropin-Releasing Hormone; Cues; Data; Development; Diestrus; Electrophysiology (science); Emotional; Ensure; Environment; Estradiol; Feedback; Female; Fertility; Follicle Stimulating Hormone; Frequencies; Future; GNRH1 gene; Genetic; Glucocorticoids; Goals; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Hormones; Human; Hypothalamic structure; Impairment; Individual; Interruption; KISS1 gene; Lead; Life; Luteinizing Hormone; Maps; Mediating; Mediator; Modeling; Mus; Nature; Neurobiology; Neurohormones; Neurons; Neuropeptides; Neurosecretory Systems; Output; Ovulation; Pathway interactions; Physiologic pulse; Physiological; Pituitary Gland; Pituitary-Adrenal System; Play; Population; Predisposition; Probability; Proestrus; Property; Psychosocial Stress; Reaction; Recording of previous events; Reproduction; Reproductive system; Rodent; Rodent Model; Role; Shapes; Signal Transduction; Slice; Stress; Stress Tests; Synapses; Synaptic Transmission; System; Testing; Time; Ventricular; Whole-Cell Recordings; acute stress; adverse childhood events; biological adaptation to stress; design; early life stress; high risk sexual behavior; in vivo; insight; mouse model; neural circuit; neurobiological mechanism; neuromechanism; neuronal excitability; paraventricular nucleus; pituitary gonadal axis; prevent; programs; proliferative phase Menstrual cycle; receptor; reproductive; reproductive axis; reproductive outcome; resilience; response; sex; social health determinants; stressor; therapeutic target; tool

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.

项目概要 不良童年经历（ACE）对生理发育具有深远的影响， 健康的重要社会决定因素。 ACE 可以改变生殖结果，包括初潮年龄、 从事危险的性行为和生育能力。早年的压力也会塑造一个人的生活方式 对成年期的压力做出反应，提高对以后压力的弹性或敏感性。成人的压力有 已被独立证明会破坏生育能力。两个神经内分泌轴在调节两者方面发挥着关键作用 应激反应（下丘脑-垂体-肾上腺 [HPA] 轴）和生殖（下丘脑-垂体- 性腺 [HPG] 轴）。促肾上腺皮质激素释放激素（CRH）是主要的中枢神经激素 HPA 轴的下丘脑成分，由室旁核 (PVN) 神经元释放。 CRH也 作为 PVN 外部的信号传导神经肽，调节应激反应的其他组成部分 包括情感和行为方面。促性腺激素释放激素 (GnRH) 神经元 下丘脑是生殖中央控制的最终共同通路。 GnRH 神经元接收 来自许多传入群体的输入，包括前腹侧室周核中的 Kisspeptin 神经元 （AVPV）。 GnRH 导致黄体生成素 (LH) 和卵泡刺激素 (FSH) 的释放 脑下垂体，从而刺激性类固醇的合成。在女性中，雌二醇从负值转变为 排卵前阶段的正反馈作用，导致 GnRH 和 LH 释放激增， 促进排卵。至关重要的是，急性压力会破坏 LH 激增，而这种破坏可能涉及 CRH 神经元。研究急性应激破坏 LH 激增的神经机制，并确定 如果 ACE 的历史能够调节这种现象，我们必须求助于动物模型。啮齿动物模型共享核心 人类生殖系统的组成部分，并且它们允许使用遗传工具来审问 生物电路。在这里，我们将使用有限的铺垫和筑巢（LBN）模型来应对早期生活的压力和 成人压力的急性、分层、心理社会压力（ALPS）范式。在目标 1 中，我们将研究这些 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，对应 LH 激增的时间。这一目标还将检验以下假设： LBN 模型的早期生命压力赋予了对成年期生殖急性压力影响的恢复能力。 在目标 2 中，将采用视紫红质通道辅助电路测绘 (CRACM) 来询问功能 CRH 和 GnRH 神经元与 AVPV Kisspeptin 神经元之间的连接。体内化学遗传学工具将 解决投射到 AVPV 的 CRH 神经元的激活是否足以破坏 LH 激增和 压力对于扰乱发情前期的激增是必要的。拟议的研究将为以下问题提供重要见解： 压力和生殖轴之间的神经生物学相互作用，增强了我们对 压力导致负面生殖结果的机制并指导未来的治疗目标。