Suprachiasmatic nucleus to kisspeptin circuit in the circadian control of reproduction

视交叉上核至 Kisspeptin 回路在生殖昼夜节律控制中的作用

• 批准号: 10660156
• 负责人: Richard Piet
• 金额: $ 34.2万
• 依托单位: KENT STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-05 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660156
• 关键词: Action Potentials; Address; Anatomy; Area; Argipressin; Automobile Driving; Axon; Behavior; Brain; Cell Nucleus; Cells; Circadian Rhythms; Cues; Data; Diurnal Rhythm; Electrophysiology (science); Ensure; Equilibrium; Estrogen Receptor alpha; Estrogens; Estrous Cycle; Event; Exhibits; Female; Fertility; Foundations; Future; GNRH1 gene; Goals; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Hormone secretion; Hour; Human; Hypothalamic structure; Immunohistochemistry; KISS1 gene; Knowledge; Luteinizing Hormone; Mediating; Neurons; Neuropeptides; Neurosecretory Systems; Output; Ovulation; Pattern; Physiological; Physiology; Play; Population; Preoptic Areas; Preparation; Proestrus; Publishing; Receptor Signaling; Regulation; Reporting; Reproduction; Research; Rodent; Role; Sex Behavior; Signal Transduction; Slice; Synapses; Testing; Third ventricle structure; Time; Ventricular; Woman; Work; argipressin receptor; circadian; circadian pacemaker; circadian regulation; gamma-Aminobutyric Acid; neural circuit; neuromechanism; neuronal circuitry; neurotransmission; optogenetics; ovarian dysfunction; presynaptic; reproductive success; response; suprachiasmatic nucleus

The circadian clock is a fundamental regulator of many aspects of physiology and behavior, including reproduction. Reproductive success depends on appropriate daily timing of neuroendocrine events that control ovulation. Kisspeptin (Kiss1) neurons in the preoptic area (POA) of the hypothalamus play a critical role in this by driving the activity of downstream gonadotropin-releasing hormone (GnRH) neurons to generate the surge in GnRH and LH secretion that triggers ovulation. The surge in rodents is timed by the central circadian clock in the suprachiasmatic nucleus (SCN) to initiate just before the onset of diurnal activity, ensuring that ovulation, which occurs a few hours later, coincides with sexual behavior. Projections from the SCN provide timing signals to the GnRH neuronal network, including to POA Kiss1 neurons. Indeed, reports indicate that arginine vasopressin (AVP)-expressing SCN neurons may play a key role in daily timing of the surge by activating POA Kiss1 neurons. Our prior published studies provide evidence that SCN projections release AVP to stimulate POA Kiss1 neuron electrical activity, and that this circuit is most effective in driving Kiss1 neuron activity on the day the surge occurs. Recently, we have obtained exciting preliminary data that indicate that a distinct SCN population releases GABA and inhibits Kiss1 neuron activity. These new observations, along with our published work, reveal that SCN neurons may bidirectionally control the electrical activity of Kiss1 neurons, through the release of GABA and AVP. This has led us to hypothesize that a shift in the balance of SCN-derived AVP- mediated excitation and GABA-mediated inhibition contributes to gating the activation of POA Kiss1 neurons for the surge. We will employ a combination of anatomical and functional approaches to address this central hypothesis. Our first aim will be to establish that SCN neurons directly project to and release GABA on POA Kiss1 neurons using brain slice electrophysiology and optogenetics. Further, we will determine the functional impact of GABA release on Kiss1 neuron electrical activity across the estrous cycle. In the second aim, we will use tract-tracing and immunohistochemical approaches to establish that SCN neuron projections target those POA Kiss1 cells that are involved in the surge and determine the identity of the cells that contribute these projections as well as their activation patterns prior to the surge. In our third aim, we will first assess the electrical activity of SCN neuronal populations in the hours that precede the preovulatory surge. Using this information, we will then determine how Kiss1 neurons integrate SCN timing signals, mediated through GABA and AVP release, on the day of the surge. Together, this research will provide new information about the circadian control of reproduction, and specifically the daily timing of the neuroendocrine events that trigger ovulation. A better understanding of the neural mechanisms responsible for circadian regulation of these circuits under physiological conditions may open new avenues for potential future treatments of ovulatory dysfunction.

生物钟是生理和行为许多方面的基本调节器，包括 生殖。生殖成功取决于每天控制神经内分泌事件的适当时间 排卵。下丘脑视前区 (POA) 的 Kisspeptin (Kiss1) 神经元在此过程中发挥着关键作用 通过驱动下游促性腺激素释放激素 (GnRH) 神经元的活动来产生激增 GnRH 和 LH 分泌触发排卵。啮齿类动物的激增是由中央生物钟控制的 视交叉上核 (SCN) 在昼间活动开始前启动，确保排卵、 这发生在几个小时后，与性行为同时发生。 SCN 的投影提供时序信号 GnRH 神经元网络，包括 POA Kiss1 神经元。事实上，报告表明精氨酸 表达加压素（AVP）的 SCN 神经元可能通过激活 POA 在每日激增时间中发挥关键作用 Kiss1 神经元。我们之前发表的研究提供了 SCN 预测释放 AVP 来刺激 POA 的证据 Kiss1 神经元电活动，并且该电路在当天驱动 Kiss1 神经元活动方面最有效 发生浪涌。最近，我们获得了令人兴奋的初步数据，表明独特的 SCN 群体释放 GABA 并抑制 Kiss1 神经元活动。这些新的观察结果以及我们发表的 工作表明，SCN 神经元可能通过以下方式双向控制 Kiss1 神经元的电活动： GABA 和 AVP 的释放。这使我们推测 SCN 衍生的 AVP 的平衡发生了变化 介导的兴奋和 GABA 介导的抑制有助于门控 POA Kiss1 神经元的激活 激增。 我们将采用解剖学和功能学相结合的方法来解决这个核心问题 假设。我们的首要目标是确定 SCN 神经元直接投射到 POA 上并释放 GABA Kiss1 神经元使用脑切片电生理学和光遗传学。此外，我们将确定功能 GABA 释放对动情周期 Kiss1 神经元电活动的影响。在第二个目标中，我们将 使用束追踪和免疫组织化学方法来确定 SCN 神经元投射的目标 POA Kiss1 细胞参与激增并确定贡献这些的细胞的身份 预测及其在激增之前的激活模式。在我们的第三个目标中，我们将首先评估电气 排卵前高峰前数小时内 SCN 神经元群的活动。使用此信息， 然后我们将确定 Kiss1 神经元如何整合通过 GABA 和 AVP 介导的 SCN 计时信号 释放，在激增的那天。总之，这项研究将提供有关昼夜节律控制的新信息 生殖的影响，特别是触发排卵的神经内分泌事件的每日时间。更好的 了解生理情况下负责这些回路昼夜节律调节的神经机制 这些条件可能为未来治疗排卵功能障碍开辟新途径。