Role of Kiss1 neurons in the seasonal and circadian control of reproduction

项目总结(见说明)： Kissi基因编码一种名为kispeptins的蛋白质，v^rhich与G蛋白偶联受体Gpr54结合。 Kissl在调节生殖的大脑离散区域表达，在哺乳动物中表达，包括 人类，Kispeptins刺激促性腺激素释放激素(GnRH)的分泌，并 促性腺激素(促黄体生成素、卵泡刺激素)。Kissl神经元本身受性腺性激素的调节，这表明 Kispeptin信号在生殖的负反馈和正反馈调节中的关键作用。 尽管Kispeptin-Gpr54信号在控制GnRH分泌中的刺激作用已经被 Kissl nemons在环境、昼夜节律和发育调节中的作用已经研究得很好了 繁殖力更不用说cftaractenzea。这项研究的目的是阐明其生理作用 KiHlil系统在GnRH分泌的昼夜节律、光周期和发育控制中的作用。这个 第一个目标是评估Kissl神经元在节律控制的排卵前黄体生成素峰中的作用。 在雌性，排卵前的黄体生成素峰值与视交叉上核内的昼夜节律振荡器相连。 (SCN)。尽管神经回路和神经内分泌因子介导了SCN对 浪涌仍未确定，有证据表明Kissl神经元参与其中。我会调查的 Kissl神经元是否在每日黄体生成素激增时经历昼夜节律激活，并确定 在SCN和Kissl神经元之间有直接的神经联系(如果是这样的话，识别“ 参与这一回路的神经递质)。第二个主要目标是评估Kissl的作用 神经元在生殖和性成熟的季节性控制中。众所周知，季节性的 生殖和青春期的开始由松果体褪黑素(MEL)分泌(反映白天 长度)，但整合MEL信号并将其传递给GnRH神经元的神经电路仍然存在 身份不明。I WIU评估光周期/MEL对下丘脑Kissl系统的影响，确定MEL对Kissl神经元的影响是直接的还是间接的，并确定Kissl神经元的调节如何随发育状态(青春期)而变化。我还将全面评估几个候选核团在传递MEL对Kissl神经元的任何间接影响方面的作用。最后，我将研究Kissl轴突对GnRH神经元的反应性，以及Kissl神经元对性激素反馈效应的敏感性如何受光周期和发育状态的调节。

PROJECT SUMMARY (See instructions): The Kissi gene encodes proteins called kisspeptins, v^rhich bind to the G-protein coupled receptor GPR54. Kissl is expressed in discrete brain regions that regulate reproductioa and in mammals, induding humans, kisspeptins stimulate the secretion of gonadotropin-releasing hormone (GnRH) and gonadotropins (LH, FSH). Kissl neurons are themselves regulated by gonadal sex hormones, suggesting a crucial role for kisspeptin signaling in the negative and positive feedback regulation of reproduction. Although the stimulatory role of kisspeptin-GPR54 signaling in the control of GnRH secretion has been well-studied, the role of Kissl nemons in the environmental, circadian, and developmental regulation of reproductioivis much less cftaractenzea. ine goals or this research are to elucidate the physiological role Ofthe KiHlil system in the circadian, photoperiodic, and developmental control of GnRH secretion. The first objective is to evaluate the role of Kissl neurons in the drcadian-controlled pre-ovulatory LH surge. In females, the pre-ovulatory LH surge is coupled to a circadian oscillator in the suprachiasmatic nucleus (SCN). Althoiigh the rieural circuitry and neuroendocrine factors that mediate the SCN's control of the surge remain unidentified, evidence implicates the involvement of Kissl neurons. I will investigate whether Kissl neurons undergo circadian activation at the time of daily LH surges and determine whether there are direct neural cormections between the SCN and Kissl neurons (and if so, identify" the neurotransmitters involved in this circuitry). The second main objective is to evaluate the role of Kissl neurons in the seasonal control of reproduction and sexual maturation. It is known that seasoital reproduction and puberty onset are governed by pineal melatonin (MEL) secretion (which reflects day length), but the neural circuitry that integrates and relays MEL signals to GnRH neurons remains unidentified. I wiU assess the effects of photoperiod/MEL on the hypothalamic Kissl system, ascertain whether MEL's effects on Kissl neurons are direct or indirect, and determine how the regulation of Kissl neurons varies with developmental status (puberty). I will also comprehensively evaluate the roles of several candidate nuclei in relaying any indirect effects of MEL on Kissl neurons. Lastly, I will investigate how the irmervatipn of GnRH neurons by Kissl axons and the sensitivity oi Kissl neurons to feedback effects of sex steroids areregulated by photoperiod and developmental status.