Regulation of Neural Circuits Underlying Mammalian Reproduction

Kisspeptin是最近发现的一种由Kiss1基因编码的神经肽，对青春期发育和成年生育都是必要和充分的；然而，人们对位于下丘脑的Kiss1神经元本身是如何被调节的却知之甚少。在女性中，下丘脑前部的Kiss1神经元受到来自大脑的时间信号的调节。从而精确地激活生殖轴，从而导致排卵。有趣的是，Kiss1神经元的昼夜节律调节完全依赖于激素雌二醇的存在，但大脑中雌二醇是如何以及在哪里诱导Kiss1神经元的昼夜节律激活尚不清楚。此外，Kauffman实验室还在杏仁核中发现了一种新的下丘脑外的Kiss1神经元群，它也受到雌二醇的刺激；然而，这种调节的分子机制和杏仁核Kiss1神经元的功能是完全未知的。通过小鼠实验，本研究将确定下丘脑Kiss1神经元受激素信号和昼夜节律信号调控的神经解剖位置和分子机制，并将阐明位于杏仁核的新型Kiss1群体的激素调控机制和潜在功能。这项研究的智力价值在于更好地理解大脑激素，特别是雌二醇，如何、何时、何地调节关键的青春期和生殖神经回路的功能，特别是Kiss1回路。研究部分受到赞扬，并与拓展和更广泛的影响方面相结合，这些方面是直接培训和教育本科生和研究生进行实践生物学研究，参与加州大学圣地亚哥分校最大化学生多样性的倡议，该倡议吸引和指导本科少数民族学生进行生物学研究，并设计和管理一个新的动态科学网站（Neuroendo Now），作为一个公共论坛，并传播有关神经内分泌学进展的最新信息。

Kisspeptin, a recently-identified neuropeptide encoded by the Kiss1 gene, is both necessary and sufficient for puberty onset and adulthood fertility; however, exactly how Kiss1 neurons, which are known to be located in the hypothalamus, are themselves regulated is poorly understood. In females, Kiss1 neurons in the anterior hypothalamus are regulated by temporal signals from the brain?s circadian clock, thereby generating a precisely-timed activation of the reproductive axis that results in ovulation. Interestingly, this circadian regulation of Kiss1 neurons is fully dependent on the presence of the hormone estradiol, but how and where in the brain estradiol acts to induce the circadian activation of Kiss1 neurons is unknown. Additionally, the Kauffman lab has identified a novel extra-hypothalamic population of Kiss1 neurons in the amygdala which is also stimulated by estradiol; however, the molecular mechanisms of this regulation and the functions of amygdala Kiss1 neurons are completely unknown. Using mice, this research will ascertain the neuroanatomical location and molecular mechanism(s) by which hypothalamic Kiss1 neurons are regulated by both hormonal signals and circadian cues, and will also elucidate the hormonal regulatory mechanisms and potential functions of the novel Kiss1 population located in the amygdala. This intellectual merit of this research is a better understanding of how, when, and where in the brain hormones, particularly estradiol, regulate the function of critical pubertal and reproductive neural circuits, in particular, Kiss1 circuits. The research component is complimented and integrated with the outreach and broader impact aspects, which are to directly train and educate undergraduate and graduate students in hands-on biology research, to participate in the UCSD Initiative for Maximizing Student Diversity which engages and mentors undergraduate minority students in biology research, and to design and manage a new dynamic science website (Neuroendo Now) that serves as a public forum for, and disseminates current information pertaining to advances in neuroendocrinology.