Characterization of the role of the amygdala in reproductive function

摘要 成功的生殖功能取决于促性腺激素轴的适当激活和 适当的性行为的发展。而下丘脑的调节机制 促性腺激素的释放已经被广泛研究，那些调节性行为和 具体地说，那些将行为和生育联系起来的因素仍然难以捉摸。杏仁核有 已被证明可以融合性暗示，例如信息素，以引导性行为和损害 研究表明，它与GnRH在两性中的适当释放有关。有趣的是， 对生殖功能至关重要的下丘脑神经肽Kispeptin(Kiss1)也一直是 在杏仁核中被确认。我们的初步数据表明，Kiss1神经元的激活 在杏仁内侧核(MeAKiss1神经元)刺激黄体生成素的释放。因此，我们最重要的是 目的是详细描述男性和女性的MeAKiss1神经元在控制 促性腺激素释放和性行为通过功能性、药理学的结合 遗传学研究将包括：1)cre基因的光遗传和化学遗传操作。 在Kiss1-cre小鼠中表达神经元；2)使用依赖cre的方法消融MeAKiss1神经元， 诱导细胞凋亡，Casp3病毒；以及3)跟踪从MeAKiss1神经元到 下丘脑神经元的纤维标记(MCherry)、单突触轨迹示踪剂和钙 测光电路测绘。此外，我们将描述这两者之间的相互作用 功能(即促性腺激素释放和性行为)通过评估Kiss1和 交配过程中的GnRH神经元和参与性行为的下丘脑核团的激活 雌性黄体生成素高峰期间的行为。总体而言，这一项目的成功完成将 极大地扩展了我们对杏仁内侧核在整合 性行为和促性腺激素释放，这是同步交配和 排卵才能成功繁殖。预期的发现将为 治疗由中枢引起的生殖障碍，如性腺机能减退或性欲减退。

ABSTRACT Successful reproductive function depends on the proper activation of the gonadotropic axis and the development of adequate sexual behavior. While the hypothalamic mechanisms regulating gonadotropin release have been extensively studied, those regulating sexual behavior and specifically those connecting behavior and fertility have remained elusive. The amygdala has been documented to integrate sexual cues, e.g. pheromones, to elicit sexual behavior and lesion studies have indicated its relevance for proper GnRH release in both sexes. Interestingly, the hypothalamic neuropeptide, kisspeptin (Kiss1), critical for reproductive function, has also been identified in the amygdala. Our preliminary data documents that the activation of Kiss1 neurons in the medial amygdala (MeAKiss1 neurons) stimulates LH release. Therefore, our overarching aim is to characterize in detail the role of MeAKiss1 neurons in males and females in the control of gonadotropin release and sexual behavior through a combination of functional, pharmacological and genetic studies that will include: 1) optogenetic and chemogenetic manipulation of cre- expressing neurons in Kiss1-cre mice; 2) ablation of MeAKiss1 neurons using cre-dependent, apoptosis inducing, Casp3 viruses; and 3) track tracing of projections from MeAKiss1 neurons to hypothalamic neurons using fiber markers (mCherry), mono-synaptic track tracers and calcium photometry circuit mapping. Moreover, we will characterize the interaction between these two functions (i.e. gonadotropin release and sexual behavior) by assessing the activation of Kiss1 and GnRH neurons during mating, and the activation of hypothalamic nuclei involved in sexual behavior during the LH surge in females. Overall, the successful completion of this project will significantly extend our understanding of the role of the medial amygdala in the integration of sexual behavior and gonadotropin release, which is fundamental to synchronize mating and ovulation for successful reproduction. The expected findings will offer new platforms for the treatment of reproductive disorders of central origin such as hypogonadism or low sex drive.