Characterization of the role of the amygdala in reproductive function

杏仁核在生殖功能中作用的表征

基本信息

批准号：
10371092
负责人：
Victor Manuel Navarro
金额：
$ 45.44万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-22 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10371092
关键词：
Ablation Acute Amygdaloid structure Apoptosis Area Behavior Brain region Calcium Cell Nucleus Cues Data Development Exposure to Female Fertility Fiber Frequencies Generations Genetic Genetic study Goals Gonadotropin Hormone Releasing Hormone Gonadotropins Hormonal Hypogonadism Hypothalamic structure Impairment Investigation KISS1 gene Knowledge Label Lesion Libido Lordosis Medial Mediating Mus Neurons Neuropeptides Ovulation Partner in relationship Pharmacology Study Pheromone Photometry Physiologic pulse Play Population Preoptic Areas Protocols documentation Reproduction Reproductive Behavior Role Series Sex Behavior Sex Differentiation Structure of nucleus infundibularis hypothalami Testing Time Time Study Tracer Urine Virus hypothalamic pituitary gonadal axis innovation insight male optogenetics postsynaptic neurons release factor reproductive reproductive axis reproductive function reproductive system disorder sex

项目摘要

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.

抽象的成功的生殖功能取决于促性腺轴的正确激活和适当的性行为的发展。虽然下丘脑机制调节促性腺激素的释放已被广泛研究，那些调节性行为和特别是那些将行为与生育能力联系起来的因素仍然难以捉摸。杏仁核有已被记录为整合性暗示，例如信息素，引发性行为和病变研究表明，它与两性 GnRH 的正常释放有关。有趣的是，下丘脑神经肽 Kisspeptin (Kiss1) 对生殖功能至关重要，也已被在杏仁核中发现。我们的初步数据证明 Kiss1 神经元的激活内侧杏仁核（MeAKiss1 神经元）刺激 LH 释放。因此，我们的总体目的是详细描述男性和女性中 MeAKiss1 神经元在控制通过功能性、药理学的结合，促性腺激素的释放和性行为和遗传学研究，包括：1）光遗传学和化学遗传学操作 Kiss1-cre 小鼠中表达神经元； 2) 使用cre依赖性消融MeAKiss1神经元，诱导细胞凋亡的 Casp3 病毒； 3) 跟踪从 MeAKiss1 神经元到使用纤维标记 (mCherry)、单突触轨迹示踪剂和钙的下丘脑神经元光度测定电路映射。此外，我们将描述这两者之间的相互作用通过评估 Kiss1 的激活和功能（即促性腺激素释放和性行为）交配过程中的 GnRH 神经元以及参与性行为的下丘脑核团的激活女性 LH 激增期间的行为。总体而言，本项目的顺利完成将显着扩展了我们对内侧杏仁核在整合中的作用的理解性行为和促性腺激素释放，这是同步交配和性行为的基础成功繁殖的排卵。预期的发现将为治疗中枢性生殖疾病，如性腺功能减退或性欲低下。