Characterization of the role of the amygdala in reproductive function

杏仁核在生殖功能中作用的表征

• 批准号: 10612335
• 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
• 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/10612335
• 关键词: Ablation; Acute; Amygdaloid structure; Area; Behavior; Brain region; Calcium; Cell Nucleus; Cues; Data; Development; Efferent Neurons; Exposure to; Female; Fertility; Fiber; Frequencies; Generations; Genes; Genetic; Genetic study; Goals; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Hormonal; Hypogonadism; Hypothalamic structure; Impairment; Induction of Apoptosis; Investigation; KISS1 gene; Knowledge; Label; Lesion; Libido; Lordosis; Maps; 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; Ventricular; Virus; comparison control; genetic manipulation; hypothalamic pituitary gonadal axis; innovation; insight; male; optogenetics; postsynaptic neurons; reproductive; reproductive axis; reproductive function; reproductive system disorder; sex

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.

摘要 成功的生殖功能取决于促性腺激素轴的适当激活， 适当的性行为的发展。虽然下丘脑的调节机制 促性腺激素释放已被广泛研究，那些调节性行为和 特别是那些将行为和生育能力联系起来的基因仍然难以捉摸。杏仁核有 已被记录为整合性线索，例如信息素，以引起性行为和病变 研究表明其与两性中适当的GnRH释放相关。有趣的是 下丘脑神经肽，kisspeptin（Kiss 1），对生殖功能至关重要，也被 在杏仁核中被发现。我们的初步数据表明Kiss 1神经元的激活 内侧杏仁核（MeAKiss 1神经元）刺激LH释放。因此，我们的总体 目的是详细描述雄性和雌性中MeAKiss 1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 和遗传学研究，将包括：1）cre的光遗传学和化学遗传学操纵， 在Kiss 1-cre小鼠中表达神经元; 2）使用cre依赖性的MeAKiss 1神经元的消融， 凋亡诱导，Casp 3病毒;和3）追踪追踪从MeAKiss 1神经元到 使用纤维标记物（mCherry）、单突触追踪示踪剂和钙离子示踪剂的下丘脑神经元 测光电路图此外，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Kiss 1的激活， 交配过程中GnRH神经元和下丘脑核团的激活参与性行为 在女性LH激增期间的行为。总的来说，该项目的成功完成将 显著地扩展了我们对内侧杏仁核在整合 性行为和促性腺激素释放，这是同步交配的基础， 排卵成功繁殖。预期的研究结果将为 治疗中枢性生殖障碍，如性腺功能减退或性欲低下。