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.

抽象的 成功的生殖功能取决于促性腺旋转轴的适当激活 充分的性行为的发展。而下丘脑机制调节 促性腺激素的释放已被广泛研究，那些调节性行为的人和 具体来说，那些连接行为和生育能力仍然难以捉摸。杏仁核有 已被记录以整合性线索，例如信息素，引起性行为和病变 研究表明，它与两个性别中适当的GNRH释放的相关性。有趣的是， 下丘脑神经肽，Kisspeptin（Kiss1），对生殖功能至关重要 在杏仁核中鉴定。我们的初步数据证明了KISS1神经元的激活 在内侧杏仁核（Meakiss1神经元）中，刺激LH释放。因此，我们的总体 目的是详细描述Meakiss1神经元在男性和女性中的作用 通过功能，药理的结合，促性腺激素释放和性行为 以及将包括：1）CRE-的光学遗传学和化学遗传操作的遗传研究 在Kiss1-Cre小鼠中表达神经元； 2）使用CRE依赖性的Meakiss1神经元消融， 凋亡诱导，CASP3病毒； 3）从Meakiss1神经元到 使用纤维标记（MCHERRY），单突触轨迹和钙的下丘脑神经元 光度计电路映射。而且，我们将表征这两个之间的相互作用 通过评估Kiss1的激活和 gnRH神经元在交配过程中，下丘脑核的激活参与性 女性LH激增期间的行为。总体而言，该项目的成功完成将 大大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 排卵成功繁殖。预期的发现将为 治疗中心起源的生殖障碍，例如性能或性驱动力较低。