Investigation of brainstem neurons in the regulation of gonadotropin secretion

脑干神经元调节促性腺激素分泌的研究

• 批准号: 10371560
• 负责人: Richard Bryan McCosh
• 金额: $ 11.01万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371560
• 关键词: Ablation; Acetylcholine; Achievement; Address; Amenorrhea; Amygdaloid structure; Anatomy; Area; Bioinformatics; Brain; Brain Stem; Brain imaging; Cardiovascular system; Cell Nucleus; Cells; Cholecystokinin; Contraceptive methods; Coupled; Data; Data Set; Development; Diphtheria Toxin; Disease; Dynorphins; Ensure; Environment; Estradiol; Female; Future; Galanin; Glutamates; Goals; Gonadal Steroid Hormones; Gonadotropins; Hormone secretion; Hypothalamic structure; Individual; Infertility; Investigation; KISS1 gene; Knowledge; Label; Light; Location; Luteinizing Hormone; Mediating; Mental Health; Mentors; Microscopy; Mission; Musculoskeletal; Neural Pathways; Neurokinin B; Neurons; Neuropeptides; Neurotransmitters; Norepinephrine; Nucleus solitarius; Optics; Ovarian Cycles; Pattern; Phase; Phenotype; Physiologic pulse; Physiological; Polycystic Ovary Syndrome; Population; Positioning Attribute; Production; Protocols documentation; Regulation; Research; Resources; Role; Scientist; Signal Transduction; Site; Somatostatin; Stress; Structure of area postrema; Structure of nucleus infundibularis hypothalami; Structure/Function Nuclei; Techniques; Technology; Testing; Tissues; Training; Transgenic Organisms; United States National Institutes of Health; Vagus nerve structure; Viral; Work; alpha Toxin; career development; experience; gamma-Aminobutyric Acid; male; neural circuit; neural tract; neurochemistry; neuroimaging; neuropeptide Y; next generation sequencing; novel; novel therapeutics; programs; relating to nervous system; reproductive function; reproductive system disorder; response; single-cell RNA sequencing; steroid hormone receptor; success; therapy development; training opportunity; transcriptomics

PROJECT SUMMARY The long-term goal of the proposed research is to determine the neural pathways by which physiological signals regulate gonadotropin secretion, which ultimately determines reproductive function. Modulation of luteinizing hormone (LH) secretion determines fertility and controls gonadal steroid concentrations, which has profound effects on cardiovascular, musculoskeletal, and mental health. Pulses of luteinizing hormone secretion are organized by neurons in the arcuate nucleus of the hypothalamus that contain kisspeptin, neurokinin B and dynorphin (KNDy neurons) in males and females. In females, the preovulatory LH surge is induced by estradiol and is dependent upon kisspeptin cells in the anteroventral periventricular region (AVPVKiss1). However, the higher order neural circuitry that governs these populations of kisspeptin cells remains a significant outstanding question. The nucleus of the solitary tract (NTS) is located in the brainstem and consists of a heterogenous population of neurons that receive rich interoceptive and central inputs and projects widely thought the brain. Interestingly, these neurons are implicated in both the inhibition of pulsatile LH secretion during stress, and the facilitation of enhanced LH secretion during the preovulatory LH surge. To address this apparent paradox, this K99/R00 proposal will test the central hypothesis that distinct subpopulations of neurons in the NTS suppress pulsatile LH secretion via inhibition of KNDy neurons and enhance LH secretion via activation of AVPVKiss1 cells. During the mentored phase, we will employ viral-mediated cell activation labeling techniques and light sheet microscopy of optically cleared tissue to determine if the same neurons are activated during stress and the LH surge, as well as single-cell RNA sequencing to identify the subpopulations of NTS neurons that are activated during stress and the LH surge (Aim 1). The mentored phase will consist of critical training in advanced neuroanatomical and neuroimaging techniques, next generation sequencing technologies, bioinformatic analysis, as well as career development experiences that are necessary for transitioning to an independent academic research position. In the independent phase, I propose to use chemogenetic and cell- specific viral-mediated neural ablation techniques to determine whether subpopulations of neurons identified in Aim 1 are sufficient and necessary for stress-induced suppression of LH secretion and KNDy cell activation (Aim 2) or for the preovulatory LH surge and AVPVKiss1 cell activation (Aim 3) and determine the locations in the brain these subpopulations project (Aims 2 & 3). These studies will launch my independent research program and will provide a neural framework that may influence the development of therapies to treat disorders of altered LH secretion, including amenorrhea, infertility, and polycystic ovary syndrome. Collectively, the commitment of the sponsoring/co-sponsoring team to my scientific and professional development, coupled with the stimulating academic environment and impressive resources at UC San Diego available to me will ensure achievement of the aims of this Career Development proposal and the training mission of UC San Diego and the NIH.

项目摘要 拟议研究的长期目标是确定生理学的神经途径 信号调节促性腺激素分泌，最终决定生殖功能。调制 黄体生成激素（LH）分泌决定生育能力并控制性腺类固醇浓度，该浓度具有 对心血管，肌肉骨骼和心理健康的深刻影响。黄体激素分泌的豆类 由含有亲吻肽，神经蛋白B和 男性和女性的dynorphin（kndy神经元）。在女性中，雌二醇诱导了卵石前的LH振兴 并取决于前室室室中区域（AVPVKISS1）中的吻肽细胞。但是， 控制这些亲吻肽细胞种群的高阶神经回路仍然很重要 出色的问题。孤立道（NTS）的核位于脑干中，由 具有丰富感受性和中央投入和项目的神经元的异质种群广泛认为 大脑。有趣的是，这些神经元与压力期间脉动LH分泌的抑制有关， 以及在排卵前LH激增过程中促进LH分泌增强的促进。解决这个明显的 悖论，此K99/R00提案将检验以下中心假设，即神经元在 NTS通过抑制kndy神经元抑制脉冲LH分泌，并通过增强LH分泌 AVPVKISS1细胞的激活。在指导阶段，我们将采用病毒介导的细胞激活标记 光学清除组织的技术和光片显微镜，以确定是否激活相同的神经元 在压力和LH激增以及单细胞RNA测序中，以识别NTS的亚群 在压力和LH激增过程中被激活的神经元（AIM 1）。指导阶段将包括关键 高级神经解剖学和神经影像学技术的培训，下一代测序技术， 生物信息学分析以及过渡到过渡到的职业发展经验 独立的学术研究职位。在独立阶段，我建议使用化学发生和细胞 特定的病毒介导的神经消融技术，以确定是否在 AIM 1足以抑制LH分泌和KNDY细胞激活所必需（AIM） 2）或用于卵巢前LH激增和AVPVKISS1细胞激活（AIM 3），并确定大脑中的位置 这些亚群项目（目标2和3）。这些研究将启动我的独立研究计划，并将 提供一个神经框架，可能会影响治疗LH改变疾病的疗法的发展 分泌，包括闭经，不育和多囊卵巢综合征。总体而言， 赞助/共同赞助团队，与我的科学和专业发展，再加上刺激性 我可以使用的圣地亚哥分校的学术环境和令人印象深刻的资源将确保实现 这项职业发展建议的目的以及圣地亚哥分校和NIH的培训任务。