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

基本信息

批准号：
10493376
负责人：
Richard Bryan McCosh
金额：
$ 11万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
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/10493376
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

项目摘要

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.

项目概要拟议研究的长期目标是确定生理学的神经通路信号调节促性腺激素的分泌，最终决定生殖功能。调制黄体生成素 (LH) 的分泌决定生育能力并控制性腺类固醇浓度，这对心血管、肌肉骨骼和心理健康产生深远影响。黄体生成素分泌脉冲由下丘脑弓状核中的神经元组成，其中含有 Kisspeptin、神经激肽 B 和男性和女性的强啡肽（KNDy 神经元）。在女性中，排卵前 LH 激增是由雌二醇引起的并且依赖于前腹侧脑室周围区域的 Kisspeptin 细胞 (AVPVKiss1)。然而，控制这些 Kisspeptin 细胞群的高阶神经回路仍然是一个重要的悬而未决的问题。孤束核 (NTS) 位于脑干，由接受丰富的内感受和中枢输入并进行广泛思考的异质神经元群体大脑。有趣的是，这些神经元与压力期间脉冲性 LH 分泌的抑制有关，以及在排卵前 LH 激增期间促进 LH 分泌增强。为了解决这个明显的问题矛盾的是，这个 K99/R00 提案将测试中心假设，即不同的神经元亚群 NTS 通过抑制 KNDy 神经元抑制脉动 LH 分泌，并通过抑制 LH 分泌来增强 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技术和光学透明组织的光片显微镜以确定相同的神经元是否被激活在压力和 LH 激增期间，以及单细胞 RNA 测序来识别 NTS 亚群在压力和 LH 激增期间激活的神经元（目标 1）。指导阶段将包括关键的先进神经解剖学和神经影像技术、下一代测序技术的培训，生物信息分析，以及过渡到职业发展所必需的经验具有独立的学术研究地位。在独立阶段，我建议使用化学遗传学和细胞遗传学特定病毒介导的神经消融技术，以确定是否在目标 1 对于应激诱导的 LH 分泌抑制和 KNDy 细胞激活来说是充分且必要的（目标 2) 或排卵前 LH 激增和 AVPVKiss1 细胞激活（目标 3）并确定大脑中的位置这些亚人群项目（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 改变疾病的疗法的开发分泌失调，包括闭经、不孕症和多囊卵巢综合症。总的来说，各方的承诺赞助/共同赞助团队对我的科学和专业发展，以及刺激加州大学圣地亚哥分校的学术环境和令人印象深刻的资源将确保我实现本职业发展提案的目标以及加州大学圣地亚哥分校和美国国立卫生研究院的培训任务。