Hypothalamic gating of the anorexic effects of estradiol

雌二醇的厌食作用的下丘脑门控

• 批准号: 10743655
• 负责人: Stephanie Correa
• 金额: $ 51.93万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-23 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10743655
• 关键词: Ablation; Behavior; Brain; Caspase; Cavia; Cell Nucleus; Cells; Classification; Cues; Data; Dependence; Diet; Eating; Eating Disorders; Energy Metabolism; Estradiol; Estrogens; Estrous Cycle; Exclusion; Exhibits; Fatty acid glycerol esters; Feeding behaviors; Female; Flow Cytometry; Genetic Transcription; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Health; Human; Hunger; Hypothalamic structure; Label; Masks; Mediating; Menopause; Menstrual cycle; Metabolic; Morbid Obesity; Mus; Neurons; Obesity; Peripheral; Phase; Physiology; Population; Proestrus; Rattus; Regulation; Reporting; Research; Role; Sex Differences; Signal Transduction; Somatostatin; Testing; Transplantation; Wild Type Mouse; Woman; anorexic; boys; disorder risk; energy balance; feeding; girls; immunoreactivity; male; men; neural circuit; neuroregulation; permissiveness; reproductive; sex; sugar; transcriptome sequencing

PROJECT SUMMARY The overall goal of this proposal is to understand sex differences in the neural regulation of feeding, specifically how the anorexogenic effects of estradiol are modulated by a new hypothalamic node of the feeding circuit. Previous research identified somatostatin (SST)-producing neurons as part of the neural circuit that controls feeding, but sex differences were not explored. We find that activating SST neurons in the region that spans the tuberal and ventromedial nuclei of the hypothalamus increases feeding in male and female mice. However, ablating these neurons decreases feeding only in females, only during the high-estrogen phase of the estrous cycle, and only when their body mass is relatively low. These findings are consistent with previous studies but go further to reveal a context-dependent role for SST neurons in the regulation of feeding. We hypothesize that SST neurons of the tuberal nucleus are a sex-specific, modulatory node within the brain that can mask the anorexic effects of estradiol when energy reserves are low. The proposal outlines studies in mice to determine how SST neuronal function is modulated by both reproductive and metabolic cues. In Aim 1, we use cell-specific manipulations combined with gonadal hormone manipulations to reveal how SST neuron function is modulated by reproductive state. In Aim 2, we use cell-specific manipulations combined with manipulations of body mass and adiposity to reveal how SST neuron function is modulated by metabolic state. In Aim 3, we use fluorescent labeling and flow cytometry followed by RNA-sequencing (flow-Seq) to assess how SST neurons may be responsive to reproductive and metabolic conditions and whether this differs by sex. Together, these studies will help us understand how neural circuits integrate multiple peripheral signals to fine tune behavior and physiology across dynamic states.

项目摘要 这项提案的总体目标是了解摄食神经调节的性别差异， 特别是雌二醇的促性腺激素作用是如何通过进食的新下丘脑节点调节的。 电路.以前的研究确定生长抑素（SST）产生神经元作为神经回路的一部分， 控制喂养，但性别差异没有探讨。我们发现，激活SST神经元的区域， 跨越下丘脑的结节和腹内侧核，增加雄性和雌性小鼠的摄食。 然而，切除这些神经元仅在雌性中减少进食，仅在高雌激素阶段， 发情周期，只有当他们的身体质量相对较低。这些发现与以前的研究结果一致。 研究，但更进一步揭示了SST神经元在摄食调节中的上下文依赖性作用。我们 假设结节核的SST神经元是脑内性别特异性的调节节点， 可以在能量储备不足时掩盖雌二醇的副作用。该提案概述了在小鼠中进行的研究 以确定SST神经元功能是如何通过生殖和代谢线索调节的。目标1： 使用细胞特异性操作与性腺激素操作相结合，以揭示SST神经元 功能受生殖状态的调节。在目标2中，我们使用细胞特异性操作， 操纵身体质量和肥胖，以揭示SST神经元功能如何受代谢状态调节。 在目标3中，我们使用荧光标记和流式细胞术，然后进行RNA测序（flow-Seq），以评估 SST神经元可能会对生殖和代谢条件做出反应，以及这是否因性别而异。 总之，这些研究将帮助我们了解神经回路如何整合多个外围信号， 在动态状态下调整行为和生理。