5-HT NEURONS AND MEAL REGULATION

5-HT 神经元和膳食调节

• 批准号: 10678539
• 负责人: Kristine Marie McDermott
• 金额: $ 6.95万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678539
• 关键词: Action Potentials; Agonist; American; Animals; Area; Body Weight; Body Weight decreased; Brain; Consumption; DRD2 gene; Data; Development; Diabetes Mellitus; Dopamine; Dopamine D2 Receptor; Dopamine Receptor; Eating; Electrophysiology (science); Energy Intake; Energy Metabolism; Enzymes; Feeding behaviors; Fellowship; Fenfluramine; Fiber; Food; Food Intake Regulation; Functional disorder; GABA Receptor; Goals; Health; Homeostasis; Hunger; Hyperphagia; Hypertension; Hypothalamic structure; Infection; Institution; Intake; Learning; Long-Term Potentiation; Mediating; Medicine; Membrane Potentials; Mental Depression; Metabolic; Modeling; Moods; Mus; Neural Pathways; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Obesity; Outcome; Overweight; Pattern; Pharmaceutical Preparations; Photometry; Physiological; Play; Prevalence; Property; Protocols documentation; Regimen; Regulation; Research; Resources; Rest; Risk; Role; SARS-CoV-2 infection; Satiation; Scientist; Serotonin; Signal Transduction; Structure of nucleus infundibularis hypothalami; System; TPH2; Testing; Therapeutic; Training; Wild Type Mouse; Work; body system; cancer risk; career; college; comorbidity; comparison control; dorsal raphe nucleus; energy balance; feeding; gamma-Aminobutyric Acid; global health; improved; neurobiological mechanism; neurotransmission; new therapeutic target; novel; obese person; obesity prevention; optogenetics; postsynaptic; prevent; receptor; reduced food intake; response; side effect; success; therapeutic development; therapeutically effective; tool; Action Potentials; Agonist; American; Animals; Area; Body Weight; Body Weight decreased; Brain; Consumption; DRD2 gene; Data; Development; Diabetes Mellitus; Dopamine; Dopamine D2 Receptor; Dopamine Receptor; Eating; Electrophysiology (science); Energy Intake; Energy Metabolism; Enzymes; Feeding behaviors; Fellowship; Fenfluramine; Fiber; Food; Food Intake Regulation; Functional disorder; GABA Receptor; Goals; Health; Homeostasis; Hunger; Hyperphagia; Hypertension; Hypothalamic structure; Infection; Institution; Intake; Learning; Long-Term Potentiation; Mediating; Medicine; Membrane Potentials; Mental Depression; Metabolic; Modeling; Moods; Mus; Neural Pathways; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Obesity; Outcome; Overweight; Pattern; Pharmaceutical Preparations; Photometry; Physiological; Play; Prevalence; Property; Protocols documentation; Regimen; Regulation; Research; Resources; Rest; Risk; Role; SARS-CoV-2 infection; Satiation; Scientist; Serotonin; Signal Transduction; Structure of nucleus infundibularis hypothalami; System; TPH2; Testing; Therapeutic; Training; Wild Type Mouse; Work; body system; cancer risk; career; college; comorbidity; comparison control; dorsal raphe nucleus; energy balance; feeding; gamma-Aminobutyric Acid; global health; improved; neurobiological mechanism; neurotransmission; new therapeutic target; novel; obese person; obesity prevention; optogenetics; postsynaptic; prevent; receptor; reduced food intake; response; side effect; success; therapeutic development; therapeutically effective; tool

PROJECT SUMMARY Despite the rapidly growing rate in obesity and tremendous efforts in weight loss research, the development of safe and effective therapeutics has progressed significantly, yet is still limited, largely due to insufficient understanding of how the brain manages body weight and feeding. Lorcaserin, a 5-HT (serotonin) receptor agonist, showed great promise for effectively reducing weight, but was withdrawn due to increased risk for cancer development. 5-HT remains an excellent potential target for an anti-obesity therapeutic, but more work needs to be completed to determine the most effective way for targeting 5-HT. Previous work in this area has shown that GABA and dopamine inhibition of 5-HT neurons is critical for mediating food intake in mice. In fact, my preliminary work has revealed that 2 (GABA receptor subunit) deletion in TPH2 (rate limiting enzyme for 5-HT synthesis) neurons causes a decreased meal number and increased meal interval compared to wild-type mice, indicating a potential dysfunction in meal initiation. Furthermore, DRD2 (a dopamine receptor) deletion reduced miniature inhibitory post synaptic current (mIPSC) in TPH2 neurons, indicating that DRD2 plays an essential role in mediating 5-HT neuronal response to GABA inhibitory input. Finally, I found that in hungry mice, the selective activation of 5-HT neurons in the Dorsal Raphe Nucleus (DRN) which project to the Arcuate Nucleus (ARH) in the Hypothalamus during food approach significantly reduces food intake compared to control mice. Taken together, these preliminary data led me to the hypothesis that GABA inputs to 5-HTDRN neurons are regulated, in part, by DRD2 and may contribute to the regulation of meal initiation. The focus of this proposal is to 1) determine whether the 5-HTDRN→ARH circuit regulates meal initiation and 2) to determine whether DA influences GABA signaling to ARH-projecting 5-HTDRN neurons for meal initiation. To achieve these goals, I will examine (1) whether photostimulation or photoinhibition of the 5-HTDRN→ARH circuit during food approach alters meal initiation and food intake, and (2) the dynamic activity of ARH-projecting 5-HTDRN neurons before or during food approach, at meal initiation, eating and meal termination using fiber photometry. Further, I will generate mice with a selective deletion of either the GABAA γ2 subunit or DA receptor DRD2 in ARH-projecting 5-HTDRN neurons and perform metabolic and meal pattern studies, and (2) examine the electrophysiological properties (mIPSC, resting membrane potential, action potential firing, and their responses to GABA or DRD2 agonists) of ARH- projecting 5-HTDRN neurons in which either the GABAA γ2 subunit or DA receptor DRD2 is deleted. With support from this fellowship, I will utilize the extensive resources at Baylor College of Medicine to expand my expertise so that I can advance in my career and learn more novel and comprehensive approaches to studying the mechanisms underlying meal initiation. This opportunity will provide me with the necessary tools to enhance my training and move toward my career goal of becoming an independent research scientist at an academic institution.

项目摘要 尽管肥胖的速度和减肥研究的巨大努力迅速增长，但 安全有效的疗法已经取得了显着进展，但仍受到限制，这主要是由于不足 了解大脑如何管理体重和进食。 Lorcasein，5-HT（5-羟色胺）接收器 激动剂，显示出有效减轻体重的巨大希望，但由于癌症的风险增加而被撤回 发展。 5-HT仍然是抗肥胖疗法的绝佳潜在目标，但需要更多的工作 完成以确定针对5-HT的最有效方法。该领域的先前工作表明 5-HT神经元的GABA和多巴胺抑制对于介导小鼠的食物摄入至关重要。实际上，我的初步 工作表明，TPH2中的2（GABA受体亚基）缺失（5-HT合成的速率限制酶） 与野生型小鼠相比 进餐开始时潜在的功能障碍。此外，DRD2（多巴胺受体）缺失降低了微型 TPH2神经元中的抑制性突触电流（MIPSC），表明DRD2在 介导对GABA抑制输入的5-HT神经元反应。最后，我发现在饥饿的老鼠中，选择性 在背侧raphe核（DRN）中激活5-HT神经元，该神经元向弧形核（ARH）投射 与对照小鼠相比，食物方法中的下丘脑可显着降低食物摄入量。拍摄 这些初步数据一起，我提出了一个假设，即对5-HTDRN神经元的GABA输入受到调节 部分是DRD2，可能有助于对餐食的调节。该提议的重点是1）确定 5-HTDRN→ARH电路是否调节进餐开始，2）确定DA是否影响GABA 向ARH预测5-HTDRN神经元发出信号以进行膳食启动。为了实现这些目标，我将研究（1） 5-HTDRN→在食物进近期间的光刺激或光抑制→ARH电路都会改变餐 启动和食物摄入量，以及（2）食物之前或期间ARH预测5-HTDRN神经元的动态活性 使用纤维光度法，在进餐，进食，进餐和饮食终止时进行接近。此外，我会生成老鼠 选择性删除ARH预测的5-HTDRN神经元中的GABAAγ2亚基或DA受体DRD2 并进行代谢和进餐模式研究，以及（2）检查电生理特性（MIPSC， 静止的膜电势，动作潜在的射击以及它们对Arh-的对GABA或DRD2激动剂的反应 删除了GABAAγ2亚基或DA受体DRD2的5-HTDRN神经元。支持 从这个奖学金中，我将利用贝勒医学院的大量资源来扩展我的专业知识 这样我就可以在职业生涯中进步，并学习更多新颖而全面的方法来研究 膳食启动的机制。这个机会将为我提供必要的工具来增强我的 培训并朝着我的职业目标迈进，成为学者的独立研究科学家 机构。