Disentangling discrete lateral hypothalamic circuits involved in feeding and obesity

解开与进食和肥胖有关的离散外侧下丘脑回路

• 批准号: 10441656
• 负责人: Mark Allen Rossi
• 金额: $ 24.9万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10441656
• 关键词: Ablation; Acute; Affect; Anatomy; Appetitive Behavior; Area; Attenuated; Behavior; Body Weight; Brain; Brain imaging; Brain region; Calcium; Cells; Consummatory Behavior; Coupled; Data; Development; Diet; Dissection; Distal; Eating; Economic Burden; Electric Stimulation; Electrophysiology (science); Fasting; Feeding behaviors; Food; Food Intake Regulation; Future; Genetic; Glutamates; Goals; Habenula; Heterogeneity; Homeostasis; Hormonal; Hormones; Hypothalamic structure; Image; Individual; K-Series Research Career Programs; Lateral; Lateral Hypothalamic Area; Leptin; Light; Measures; Mentorship; Molecular; Monitor; Motivation; Movement; Mus; Neurologic; Neurons; Neurosciences; Obesity; Output; Pathway interactions; Physiological; Population; Population Control; Population Projection; Positioning Attribute; Prevalence; Property; Regulation; Research; Research Personnel; Rewards; Rodent; Role; Satiation; Signal Transduction; Slice; Stimulus; Structure; Structure of terminal stria nuclei of preoptic region; Synapses; Testing; Therapeutic Intervention; Training; United States; Ventral Tegmental Area; Weight Gain; Work; base; cell type; cost; diet-induced obesity; electrical property; experimental study; feeding; food consumption; ghrelin; hindbrain; in vivo; insight; molecular dynamics; neural circuit; novel; optogenetics; programs; relating to nervous system; response; tool; two-photon

Project Summary/Abstract The prevalence of obesity in the United States is projected to rise to nearly 50% and cost over $400 billion by the year 2030. Despite the staggering economic burden, the underlying physiological mechanisms contributing to obesity are largely unknown. Appetitive and consummatory behaviors, thought to be dysregulated in obesity, are governed by descending signals from the brain, but how specific neural circuits regulate such behaviors is unclear. One critical component in the neural circuitry that orchestrates feeding behavior is the lateral hypothalamic area (LHA), a molecularly and functionally heterogeneous hypothalamic area that is interconnected with limbic and hindbrain structures. Ablating LHA abolishes feeding and disrupts body weight regulation across species, while electrical stimulation of LHA potentiates appetitive behavior and promotes food intake. However, such coarse manipulations have nonspecific effects on movement and motivation, which are likely due to the striking heterogeneity of the LHA. As a result, the function of discrete cell types within the LHA their contributions to feeding, energy homeostasis, and ultimately obesity remain elusive. Recent technological developments have made it possible to acutely manipulate and monitor activity dynamics of molecularly and anatomically defined neuron populations in behaving rodents. The goal of the proposed research is to use contemporary circuit neuroscience tools to monitor and manipulate the activity of molecularly- and anatomically-defined LHA neurons to determine how divergent projection pathways uniquely contribute to obesity. This project will focus on glutamatergic output pathways from the LHA to the ventral tegmental area or the lateral habenula, two brain regions that are known to regulate feeding and reward. Activity dynamics of these neurons will be monitored using in vivo two-photon deep brain calcium imaging coupled with optogenetics and electrophysiology throughout the onset of diet-induced obesity. Completion of the proposed aims is expected to be impactful because these studies will illuminate the causal and natural neural dynamics that underlie the onset of obesity. While neurons of the lateral hypothalamic area have long been implicated in the regulation of food intake and body weight, the genetic, molecular, and circuit mechanisms underlying these influences are unknown. Identifying how obesity interacts with defined neural circuitry at the level of individual neurons is of critical importance because without this information, we are unlikely to discover the ways in which obesity arises. This career development award will provide technical and conceptual training as well as mentorship from renowned experts in the field of circuit neuroscience. Ultimately, this training will uniquely position this young investigator to transition to an independent research program focused on investigating the neuronal basis of obesity.

项目摘要/摘要 到2019年，美国的肥胖率预计将上升到近50%，耗资超过4000亿美元 2030年。尽管经济负担令人震惊，但潜在的生理机制 肥胖症的风险在很大程度上是未知的。食欲和消耗性行为，被认为是肥胖的失调行为， 是由大脑的下行信号控制的，但具体的神经回路如何调节这种行为 不清楚。协调摄食行为的神经回路中的一个关键部件是侧脑室 下丘脑区(LHA)，一个分子和功能不同的下丘脑区，是 与边缘和后脑结构相互联系。消融LHA取消进食并破坏体重 跨物种调节，而电刺激LHA增强食欲行为并促进 食物摄入量。然而，这种粗略的操作对运动和动机有非特异性的影响，这 很可能是由于LHA的显著异质性。因此，内部离散细胞类型的功能 LHA它们对进食、能量平衡和最终肥胖的贡献仍然难以捉摸。近期 技术的发展使人们有可能准确地操纵和监测 行为型啮齿动物的分子和解剖学定义的神经元群体。建议的目标是 研究是使用现代电路神经科学工具来监测和操纵大脑的活动 分子和解剖学定义的LHA神经元确定发散投射路径如何独特 会导致肥胖。本项目将重点研究从LHA到腹侧的谷氨酸能输出通路。 被盖区或外侧缰核，这是已知的两个大脑区域，负责调节摄食和奖励。 这些神经元的活动动态将使用活体双光子脑深部钙成像进行监测 再加上光遗传学和电生理学在饮食诱导肥胖的整个发病过程中的作用。完成 拟议的目标预计将产生影响，因为这些研究将阐明 自然神经动力学是肥胖症发生的基础。而下丘脑外侧的神经元 长期以来，区域一直与食物摄入量和体重的调节有关，遗传， 这些影响背后的分子和电路机制尚不清楚。确定肥胖是如何 在单个神经元的水平上与定义的神经回路相互作用是至关重要的 因为没有这些信息，我们就不太可能发现肥胖是如何产生的。这 职业发展奖将提供技术和概念培训以及 电路神经科学领域的知名专家。最终，此培训将独一无二地定位 年轻的调查员将过渡到一个独立的研究项目，专注于调查 肥胖的神经基础。