A novel lateral hypothalamic neurocircuit enhances rewarding aspects of feeding

一种新型的下丘脑外侧神经回路增强了进食的奖励性

• 批准号: 9756766
• 负责人: Ryan M Cassidy
• 金额: $ 3.25万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756766
• 关键词: Affect; Alcohol consumption; Alcohols; Anxiety; Appetitive Behavior; Automobile Driving; Behavior; Behavioral; Brain; Brain region; Calories; Candy; Cell Nucleus; Consumption; Cues; Data; Decision Making; Developed Countries; Development; Diagonal Band of Broca; Eating; Electrophysiology (science); Equilibrium; Esthesia; Evaluation; Fasting; Feeding behaviors; Fiber Optics; Food; Food deprivation (experimental); Future; Hunger; Hypothalamic structure; Immunohistochemistry; Individual; Laboratories; Lasers; Lateral; Medial; Mediating; Mediator of activation protein; Metabolic; Metabolic Diseases; Midbrain structure; Modernization; Molecular; Motivation; Mus; Neurobiology; Neurons; Neurosciences; Neurosecretory Systems; Nicotine; Obesity; Obesity Epidemic; Opioid; Palate; Pathogenesis; Peripheral; Phenotype; Physicians; Physiological; Population; Property; Psychiatrist; Relapse; Reporting; Research; Rewards; Role; Satiation; Scientist; Self Stimulation; Signal Transduction; Somatostatin; Substance abuse problem; Substance of Abuse; Synapses; System; Techniques; Testing; Time; Tracer; Training; United States; Veins; addiction; basal forebrain; behavior test; cholinergic; cholinergic neuron; craving; energy balance; experience; fast food; feeding; food consumption; gamma-Aminobutyric Acid; ghrelin; hormonal signals; in vivo calcium imaging; innovation; insight; interest; intravenous administration; motivated behavior; neurotransmission; novel; novel therapeutics; obesity treatment; optogenetics; postsynaptic neurons; preference; presynaptic neurons; relating to nervous system; reward circuitry; soft drink; systems research

Project Summary/Abstract The percentage of the population afflicted by obesity has relentlessly increased over the past century in industrialized countries. This has closely tracked the development of widely available, calorically dense, highly palatable foods (fast food, candy, soda, etc). Overconsumption is a necessary component in the pathogenesis of obesity. However, the mechanisms by which the homeostatic neurocircuits regulating the balance between sensations of hunger and satiety are disrupted is not yet known. Interestingly, there is mounting evidence that the neural and hormonal signals indicating negative energy balance (e.g. ghrelin) directly increase the sensitivity of the motivational neurocircuitry. It appears that hunger may represent a state of reward sensitivity; thus, food consumption may primarily rely upon the evaluated rewarding properties of the food in question. Understanding the brain phenomena which make food seem so rewarding will allow the development of novel therapies and more targeted approaches in treatment of obesity. The lateral hypothalamus is a key mediator of cue- and reward-mediated feeding behavior and understanding its function in both reward and food acquisition will lend this insight. In this proposal, we aim to characterize, for the first time, the behavioral consequence of activating the lateral hypothalamus (LH) projections to basal forebrain nuclei (medial septum and diagonal band of broca M/D). We have identified a unique combination of both induced food consumption - indicating hunger - and preference for self-stimulation over food consumption despite being in a food deprived state -indicating it is intrinsically rewarding. Thus, we propose to elaborate and characterize on this unique phenotype. We also propose to identify the molecular identity of both the pre- and postsynaptic neurons in this circuit, with the hypothesis that lateral hypothalamic GABAergic neurons synapse on dual GABAergic and cholinergic neurons in the basal forebrain. This comprehensive study of the function of the LHM/D circuit will be the first to report on this projection and lend further mechanistic insight into the crosstalk between hunger and reward. It will also provide the PI with substantial training and experience to become a productive and innovative psychiatrist and physician scientist in the future.

项目概要/摘要 在过去的一个世纪里，受肥胖困扰的人口比例不断增加 工业化国家。这密切关注了广泛使用、热量密集、高度 可口的食物（快餐、糖果、苏打水等）。过度消费是发病的必要组成部分 肥胖症。然而，稳态神经回路调节之间平衡的机制 饥饿感和饱腹感是否受到干扰尚不清楚。有趣的是，越来越多的证据表明 指示负能量平衡的神经和激素信号（例如生长素释放肽）直接增加敏感性 动机神经回路。看来饥饿可能代表了一种奖赏敏感的状态。因此，食物 消费可能主要取决于所评估的相关食品的有益特性。理解 使食物看起来如此有益的大脑现象将有助于开发新的疗法和 治疗肥胖症的更有针对性的方法。下丘脑外侧是提示和信号的关键调节者 奖励介导的进食行为并了解其在奖励和食物获取中的功能将有助于 这种洞察力。在这个提案中，我们的目标是首次描述激活的行为后果 下丘脑外侧 (LH) 投射至前脑基底核（内侧隔膜和布罗卡对角线带） 医学博士）。我们已经确定了诱导食物消费（表明饥饿）和 尽管处于食物匮乏的状态，但仍偏爱自我刺激而不是食物消费——表明这是 本质上是有益的。因此，我们建议对这种独特的表型进行详细阐述和表征。我们也 提议识别该电路中突触前和突触后神经元的分子身份，其中 假设下丘脑外侧 GABA 能神经元与双 GABA 能和胆碱能神经元有突触 在基底前脑中。本文全面研究LHM/D电路的功能，将率先报道 在此预测上，并进一步深入了解饥饿与奖励之间的相互作用。它还将 为 PI 提供大量培训和经验，使其成为一名富有成效和创新精神的精神科医生， 未来的医生科学家。