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.

项目总结/摘要 在过去的世纪里，受肥胖困扰的人口比例不断增加。 工业化国家。这密切跟踪了广泛可用的，高热量的，高密度的 可口的食物（快餐、糖果、汽水等）。过度消费是发病机制中的必要组成部分 肥胖症。然而，自我平衡的神经回路调节细胞之间平衡的机制， 饥饿和饱腹的感觉是否会被破坏尚不清楚。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（例如生长激素释放肽）直接增加敏感性 动机神经回路饥饿似乎代表了一种对奖赏敏感的状态;因此，食物 消费量可以主要依赖于所讨论的食物的评价的有益特性。理解 大脑的现象，使食物似乎是如此有益的将允许开发新的疗法， 更有针对性的方法来治疗肥胖症。外侧下丘脑是一个关键的调解员的线索， 奖励介导的摄食行为和了解其在奖励和食物获取中的功能将有助于 这种洞察力。在这个提议中，我们的目标是第一次描述激活的行为后果， 下丘脑外侧核（LH）向基底前脑核团（内侧隔核和斜角带）的投射 M/D）。我们已经确定了一个独特的组合，既诱导食物消费-表明饥饿-和 尽管处于食物剥夺状态，但对自我刺激的偏好超过了食物消费-这表明 内在的回报因此，我们建议阐述和表征这种独特的表型。我们也 我建议确定这条回路中突触前和突触后神经元的分子身份， 下丘脑外侧区GABA能神经元与GABA能和胆碱能双重神经元形成突触假说 在基底前脑这一全面研究的功能，LH的M/D电路将是第一次报告 在这个投影上，并提供进一步的机械洞察饥饿和奖励之间的串扰。它还将 为PI提供大量的培训和经验，使其成为一名富有成效和创新的精神科医生， 未来的医学科学家