Role of Nucleus Accumbens and Its Glutamatergic Inputs in High-Fat intake

伏核及其谷氨酸能输入在高脂肪摄入中的作用

• 批准号: 10443902
• 负责人: Daniel Joseph Christoffel
• 金额: $ 24.78万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2024-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10443902
• 关键词: Abstinence; Advisory Committees; Anatomy; Anterior; Automobile Driving; Award; Behavior; Behavioral Assay; Binge Eating; Brain; Brain region; Calcium; Chronic; Clinical; Complement; Consumption; Data; Desire for food; Detection; Development; Diet Habits; Disease; Dopamine Receptor; Eating; Epidemic; Epidemiology; Exposure to; FOS gene; Failure; Fatty acid glycerol esters; Feeding behaviors; Fiber; Food; Future; Glutamates; Goals; Health; Hour; Hyperphagia; Image; Individual; Intake; Investigation; Knowledge; Label; Light; Maps; Medial; Mentors; Mentorship; Modeling; Motivation; Mus; Negative Valence; Neural Pathways; Neurons; Nucleus Accumbens; Obesity; Obesity Epidemic; Operant Conditioning; Palate; Phase; Photometry; Population; Positive Valence; Prefrontal Cortex; Proxy; Rabies; Relapse; Research; Research Personnel; Rewards; Role; Schedule; Societies; Stains; Stimulus; Structure of paraventricular nucleus of thalamus; Synapses; Synaptic plasticity; Techniques; Therapeutic; Thinness; Training; addiction; base; calcium indicator; cell type; cost; experience; experimental study; feeding; food consumption; hedonic; improved; in vivo; in vivo calcium imaging; interdisciplinary approach; motivational processes; neural circuit; neuromechanism; obesity development; optogenetics; programs; rabies label; rabies viral tracing; relating to nervous system; reward circuitry; therapy development; trend

Project Summary A major contributor to the development of obesity is compulsive eating with periods of abstaining from unhealthy eating habits but eventual relapse. This failure to self-regulate food intake has been attributed to the consumption of palatable foods that are highly rewarding, which reinforces compulsive feeding behavior. The cost on society of this health epidemic cannot be overstated and continues to grow. The nucleus accumbens (NAc) is a primary hub of the circuitry regulating motivation for food and has been extensively shown to be involved in other disorders with poor impulse control, notably addiction. This evidence makes the NAc a prime candidate region to investigate how the function of the brain’s reward circuity is impacted by chronic palatable food consumption. This proposal will employ a model of chronic limited-access high-fat intake to investigate the neural circuits regulating motivation to consume palatable food. The objectives of this proposal are to 1) identify neural circuits altered by chronic high-fat intake, with a focus on the NAc 2) establish the causative role of these neural circuits in the motivation to obtain high-fat through modulation of circuit activity, and 3) provide the applicant with the necessary intellectual and technical training to carry out an independent research program focused on elucidating the synaptic and neural circuit mechanisms underlying compulsive overeating. These objectives will be achieved using state of the art techniques, such as monosynaptic rabies tracing to map brain wide connectivity of specific cell types, in vivo calcium imaging of specific cell types and neural circuits, optogenetic modulation of circuit activity in sophisticated behavioral assays under the mentorship of leading experts in these techniques who are present at Stanford. Preliminary data demonstrate that chronic high-fat intake alters the intrinsic excitability of NAc neurons in a cell-type specific manner. Chronic high-fat also alters the synaptic strength at discrete inputs to NAc neurons, also in a cell-type specific manner. Furthermore, the population activity of a specific input to the NAc is increased during high-fat intake. Collectively these findings demonstrate the need for the proposed studies and likelihood that they will generate knowledge that will aid in the development of future therapeutic strategies for obesity. Moreover, this proposal will generate many new lines of inquiry for the applicant to pursue as an independent investigator.

项目摘要 导致肥胖的一个主要原因是强迫性进食和禁食期。 不健康的饮食习惯，但最终会复发。这种自我调节食物摄入量的失败已经 被归因于食用美味的食物是非常有回报的，这加强了 强迫性进食行为。这种健康流行病给社会带来的代价怎么夸大都不为过。 而且还在继续增长。伏隔核(NAC)是回路调节的主要中枢 对食物的动力，并已被广泛证明与其他贫困的障碍有关 控制冲动，尤其是上瘾。这一证据使南汽成为 研究慢性美味食物对大脑奖赏回路功能的影响 消费。该提案将采用一种慢性有限获取高脂肪摄入的模式来 研究调节美味食物消费动机的神经回路。 这项提议的目标是：1)识别长期高脂肪摄入改变的神经回路， 重点研究NAC 2)建立这些神经回路在动机中的因果作用 通过调节电路活性获得高脂肪，以及3)为申请人提供 开展独立研究项目所需的智力和技术培训 重点阐明了强迫症背后的突触和神经回路机制 暴饮暴食。这些目标将使用最先进的技术来实现，例如 单突触狂犬病示踪法绘制脑内特定细胞类型、体内钙离子的广泛连接 对特定细胞类型和神经电路的成像，对电路活动的光遗传调制 在这些技术的领先专家的指导下进行的复杂的行为分析 都在斯坦福大学。 初步数据显示，长期高脂肪摄入改变了NAC的内在兴奋性 神经元以一种细胞类型特定的方式。慢性高脂肪也会改变突触的强度 对NAC神经元的离散输入，也是以特定细胞类型的方式。此外，人口 在高脂肪摄入期间，NAC的特定输入活动会增加。总而言之，这些发现 证明拟议研究的必要性以及它们将产生知识的可能性 这将有助于开发未来的肥胖症治疗策略。此外，这项建议 将产生许多新的调查线索，供申请者作为独立调查员进行调查。