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

项目摘要 导致肥胖的一个主要因素是强迫性进食和戒食期 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 被归因于高回报的美味食物的消费，这加强了 强迫性进食行为这种流行病给社会造成的代价怎么说也不为过 并继续增长。丘脑核（NAc）是调节神经元内信号传导的主要中枢。 食物的动机，并已被广泛证明参与其他疾病与穷人 冲动控制，特别是成瘾。这一证据使NAc成为一个主要的候选区域， 研究大脑奖赏回路的功能如何受到长期美味食物的影响 消费该提案将采用一种慢性限制高脂肪摄入的模型， 研究调节食用可口食物动机的神经回路。 这项提案的目标是：1）识别因慢性高脂肪摄入而改变的神经回路， 重点放在NAc 2）建立这些神经回路在动机中的因果作用 以通过调节回路活动获得高脂肪，以及3）为申请人提供 进行独立研究计划所需的知识和技术培训 集中于阐明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，以绘制特定细胞类型的脑广泛连接性，体内钙 特定细胞类型和神经回路的成像， 在这些技术的领先专家的指导下， 都在斯坦福大学。 初步数据表明，慢性高脂肪摄入改变了NAc的内在兴奋性 以细胞类型特异性的方式对神经元进行调控。慢性高脂肪也会改变突触强度， 离散输入NAc神经元，也以细胞类型特异性方式。此外，人口 在高脂肪摄入期间，NAc的特定输入的活性增加。总的来说，这些发现 证明拟议研究的必要性及其产生知识的可能性 这将有助于制定未来的肥胖治疗策略。此外，该提案 将为申请人作为独立调查员进行调查提供许多新的线索。

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.