Neural circuit mechanisms controlling non-homeostatic feeding

项目摘要 强迫性进食是美国肥胖症流行的主要原因，现在超过35%的成年人 被归类为超重或肥胖。强迫性进食等行为结果源于一种复杂的 遗传学、先天行为和对先前经历的学习的相互作用。提示食品协会（如 广告、在电视机前吃饭等）在饥饿时期形成的， 控制非稳态过度消费的记忆然而，神经回路，特别是 控制这种行为的分子细胞类型还没有很好的定义。使用一个原始的范例， 在有背景线索的饱足小鼠中过度消费，我已经建立了岛叶皮层的作用， 特别是岛叶皮层内的Nos1神经元，作为习得性过度消费的关键介质。这些 神经元在自我平衡进食本身中不起作用，因此被假设为提供自上而下的 控制稳态进食回路以控制食物摄入。此外，从岛叶皮质到 中央杏仁核是产生这种过度消费反应所必需的。 在洛克菲勒大学杰弗里·弗里德曼博士的主要指导下， 丹妮丝蔡在西奈山伊坎医学院，我将继续建立我的行为和分子 神经科学专业知识，同时发展我在光遗传学和体内钙成像方面的培训。在 指导K阶段的这项赠款，我将分析分子定义的皮质杏仁核电路的作用， 过度消耗使用光遗传学和钙成像技术。我还会确定杏仁核的目标 岛叶皮层Nos1神经元的数量。在独立阶段（R00），我将利用逆行追踪技术， 检查直接投射到岛叶皮层神经元的区域并对其进行分子分析， 控制过度消费，并测试因果关系，他们是如何在功能上参与非稳态喂养。 总之，这些数据将通过岛叶皮层建立一个细胞类型特异性回路， 对环境刺激的过度消费。这些数据将扩展更高阶大脑的知识 参与摄食行为的区域，并可能导致新的治疗途径的发展，以控制 暴饮暴食同时，本申请中提出的研究和培训计划将使我能够 发展我的技术和专业技能，以便过渡到一个独立的研究职位。与 成功完成这个项目后，我将拥有一个完全独立的研究计划平台 旨在了解大脑如何协调先天和后天行为之间的相互作用， 不适应的选择

PROJECT SUMMARY Compulsive eating is a major contributor to the obesity epidemic in the US, as over 35% of adults are now classified as overweight or obese. Behavioral outcomes such as compulsive eating derive from a complex interaction of genetics, innate behaviors and learning about previous experiences. Cue-food associations (e.g. advertising, eating in front of the television, etc.) that are formed during periods of hunger lead to long-lasting memories that control non-homeostatic overconsumption. However, the neural circuitry, and specifically the molecular cell types, governing this behavior are not well defined. Using an original paradigm that induced overconsumption in sated mice with contextual cues, I have established a role of the insular cortex, and specifically Nos1 neurons within the insular cortex, as critical mediators of learned overconsumption. These neurons do not play a role in homeostatic feeding itself and are therefore hypothesized to provide top down control of homeostatic feeding circuitry to control food intake. Moreover, a projection from the insular cortex to the central amygdala is necessary to generate this overconsumption response. Under the primary mentorship of Dr. Jeffrey Friedman at the Rockefeller University and the co-mentorship of Dr. Denise Cai at the Icahn School of Medicine at Mount Sinai, I will continue to build on my behavioral and molecular neuroscience expertise while developing my training in optogenetics and in vivo calcium imaging. In the mentored K-phase of this grant, I will analyze the role of a molecularly defined cortical-amygdalar circuit in overconsumption using optogenetics and calcium imaging techniques. I will also determine the amygdala targets of insular cortex Nos1 neurons. In the independent phase (R00), I will utilize retrograde tracing techniques to examine the regions and molecularly profile the cell types that directly project to the insular cortex neurons that control overconsumption, and test causally how they are functionally involved in non-homeostatic feeding. Together, these data will establish a cell-type specific circuit through the insular cortex that controls overconsumption in response to environmental stimuli. This data will expand the knowledge of higher-order brain regions involved in feeding behavior and may lead to the development of novel therapeutic avenues to control overeating. At the same time, the research and training plans proposed in this application will enable me to develop my technical and professional skills in order to transition to an independent research position. With the successful completion of this project, I will have developed a platform for a fully independent research program aimed at understanding how the brain coordinates the interplay between innate and learned behaviors that drive maladaptive choices.