Neural circuit mechanisms controlling non-homeostatic feeding

项目总结 强迫进食是美国肥胖症流行的主要原因，因为现在超过35%的成年人 被归类为超重或肥胖。行为结果，如强迫进食，源于一种复杂的 遗传、先天行为和对先前经验的学习之间的相互作用。主食-食物协会(例如 广告、在电视前吃饭等。)在饥饿时期形成的物质会导致持久的 控制非稳态过度消费的记忆。然而，神经电路，特别是 控制这种行为的分子细胞类型还没有很好的定义。使用一种原创的范式，导致 在有上下文线索的饱足小鼠中，我已经确立了岛叶皮质的作用，并且 具体地说，岛叶皮质中的NOS1神经元是习得性过度消费的关键中介。这些 神经元本身在动态平衡的摄食中不起作用，因此被假设为提供自上而下的 控制体内平衡的进食回路，以控制食物摄入量。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，以及洛克菲勒博士的共同指导下， 西奈山伊坎医学院的Denise Cai，我将继续在我的行为和分子基础上 在发展我的光遗传学和活体钙成像培训的同时，我获得了神经科学方面的专业知识。在 在这项资助的K期指导下，我将分析分子定义的皮质-杏仁核环路在 使用光遗传学和钙成像技术的过度消费。我还会确定杏仁核的目标 岛叶皮质NOS1神经元。在独立阶段(R00)，我将利用逆行跟踪技术来 检查区域和分子图谱直接投射到岛叶皮质神经元的细胞类型 控制过度消费，并因果测试它们在非内环境平衡喂养中的作用。 这些数据结合在一起，将通过岛叶皮质建立一个细胞类型的特定电路，控制 对环境刺激的过度消费。这些数据将扩展更高阶脑的知识 参与摄食行为的区域，并可能导致开发新的治疗途径来控制 暴饮暴食。同时，申请书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岗位。与 成功完成这个项目，我将开发一个完全独立的研究计划的平台 旨在了解大脑如何协调先天行为和后天习得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.