Neural circuit mechanisms controlling non-homeostatic feeding

强迫性进食是美国肥胖症流行的主要原因，因为超过35%的成年人现在被归类为超重或肥胖。强迫性进食等行为结果来自遗传、先天行为和对以往经历的学习的复杂相互作用。暗示食物协会（例如广告，在电视机前吃饭等）在饥饿期间形成的记忆会导致控制非稳态过度消费的持久记忆。然而，控制这种行为的神经回路，特别是分子细胞类型还没有很好的定义。使用一个原始的范例，诱导过度消费的饱足小鼠与上下文线索，我已经建立了岛叶皮层的作用，特别是岛叶皮层内的Nos 1神经元，作为学习过度消费的关键介质。这些神经元在稳态进食本身中不起作用，因此被假设为提供自上而下的稳态进食回路控制食物摄入。此外，从岛叶皮质到中央杏仁核的投射是产生这种过度消费反应所必需的。在洛克菲勒大学的Jeffrey Friedman博士和西奈山伊坎医学院的Denise Cai博士的共同指导下，我将继续发展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。在本基金的指导K阶段，我将使用光遗传学和钙成像技术分析分子定义的皮质-杏仁核回路在过度消费中的作用。我还将确定岛叶皮层Nos 1神经元的杏仁核目标。在独立阶段（R 00），我将利用逆行追踪技术来检查直接投射到控制过度消费的岛叶皮层神经元的区域和细胞类型的分子特征，并因果地测试它们在功能上如何参与非稳态喂养。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，控制对环境刺激的过度消费。这些数据将扩大涉及进食行为的高级大脑区域的知识，并可能导致控制暴饮暴食的新治疗途径的发展。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，以便过渡到独立的研究职位。随着这个项目的成功完成，我将为一个完全独立的研究项目开发一个平台，该项目旨在了解大脑如何协调驱动适应不良选择的先天行为和习得行为之间的相互作用。

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.