Neural circuit mechanisms controlling non-homeostatic feeding

控制非稳态进食的神经回路机制

• 批准号: 10297901
• 负责人: Sarah Stern
• 金额: $ 24.9万
• 依托单位: MAX PLANCK FLORIDA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10297901
• 关键词: Adult; Advertising; Amygdaloid structure; Anatomy; Animals; Area; Automobile Driving; Behavior; Behavioral; Behavioral Paradigm; Binge Eating; Biological; Brain; Brain region; Calcium; Cells; Characteristics; Cognitive; Complex; Cues; Data; Development; Disease; Eating; Emotional; Environmental Risk Factor; Fasting; Feeding behaviors; Fluorescent in Situ Hybridization; Food; Gene Expression Profile; Genetic; Goals; Grant; Healthcare; High Prevalence; Hunger; Hyperphagia; Hypothalamic structure; Image; Imaging Techniques; Immunoprecipitation; Incidence; Instinct; Knowledge; Laboratories; Lead; Learning; Maps; Mediating; Mediator of activation protein; Memory; Mentors; Mentorship; Modeling; Molecular; Molecular Profiling; Monitor; Mus; Nature; Neurons; Neurosciences; Nitric Oxide Synthase Type I; Obesity; Obesity Epidemic; Overweight; Pathway interactions; Phase; Population; Positioning Attribute; Pseudorabies; Research; Research Training; Role; Satiation; Signal Transduction; Site; Stimulus; Techniques; Television; Testing; Therapeutic; Time; Training; United States; Universities; Weight Gain; behavioral outcome; cell type; classical conditioning; craving; experience; feeding; hedonic; in vivo calcium imaging; inhibitory neuron; learned behavior; medical schools; motivated behavior; neural circuit; novel; novel therapeutics; obese person; obesity treatment; optogenetics; programs; psychologic; rabies viral tracing; relating to nervous system; response; skills; therapy development; transcriptome sequencing; tv watching

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.

强迫性饮食是美国肥胖症流行的主要原因，目前超过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基因、先天行为和对先前经历的学习等复杂交互作用。暗示-食物协会(例如，广告、在电视前吃饭等)在饥饿期间形成的记忆会产生持久的记忆，从而控制非稳态的过度消费。然而，支配这种行为的神经回路，特别是分子细胞类型并没有得到很好的定义。使用一种原始的范式，通过上下文线索在饱足的小鼠中诱导过度消费，我已经确立了岛叶皮质的作用，特别是岛叶皮质内的NOS1神经元，作为习得性过度消费的关键中介。这些神经元本身并不在平衡摄食中起作用，因此被假设为提供自上而下的控制平衡摄食回路，以控制食物摄入量。此外，从岛叶皮质到中央杏仁核的投射对于产生这种过度消费反应是必要的。在洛克菲勒大学Jeffrey Friedman博士的主要指导和西奈山伊坎医学院Denise Cai博士的共同指导下，我将继续利用我的行为和分子神经科学专业知识，同时发展我的光遗传学和活体钙成像方面的培训。在这项资助的指导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。我还将确定岛叶皮质Nos1神经元的杏仁核靶点。在独立阶段(R00)，我将利用逆行追踪技术来检查区域和分子图谱，这些细胞类型直接投射到控制过度消耗的岛叶皮质神经元，并因果地测试它们如何在功能上参与非内环境平衡的喂养。综合起来，这些数据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。这些数据将扩展涉及摄食行为的高级大脑区域的知识，并可能导致开发控制暴食的新的治疗途径。同时，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岗位。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，旨在了解大脑如何协调推动不适应选择的先天行为和后天行为之间的相互作用。