Neural circuit mechanisms controlling non-homeostatic feeding

控制非稳态进食的神经回路机制

• 批准号: 10327339
• 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/10327339
• 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; obesity treatment; optogenetics; programs; psychologic; rabies viral tracing; relating to nervous system; response; skills; therapy development; transcriptome sequencing; tv watching

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.

项目摘要 强迫性饮食是美国肥胖症流行的主要因素，因为现在有超过35％的成年人 归类为超重或肥胖。诸如强迫饮食之类的行为结果来自复合物 遗传学，先天行为和学习以前的经历的相互作用。提示食品协会（例如 广告，在饥饿期间形成的电视前面进食等） 控制非际压局过度消费的记忆。但是，神经回路，特别是 分子细胞类型，管理这种行为的定义没有很好地定义。使用诱导的原始范式 我在具有上下文提示的小鼠中过度消费，我已经确立了岛状皮质的作用，并且 特定于岛状皮质中的NOS1神经元，作为学习过度消耗的关键介体。这些 神经元在稳态喂养中不起作用，因此假设可以提供自上而下 控制稳态进食电路以控制食物摄入。此外，从岛状皮质到 中央杏仁核对于产生这种过度消费响应是必要的。 在洛克菲勒大学的杰弗里·弗里德曼（Jeffrey Friedman）博士的主要指导下，并在博士博士的教会中 丹妮丝·凯（Denise Cai）在西奈山（Mount Sinai）的伊坎医学院，我将继续以行为和分子为基础 神经科学专业知识在开发我在光遗传学和体内钙成像方面的培训时。在 指导了该赠款的K期，我将分析分子定义的皮质 - 杏仁核电路的作用 使用光遗传学和钙成像技术过度消费。我还将确定杏仁核目标 岛状皮质NOS1神经元。在独立阶段（R00），我将利用逆行跟踪技术 检查区域并分子介绍直接投射到岛状皮质神经元的细胞类型 控制过度消费，并通过因果测试它们在功能上如何参与非室外喂养。 这些数据将共同通过控制的岛状皮质建立一个细胞类型的特定电路 响应环境刺激的过度消费。这些数据将扩大高阶大脑的知识 参与进食行为的区域，可能导致新的治疗途径的发展 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，以过渡到独立的研究职位。与 我将成功完成该项目，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驱动的先天和学识渊博的行为之间的相互作用 适应不良的选择。