Neural circuit mechanisms controlling non-homeostatic feeding

控制非稳态进食的神经回路机制

基本信息

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
项目类别：
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

项目摘要

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病的主要因素，因为现在超过35％的成年人被归类为超重或肥胖。诸如强迫性饮食之类的行为结果源于遗传学，先天行为和学习以前的经历的复杂相互作用。在饥饿时期形成的提示食品协会（例如，广告，在电视前的饮食等）会导致持久的记忆，这些记忆控制着非固定的过度消费。但是，神经回路，尤其是分子细胞类型，管理这种行为的定义尚未得到很好的定义。使用原始的范式，该范式诱导了具有上下文提示的小鼠过度消费，我已经确立了岛状皮质的作用，尤其是在岛状皮质中的NOS1神经元，作为学习过度耗尽的关键介体。这些神经元在稳态喂养中不发挥作用，因此假设可以自上而下地控制稳态喂养电路以控制食物的摄入量。此外，需要从岛状皮质到中央杏仁核的投影来产生这种过度消费响应。在洛克菲勒大学（Rockefeller University）的杰弗里·弗里德曼（Jeffrey Friedman）博士的主要指导下，以及西奈山伊坎医学院（Icahn Medicine）的丹妮丝·凯（Denise Cai）博士的职务，我将继续以我的行为和分子神经科学专业知识为基础，同时发展我在光源质学和体内钙化成像方面的培训。在这笔赠款的指导K阶段中，我将使用光遗传学和钙成像技术分析分子定义的皮质 - 杏仁核电路在过度消费中的作用。我还将确定Insular Cortex NOS1神经元的杏仁核靶标。在独立阶段（R00）中，我将利用逆行追踪技术来检查区域，并分子介绍了直接投射到控制过度消耗过度消耗的岛状皮质神经元的细胞类型，并在因果关系中测试它们如何在非室内饲料中涉及。这些数据将共同通过岛状皮质建立一个细胞类型的特定电路，该电路控制对环境刺激的响应过度消费。该数据将扩大参与进食行为涉及的高阶大脑区域的知识，并可能导致新型治疗途径的发展以控制过度饮食。同时，本申请中提出的研究和培训计划将使我能够发展自己的技术和专业技能，以过渡到独立的研究职位。随着该项目的成功完成，我将为一个完全独立的研究计划开发一个平台，旨在了解大脑如何协调驱动不良适应性选择的先天和学到的行为之间的相互作用。