Dissecting a novel prefrontal cortical pathway regulating feeding behavior

剖析调节进食行为的新型前额皮质通路

• 批准号: 10667774
• 负责人: Rachel A Ross
• 金额: $ 12.72万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-28 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10667774
• 关键词: Advisory Committees; Affect; Agonist; Animal Model; Animals; Anorexia; Association Learning; Back; Behavior; Behavioral Assay; Body Weight; Brain; Brain region; Cells; Cognitive; Communities; Complex; Data; Decision Making; Dedications; Development; Eating; Eating Disorders; Emotions; Endocrinology; Energy Metabolism; Environment; Feeding behaviors; Female; Fiber; Food; Foundations; Functional disorder; Genes; Genetic; Genetic Engineering; Genetically Engineered Mouse; Goals; Habits; Hospitals; Human; Hyperphagia; Hypothalamic structure; Individual; International; Intervention; Israel; Learning; Ligands; Link; Measures; Medial; Medical center; Melanocortin 4 Receptor; Mental disorders; Mentorship; Metabolic; Metabolic Diseases; Metabolism; Methods; Morbidity - disease rate; Mus; Neurobiology; Neurons; Neurosciences; Nutrient; Obesity; Obesity Epidemic; Output; Pathology; Pathway interactions; Peptides; Pharmaceutical Preparations; Pharmacology; Photometry; Physicians; Physiological; Play; Population; Population Projection; Prefrontal Cortex; Proteins; Psychiatry; Regulation; Research; Rest; Rodent; Role; Satiation; Scientist; Sex Differences; Signal Transduction; Site; Societies; Synapses; Techniques; Testing; Time; Training; Translating; Viral; Virus; Weight Gain; Work; awake; base; career; career development; cell type; cost; executive function; experimental study; feeding; flexibility; human imaging; imaging study; improved; integration site; interest; male; mortality; mouse model; neural circuit; neuromechanism; novel; obese person; obesity treatment; relating to nervous system; response; sex; sexual dimorphism; side effect; therapeutic target; tool

PROJECT SUMMARY/ABSTRACT Eating disorders, spanning obesity to anorexia, are highly prevalent and problematic in our society. They are difficult to treat, affect a large proportion of the population, and underlie many other causes of morbidity that have become increasingly costly to manage. Furthermore, feeding behavior is upset in multiple psychiatric disorders and weight gain is a common side effect of many psychotropic medications, but the pathophysiology of these effects is unknown. Therefore, the study of feeding behavior and the neurocircuitry of metabolism are of great interest to psychiatry. Using cutting-edge neuroscience tools to build on traditional genetic methods, the applicant proposes a functional mechanism for projections from satiety-associated neurons in the hypothalamus (POMC neurons) to medial prefrontal cortex melanocortin-4 receptor-expressing neurons (mPFCMC4R) in the pathophysiology of overeating related to obesity. In this mouse-based study, the applicant will examine a novel pathway from POMC neurons to the infralimbic region of the mPFC and investigate the relevance to feeding behavior. First, she will determine if mPFCMC4R neurons, and specifically those that receive projections from POMC neurons, play a role in executive function specific to food-related decisions, focusing on set-shifting and rule reversal (Aim 1). Next, she will perform the same behavioral assays while recording the activity of the mPFCMC4R neurons in awake, behaving mice (Aim 2). These studies will employ genetically engineered mice and viruses that together enable temporal and spatial control and study of specific subpopulations of neurons, and will be performed in both male and female mice. Together, these aims will show that the POMCà mPFCMC4R circuit is a key node in the development of overeating behavior, and consider sex-specific vulnerability to overeating at this unique site of integration of feeding behavior and executive function. Further, this work will provide new animal models for future research with dissociable behavior and physiologic outputs as well as potential therapeutic targets which are urgently needed for eating disorders. The applicant, Dr. Rachel Ross, is well qualified to execute the proposed experiments. She is committed to pursuing a scientific career in neuroscience of behavior and has proposed a comprehensive four-year plan to meet her goal of becoming an independent physician-scientist. Dr. Ross will be working under the primary mentorship of Dr. Kerry Ressler with co-mentorship from Dr. Bradford Lowell. She has enlisted a research advisory committee of internationally-recognized experts in neuroscience and psychiatry to support her. The Department of Psychiatry at McLean Hospital (and secondary site of the Division of Endocrinology at Beth Israel Deaconess Medical Center) is an ideal environment for completion of her scientific and career development objectives given the outstanding research community, tradition of scientific discovery, and ongoing dedication to trainee mentorship in this field.

项目概要/摘要 从肥胖到厌食症的饮食失调在我们的社会中非常普遍且存在问题。 难以治疗，影响很大一部分人口，并且是许多其他发病原因的基础 此外，许多精神病患者的喂养行为也受到干扰。 疾病和体重增加是许多精神药物的常见副作用，但病理生理学 因此，对进食行为和代谢神经回路的研究尚不清楚。 对精神病学非常感兴趣。 申请人利用尖端的神经科学工具以传统的遗传方法为基础，提出了一种 下丘脑中与饱足感相关的神经元（POMC 神经元）投射到 内侧前额皮质黑皮质素 4 受体表达神经元 (mPFCMC4R) 在病理生理学中的作用 在这项基于小鼠的研究中，申请人将研究一种新的途径。 POMC 神经元连接到 mPFC 的边缘下区域并研究与进食行为的相关性。 她将确定 mPFCMC4R 神经元，特别是那些接收 POMC 神经元投射的神经元， 在食品相关决策的执行功能中发挥作用，重点关注设定转移和规则逆转 （目标 1）接下来，她将执行相同的行为分析，同时记录 mPFCMC4R 的活动。 清醒、行为正常的小鼠中的神经元（目标 2）将采用基因工程小鼠和病毒。 它们共同实现了对特定神经元亚群的时间和空间控制和研究，并将 在雄性和雌性小鼠中共同进行，这些目标将表明 POMCà mPFCMC4R 电路是 暴饮暴食行为发展的关键节点，并考虑性别特定的暴饮暴食脆弱性 此外，这项工作还将提供新的进食行为和执行功能整合的独特场所。 用于未来研究的动物模型，具有分离行为和生理输出以及潜力 饮食失调迫切需要的治疗目标。 申请人雷切尔·罗斯博士完全有资格执行所提议的实验。 追求行为神经科学的科学事业，并提出了一个全面的四年计划 罗斯博士将在初级学院工作，以实现她成为一名独立医师科学家的目标。 在 Kerry Ressler 博士的指导下，在 Bradford Lowell 博士的共同指导下，她参与了一项研究。 由国际公认的神经科学和精神病学专家组成的咨询委员会为她提供支持。 麦克莱恩医院精神病科（以及贝斯内分泌科二级站点） 以色列女执事医疗中心）是完成她的科学和职业生涯的理想环境 考虑到杰出的研究团体、科学发现的传统以及 持续致力于该领域的实习生指导。