Deciphering Neural Circuits Underlying Hippocampal Suppression of Food Intake

破译海马抑制食物摄入的神经回路

• 批准号: 9899824
• 负责人: Yunlei Yang
• 金额: $ 41.75万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899824
• 关键词: Anorexia; Anorexia Nervosa; Anxiety; Anxiety Disorders; Area; Brain; Brain region; Cells; Clinical; Data; Desire for food; Development; Disease; Eating; Eating Disorders; Elements; Emotional; Emotional disorder; Emotions; Genes; Glutamates; Goals; Health; Hippocampus (Brain); Hypothalamic structure; Individual; Lateral; Literature; Mediating; Methodology; Methods; Neurons; Pharmacology; Population; Process; Research; Societies; Techniques; Testing; Therapeutic; Work; base; behavior test; comorbidity; dentate gyrus; effective therapy; emotional eating; feeding; food restriction; insight; neural circuit; neural model; neuromechanism; new therapeutic target; novel; optogenetics; prevent; relating to nervous system

Project Summary Anorexia nervosa (AN) and its associated complications impose a huge burden to our society. However, the cellular and circuits mechanisms underlying this eating disorder are largely unknown, and effective treatments are still lacking. At its core, anorexia nervosa is an emotional disorder characterized by persistent and severe self-restriction of food intake and commonly co-occurring with anxiety. Most work has focused on hypothalamic homeostatic control of food intake. An important but poorly understood element is the emotional aspect of food intake. To further our understandings of the neural mechanisms of anorexia nervosa and develop new clinical therapeutic strategies to treat this eating disorder, it thus is critical to decipher the neural circuits underlying this disorder and determine whether the neural circuits for anorexia and anxiety are distinct or overlapping. Our long-term goal is to enable the development of novel targets to correct or reverse eating disorders, such as anorexia nervosa. Our overall objective for this application is to dissect the neural circuits that mediate the ventral hippocampal anorexigenic effects on food intake and their anxiogenic effects. Our central hypothesis is that the ventral hippocampus suppresses food intake by projecting glutamatergic inputs to the lateral septum (LS) to activate GABAergic neurons in the LS, which subsequently inactivates GABAergic neurons in the lateral hypothalamus (LH). Our hypothesis has been formulated on the basis of our recent study and our preliminary data which will be detailed in the Approach section. The work of Jennings et al. (2014) and Wu et al. (2015) provides additional support for this hypothesis. The rational for the proposed research is that, once the neural circuits underlying the ventral hippocampus (vHPC)-based anorexia nervosa are identified, it may be feasible to pharmacologically manipulate them to treat this disorder, and potentially other eating disorders. To accomplish our goals, we have assembled a research team that combines expertise of feeding and emotions. To test our central hypothesis and thereby accomplish our overall objective, we will carry out three Specific Aims: (1) Identify and characterize LS neuron populations mediating vHPC suppression of feeding; (2) Identify LS neuron populations that relay the vHPC appetitive suppressive information to LH; (3) Determine the anxiogenic effects of the neural circuits mediating the vHPC-based anorexia. Collectively, the vHPC-based anorexia and anxiety and the involved neural circuits will be studied using state-of-the-art methodologies that include optogenetic-assisted circuit mapping, single-cell gene analysis, feeding and emotional behavioral tests, chemogenetic-and optogenetic neural manipulations. Results using these cutting-edge methods will give us unprecedented access to understanding the cellular and circuit mechanisms of the vHPC-based anorexia nervosa. The proposed research represents a new and substantial departure from other studies in that it shifts the focus to understanding emotional aspects of food intake and developing new therapeutic targets for AN.

项目摘要 神经性厌食症（AN）及其相关的并发症给我们的社会带来了巨大负担。但是， 该饮食失调障碍的基础的细胞和电路机制在很大程度上是未知的，有效的治疗方法 仍然缺乏。从本质上讲，神经性厌食症是一种情绪障碍，其特征是持续且严重 食物摄入量的自限制，通常与焦虑症共同出现。大多数工作都集中在下丘脑上 食物摄入的稳态控制。食物的情感方面是一个重要但知之甚少的元素 进气。进一步了解我们对神经神经神经机制的理解，并发展出新的临床 治疗这种饮食失调的治疗策略，因此，破译这一基础的神经回路至关重要 障碍并确定厌食和焦虑的神经回路是不同的还是重叠的。我们的 长期目标是使新目标的发展纠正或逆转饮食失调，例如 神经性厌食症。我们对此应用的总体目标是剖析介导的神经回路 腹侧海马厌食症对食物摄入及其焦虑作用的影响。我们的中心假设是 腹侧海马通过将谷氨酸能输入投入到外侧隔隔隔隔室来抑制食物摄入量 （LS）激活LS中的GABA能神经元，随后使GABA能神经元失活 下丘脑（LH）。我们的假设是根据我们最近的研究和我们的 初步数据将在“进近”部分中详细介绍。詹宁斯等人的工作。 （2014年）和WU ET al。 （2015）为这一假设提供了额外的支持。拟议的研究的理性是，曾经 确定了基于腹侧海马（VHPC）的神经性神经性厌食的神经回路，可能是 可行的药理操纵它们以治疗这种疾病，并可能是其他饮食失调。 为了实现我们的目标，我们组建了一个研究团队，结合了喂养专业知识和 情绪。为了检验我们的中心假设并实现我们的整体目标，我们将执行三个 具体目的：（1）识别和表征介导VHPC抑制喂养的LS神经元种群； （2） 识别LS神经元种群将VHPC的抑制性信息传达给LH； （3）确定 介导基于VHPC的厌食症的神经回路的焦虑作用。共同基于VHPC 将使用最先进的方法来研究厌食和焦虑以及所涉及的神经回路 包括光学辅助电路映射，单细胞基因分析，进食和情绪行为测试， 化学遗传学和光学神经操纵。使用这些尖端方法的结果将为我们提供 前所未有的访问理解基于VHPC的厌食的细胞和电路机制 神经。拟议的研究代表了与其他研究的新事物，因为它发生了变化 理解食物摄入量的情感方面并为AN开发新的治疗靶点的重点。