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.

项目概要 神经性厌食症（AN）及其相关并发症给我们的社会带来了巨大的负担。然而， 这种饮食失调背后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 自我限制食物摄入量，通常与焦虑同时发生。大多数工作都集中在下丘脑 食物摄入的稳态控制。一个重要但鲜为人知的因素是食物的情感方面 摄入量。进一步了解神经性厌食症的神经机制并开发新的临床 治疗这种饮食失调的治疗策略，因此破译其背后的神经回路至关重要 紊乱并确定厌食症和焦虑症的神经回路是不同的还是重叠的。我们的 长期目标是开发新的靶标来纠正或逆转饮食失调，例如 神经性厌食症。我们此应用的总体目标是剖析介导 腹侧海马对食物摄入的厌食作用及其致焦虑作用。我们的中心假设是 腹侧海马体通过将谷氨酸能输入投射到外侧隔膜来抑制食物摄入 (LS) 激活 LS 中的 GABA 能神经元，随后使 LS 中的 GABA 能神经元失活 下丘脑外侧（LH）。我们的假设是根据我们最近的研究和我们的研究提出的 初步数据将在方法部分详细介绍。詹宁斯等人的工作。 (2014) 和吴等人 等人。 （2015）为这一假设提供了额外的支持。拟议研究的理由是，一旦 确定了基于腹侧海马（vHPC）的神经性厌食症的神经回路，这可能是 通过药理学操纵它们来治疗这种疾病以及潜在的其他饮食失调是可行的。 为了实现我们的目标，我们组建了一个研究团队，结合了喂养和 情绪。为了检验我们的中心假设并从而实现我们的总体目标，我们将进行三个 具体目标：(1) 识别和表征介导 vHPC 摄食抑制的 LS 神经元群； (2) 识别将 vHPC 食欲抑制信息传递给 LH 的 LS 神经元群； (3) 确定 介导基于 vHPC 的厌食症的神经回路的致焦虑作用。总的来说，基于 vHPC 的 将使用最先进的方法来研究厌食症和焦虑症以及所涉及的神经回路 包括光遗传学辅助电路图谱、单细胞基因分析、喂养和情绪行为测试， 化学遗传学和光遗传学神经操作。使用这些尖端方法的结果将为我们提供 前所未有地了解基于 vHPC 的厌食症的细胞和电路机制 紧张。拟议的研究代表了与其他研究的新的实质性区别，因为它改变了 重点是了解食物摄入的情绪方面并为 AN 开发新的治疗目标。