Deciphering Neural Circuits Underlying Hippocampal Suppression of Food Intake

项目摘要 神经性厌食症及其相关并发症给我们的社会带来了巨大的负担。然而， 这种进食障碍背后的细胞和回路机制在很大程度上是未知的，有效的治疗方法 仍然缺乏。神经性厌食症的核心是一种情绪障碍，其特征是持续和严重的 自我限制进食量，常伴有焦虑。大多数研究都集中在下丘脑上。 食物摄入量的动态平衡控制。一个重要但鲜为人知的因素是食物的情感方面 入口处。加深对神经性厌食症神经机制的认识，开发新的临床应用 治疗这种进食障碍的治疗策略，因此破译其背后的神经回路至关重要 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 长期目标是能够开发新的目标来纠正或逆转饮食失调，例如 神经性厌食症。我们这项应用的总体目标是剖析神经回路 腹侧海马区厌食对摄食量的影响及其引起焦虑的作用。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区来抑制食物摄取 (LS)激活LS中的GABA能神经元，从而使LS中的GABA能神经元失活。 下丘脑外侧核(Lh)。我们的假设是基于我们最近的研究和我们的 将在方法部分详细介绍的初步数据。詹宁斯等人的工作。(2014)和吴以特 艾尔(2015)为这一假说提供了额外的支持。提出这项研究的理由是，一旦 基于腹侧海马体(VHPC)的神经性厌食症的神经回路被识别出来，它可能是 在药物上操纵它们来治疗这种疾病，以及潜在的其他饮食障碍是可行的。 为了实现我们的目标，我们组建了一个研究团队，将喂养和 感情。为了检验我们的中心假设，从而实现我们的总体目标，我们将执行三个 具体目标：(1)鉴定和表征介导vHPC抑制摄食的LS神经元群体；(2) 确定将vHPC食欲抑制信息传递给黄体生成素的LS神经元群体；(3)确定 介导vHPC所致厌食症的神经回路的焦虑效应。总体来说，基于vHPC的 厌食症和焦虑及其涉及的神经回路将使用最先进的方法进行研究， 包括光遗传辅助电路绘图、单细胞基因分析、喂养和情绪行为测试， 化学发生和光发生神经操作。使用这些尖端方法的结果将给我们带来 史无前例地了解基于vHPC的厌食症的细胞和电路机制 神经质。拟议的研究代表了与其他研究的新的和实质性的背离，因为它改变了 重点了解食物摄入的情绪方面，并为AN开发新的治疗靶点。

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.