Dissecting a central amygdala-parasubthalamic nucleus circuitry underlying appetite control

解剖中央杏仁核-旁丘脑核电路控制食欲

• 批准号: 10358605
• 负责人: Haijiang Cai
• 金额: $ 37.69万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10358605
• 关键词: Adult; Affect; Amygdaloid structure; Anorexia; Appetite Regulation; Area; Attenuated; Body Weight; Brain; Brain region; Cell Nucleus; Cholecystokinin; Data; Desire for food; Development; Disease; Eating; Eating Disorders; Fasting; Feeding behaviors; Food; Gastrointestinal tract structure; Genetic; Genetic Markers; Goals; Health; Knowledge; Label; Maps; Mediating; Methods; Neural Pathways; Neurons; Obesity; Outcome; Peptides; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Play; Population; Public Health; Regulation; Research; Role; Satiation; Structure; Synapses; Testing; United States; Vagus nerve structure; anorexic; base; effective therapy; feeding; gamma-Aminobutyric Acid; inhibitory neuron; innovation; neural circuit; neuromechanism; novel; novel strategies; novel therapeutics; obesity treatment; protein expression; protein kinase C-delta; receptor; relating to nervous system; therapy development; tool

Project Summary/Abstract Appetite suppressing agents secreted from the gut, such as cholecystokinin (CCK), play a critical role in regulating feeding behavior. However, drugs based on CCK or its receptors failed to effectively treat obesity. These drugs lack a specific neural target because the central neural mechanism underlying how peripheral CCK regulates appetite is not fully understood. Our long-term goal is to understand the neural mechanisms that regulate appetite and body weight, and to develop corresponding therapies to treat obesity and eating disorders. Using novel genetic methods, we identified a specific population of central amygdala (CEA) neurons, marked by the expression of protein kinase C delta (PKC-δ), that are necessary for the effect of CCK on appetite suppression. We demonstrated that CEA PKC-δ neurons suppress feeding through inhibitory synaptic connections with CEA PKC-δ negative neurons. However, the identity of CEA PKC-δ negative neurons and their downstream targets for CCK-induced anorexia are unknown. The objective of this application is to determine the neural circuits in the central brain areas that are downstream of CEA involved in regulating CCK-elicited feeding suppression. The central hypothesis is that the intersectional brain regions, i.e. disynaptically disinhibited by CEA PKC-δ neurons and activated by CCK, mediate CCK-induced feeding suppression and appetite control. The rationale for the proposed research is that the identification of the central brain neural circuits for appetite control will advance our understanding of the neural mechanisms of CCK-induced anorexia and feeding control, and suggest novel strategies for developing effective therapies to treat obesity and eating disorders. Guided by strong preliminary data, the hypothesis will be tested by pursuing three Specific Aims: (1) Establish functional circuitry connections from CEA PKC-δ neurons to the downstream targets. (2) Determine the role of the neurons downstream of CEA PKC-δ negative neurons in CCK-induced feeding suppression. We will test the working hypothesis that feeding is regulated by the neurons that are downstream of CEA PKC-δ negative neurons and activated by CCK. (3) Determine the specific neural pathways through which CEA PKC-δ negative neurons regulate the effect of CCK on feeding suppression. We will test the working hypothesis that neural circuits project from CEA PKC-δ negative neurons to their downstream neurons to regulate CCK-elicited feeding suppression. The innovation of the proposed research includes the intersectional approach of using unique genetic marker labeling of neurons combined with a well-established appetite suppression agent to map the central brain neural circuits for feeding regulation, and will develop and apply new tools to dissect functional-specific neural circuits. Finally, the proposed research is significant because it will provide novel neural targets in the central brain regions and determine their role in the neural axis of appetite control. Such knowledge has the potential to inform the development of novel therapies that include specific neural targets to treat obesity and eating disorders.

项目总结/摘要 从肠道分泌的食欲抑制剂，如胆囊收缩素（CCK），在胃肠道疾病中起关键作用。 调节摄食行为。然而，基于CCK或其受体的药物未能有效治疗肥胖。 这些药物缺乏一个特定的神经靶点，因为中枢神经机制如何外周CCK 调节食欲的方法还不完全清楚。我们的长期目标是了解 调节食欲和体重，并开发相应的治疗肥胖和饮食失调的疗法。 使用新的遗传学方法，我们确定了一个特定的中央杏仁核（CEA）神经元群体，标记为 蛋白激酶C-δ（PKC-δ）的表达，这是CCK影响食欲所必需的 镇压我们证明CEA PKC-δ神经元通过抑制性突触抑制摄食， 与CEA PKC-δ阴性神经元的连接。然而，CEA PKC-δ阴性神经元的身份及其 CCK诱导的厌食症的下游靶点是未知的。本申请的目的是确定 CEA下游的中枢脑区中的神经回路参与调节CCK引起的进食 镇压中心假设是，交叉脑区，即由神经元引起的突触解除抑制， CEA PKC-δ神经元被CCK激活，介导CCK诱导的摄食抑制和食欲控制。 这项研究的基本原理是，确定食欲的中枢脑神经回路 控制将促进我们对CCK诱导的厌食和进食控制的神经机制的理解， 并提出了开发有效治疗肥胖和饮食失调的新策略。指导 强有力的初步数据，假设将通过追求三个具体目标进行测试：（1）建立功能 从CEA PKC-δ神经元到下游靶点的电路连接。(2)确定神经元的作用 在CCK诱导的摄食抑制中，CEA PKC-δ阴性神经元的下游。我们将测试 假设进食受CEA PKC-δ阴性神经元下游的神经元调节， 由CCK激活(3)确定CEA PKC-δ阴性神经元的特异性神经通路 调节CCK对摄食抑制的影响。我们将测试神经回路投射的工作假设 从CEA PKC-δ阴性神经元到其下游神经元调节CCK引起的摄食抑制。 本研究的创新之处在于采用独特的遗传标记进行交叉研究 标记神经元结合成熟的食欲抑制剂以绘制中枢脑神经系统 回路的喂养调节，并将开发和应用新的工具来解剖功能特定的神经回路。 最后，这项研究具有重要意义，因为它将为中枢神经系统提供新的靶点 区域，并确定其在食欲控制的神经轴中的作用。这些知识有可能为我们提供信息， 开发新的治疗方法，包括治疗肥胖和饮食失调的特定神经靶点。