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: 10208067
• 负责人: Haijiang Cai
• 金额: $ 37.74万
• 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/10208067
• 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.

项目概要/摘要 肠道分泌的食欲抑制剂，例如胆囊收缩素（CCK），在抑制食欲方面发挥着关键作用。 调节进食行为。然而，基于CCK或其受体的药物未能有效治疗肥胖。 这些药物缺乏特定的神经靶标，因为外周 CCK 的中枢神经机制 调节食欲尚不完全清楚。我们的长期目标是了解神经机制 调节食欲和体重，并开发相应的疗法来治疗肥胖和饮食失调。 使用新颖的遗传方法，我们鉴定了中央杏仁核（CEA）神经元的特定群体，其标记为 蛋白激酶 C δ (PKC-δ) 的表达，这是 CCK 对食欲的影响所必需的 抑制。我们证明 CEA PKC-δ 神经元通过抑制性突触抑制进食 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 引起的厌食症的下游靶标尚不清楚。该应用程序的目的是确定 位于 CEA 下游的中央大脑区域的神经回路参与调节 CCK 引发的摄食 抑制。中心假设是大脑交叉区域，即突触去抑制 CEA PKC-δ 神经元由 CCK 激活，介导 CCK 诱导的摄食抑制和食欲控制。 拟议研究的基本原理是，识别食欲的中枢大脑神经回路 控制将促进我们对 CCK 引起的厌食和进食控制的神经机制的理解， 并提出开发治疗肥胖和饮食失调的有效疗法的新策略。指导者 有了强有力的初步数据，该假设将通过追求三个具体目标来检验：（1）建立功能性 从 CEA PKC-δ 神经元到下游目标的电路连接。 (2)确定神经元的作用 CCK 诱导的摄食抑制中 CEA PKC-δ 阴性神经元的下游。我们将测试工作 假设进食是由 CEA PKC-δ 阴性神经元下游的神经元调节的 由CCK激活。 (3)确定CEA PKC-δ阴性神经元通过的具体神经通路 调节 CCK 对摄食抑制的作用。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来调节 CCK 引起的摄食抑制。 拟议研究的创新包括使用独特遗传标记的交叉方法 神经元标记与成熟的食欲抑制剂相结合，以绘制中枢大脑神经元图谱 喂养调节回路，并将开发和应用新工具来剖析特定功能的神经回路。 最后，所提出的研究意义重大，因为它将提供中枢大脑中的新神经目标 区域并确定它们在食欲控制神经轴中的作用。这些知识有可能提供信息 开发包括治疗肥胖和饮食失调的特定神经靶点的新疗法。