Amylin modulates food reward

胰淀素调节食物奖励

• 批准号: 10317621
• 负责人: MATTHEW R HAYES
• 金额: $ 62.73万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 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 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10317621
• 关键词: 3-Dimensional; Acute; Adult; Affect; Agonist; Animal Model; Animals; Appetite Depressants; Basic Science; Behavior Control; Behavioral; Body Weight; Brain; Brain Stem; Calcitonin Receptor; Calcium; Cell Nucleus; Cells; Chronic; Complex; Consumption; Cues; DRD2 gene; Development; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Dorsal; Eating; Economic Burden; Fiber; Fluorescent in Situ Hybridization; Food; Future; G-Protein-Coupled Receptors; Genetic Transcription; Hormones; Impulsivity; Intake; Knowledge; Lateral; Manuscripts; Measures; Mediating; Metabolic; Modeling; Motivation; Neurons; Nucleus Accumbens; Obesity; Obesity Epidemic; Overweight; Palate; Pharmacologic Substance; Pharmacotherapy; Phenotype; Photometry; Physiological; Population; Psychological reinforcement; Public Health; Ramp; Rattus; Receptor Activation; Receptor Signaling; Rewards; Role; Satiation; Self Administration; Series; Signal Transduction; Site; Structure of area postrema; System; Testing; Time; Transgenic Organisms; Ventral Tegmental Area; Viral; Weight Gain; Work; amylin receptor; base; calcium indicator; discounting; experience; experimental study; feeding; food consumption; gamma-Aminobutyric Acid; genomic platform; health economics; human model; in vivo; innovation; islet amyloid polypeptide; knock-down; motivated behavior; neurochemistry; neuroregulation; obesity treatment; reduced food intake; relating to nervous system; response; selective expression; small hairpin RNA; transcriptomics

Summary Overweight/obesity affects more than 70% of US adults creating an enormous health and economic burden, yet effective non-invasive treatments are limited, underscoring the importance of identifying new pharmacotherapies that promote and sustain reductions in food intake and body weight. Amylin receptor agonists reduce food intake and body weight in both humans and animal models, providing a platform for the development of new amylin-based pharmacotherapies to treat obesity. Our work identifies amylin signaling in the mesolimbic reward system as a key substrate in the control of feeding and food reward-motivated behaviors. In a series of complementary manuscripts, we showed that ventral tegmental area (VTA) amylin receptors are essential for the control of palatable food intake via downstream suppression of dopaminergic signaling to the nucleus accumbens (NAc). While these combined studies highlight the VTA as a neural substrate for amylin's control of food reward, the behavioral and physiological mechanisms, neurochemical phenotype(s), and additional amylin modulated circuitry within the CNS that control food reward remain unknown. As the neural control of body weight involves the contribution of many nuclei, clearly the most effective of future amylin-based anti-obesity pharmacotherapies will be those that act in multiple CNS sites to modulate motivated feeding. To this end, we will investigate the hypothesis that amylin signaling within the lateral dorsal tegmental nucleus (LDTg) and the dorsal vagal complex (DVC) of the brainstem modulate food reward by influencing VTA neural activity. Preliminary studies also provide compelling rationale to explore endogenous amylin signaling in the NAc in control of behaviors directed at food reward. Using innovative approaches, we will investigate the following aims. Aim I: Investigate the endogenous contribution and underlying neuroanatomical circuitry of LDTg and DVC amylin receptor expressing neurons in the control of food reward. Aim II: Examine the neural activity of VTA dopaminergic and GABAergic neurons that are downstream of DVC or LDTg amylin receptor activation. Aim III: Investigate the contribution of amylin receptor signaling on D1 and D2 receptor expressing neurons in the NAc in the control of food intake and modulation of food impulsivity.

概括 超重/肥胖会影响70％以上的美国成年人，从而产生巨大的健康状况 经济负担，但有效的非侵入性治疗有限，强调了重要性 识别新的药物治疗，以促进和维持食物摄入和身体的减少 重量。氨基蛋白受体激动剂减少了人类和动物的食物摄入和体重 模型，为开发新的基于Amylin的药物治疗提供了一个平台 肥胖。我们的工作将中胶质奖励系统中的链淀粉信号识别为关键基板 喂养和食物奖励动机行为的控制。在一系列补充中 手稿，我们表明腹侧对盖面积（VTA）链氨夹受体对于 通过下游抑制多巴胺能信号传导来控制可口的食物摄入 伏隔核（NAC）。尽管这些联合研究突出了VTA为神经基板 为了控制淀粉素的食物奖励，行为和生理机制，神经化学 表型和控制食物奖励的中枢神经系统内的额外的AMYLIN调制电路 仍然未知。由于体重的神经控制涉及许多核的贡献， 显然，未来基于Amylin的抗肥胖药物治疗中最有效的是那些 在多个CNS站点上作用以调节动机喂养。为此，我们将调查 假设背侧侧侧核（LDTG）和背侧的链氨基信号传导 脑干的迷走神经复合物（DVC）通过影响VTA神经活动来调节食物奖励。 初步研究还为探索内源性淀粉素信号传导提供了令人信服的理由 控制行为的NAC针对食物奖励。使用创新的方法，我们将 调查以下目标。目的I：研究内源性贡献和基础 在控制中表达神经元的LDTG和DVC链淀粉蛋白受体的神经解剖电路 食物奖励。 AIM II：检查VTA多巴胺能和GABA能神经元的神经活动 是DVC或LDTG淀粉蛋白受体激活的下游。 AIM III：调查 链氨基受体信号传导在NAC中表达神经元的D1和D2受体的贡献 在控制食物摄入量和食物冲动的调节中。