Amylin modulates food reward

胰淀素调节食物奖励

基本信息

批准号：
10470394
负责人：
MATTHEW R HAYES
金额：
$ 59.24万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
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/10470394
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 antagonist 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

项目摘要

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/肥胖影响超过 70% 的美国成年人，对健康和健康造成巨大影响经济负担，但有效的非侵入性治疗有限，凸显了重要性确定新的药物疗法，促进和维持食物摄入量和身体的减少重量。胰淀素受体激动剂可减少人类和动物的食物摄入量和体重模型，为开发新的基于胰淀素的药物疗法提供平台来治疗肥胖。我们的工作将中脑边缘奖励系统中的胰淀素信号传导确定为关键底物控制喂养和食物奖励驱动的行为。在一系列互补的手稿中，我们表明腹侧被盖区（VTA）胰淀素受体对于通过抑制下游的多巴胺能信号来控制可口的食物摄入伏隔核（NAc）。虽然这些综合研究强调 VTA 作为神经基质用于胰淀素对食物奖励的控制、行为和生理机制、神经化学表型，以及中枢神经系统内控制食物奖励的额外胰淀素调节电路仍然未知。由于体重的神经控制涉及许多细胞核的贡献，显然，未来最有效的基于胰淀素的抗肥胖药物疗法将是在多个中枢神经系统部位发挥作用，调节主动进食。为此，我们将调查假设胰岛淀粉样蛋白信号传导在背侧被盖核（LDTg）和背侧被盖核内。脑干迷走神经复合体 (DVC) 通过影响 VTA 神经活动来调节食物奖赏。初步研究还为探索内源性胰淀素信号传导提供了令人信服的理由。 NAc 控制针对食物奖励的行为。通过创新方法，我们将调查以下目标。目标一：调查内生贡献和根本原因 LDTg 和 DVC 胰岛淀粉样多肽受体表达神经元的神经解剖电路食物奖励。目标 II：检查 VTA 多巴胺能和 GABA 能神经元的神经活动位于 DVC 或 LDTg 胰淀素受体激活的下游。目标三：调查胰淀素受体信号传导对 NAc 中表达 D1 和 D2 受体的神经元的贡献控制食物摄入和调节食物冲动。