Amylin modulates food reward

总结 超重/肥胖影响了超过70%的美国成年人， 经济负担，但有效的非侵入性治疗是有限的，强调了重要性 确定新的药物疗法，促进和维持减少食物摄入量和身体 重量.胰淀素受体激动剂减少人和动物的食物摄入和体重 模型，为开发新的基于胰淀素的药物治疗提供了平台， 肥胖我们的工作确定了在中脑边缘奖励系统中胰淀素信号传导作为一个关键底物， 控制进食和食物奖励动机行为。在一系列互补的 我们发现腹侧被盖区（VTA）胰淀素受体对大脑皮层的发育是必不可少的。 通过下游抑制多巴胺能信号传导至 丘脑核（NAc）。虽然这些综合研究强调腹侧被盖区作为神经基质 胰淀素对食物奖赏的控制，行为和生理机制，神经化学 表型，以及CNS内控制食物奖赏的额外胰淀素调节回路 仍然未知。由于体重的神经控制涉及许多核团的贡献， 显然，未来最有效的基于胰淀素的抗肥胖药物疗法将是那些 作用于多个中枢神经系统部位，以调节主动进食。为此，我们将调查 假设胰淀素信号在外侧背被盖核（LDTg）和背侧 脑干的迷走神经复合体（DVC）通过影响VTA神经活动来调节食物奖赏。 初步研究还提供了令人信服的理由，探索内源性胰淀素信号转导， NAc控制食物奖励行为。通过创新方法，我们将 研究以下目标。目的一：调查内生贡献和潜在的 LDTg和DVC胰淀素受体表达神经元的神经解剖学回路， 食物奖励目的II：检测腹侧被盖区多巴胺能和GABA能神经元的神经活动 其位于DVC或LDTg胰淀素受体活化的下游。目标三：调查 胰淀素受体信号对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。

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.