Amylin modulates food reward

摘要 超重/肥胖影响了超过70%的美国成年人，创造了巨大的健康和 经济负担，但有效的非侵入性治疗是有限的，强调了 确定促进和维持食物摄入量和身体减少的新药物疗法 重量。胰淀素受体激动剂减少人类和动物的摄食量和体重 模型，为开发基于胰淀素的新的药物疗法提供了一个平台 肥胖。我们的工作发现，中脑边缘奖赏系统中的胰淀素信号是 控制摄食和食物奖励激励行为。在一系列互补的 手稿，我们表明腹侧被盖区(VTA)胰淀素受体是必不可少的 通过下游抑制多巴胺能信号对可口食物摄入量的控制 伏核(NAC)。虽然这些联合研究强调了VTA是一种神经基质 对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(S)，和控制食物奖励的中枢神经系统内额外的淀粉素调制电路 仍然不为人所知。由于体重的神经控制涉及多个核团的贡献， 显然，未来基于胰淀素的减肥药物疗法中最有效的将是那些 在多个中枢神经系统部位发挥作用，调节有动机的进食。为此，我们将调查 被盖背外侧核(LDTg)和背侧的胰淀素信号传导假说 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。 初步研究也为探索内源胰淀素信号通路提供了令人信服的理论基础。 NAC在控制针对食物奖励的行为。使用创新的方法，我们将 调查以下目标。目标一：调查内生贡献和潜在原因 LDTg和DVC胰淀素受体表达神经元在中枢神经系统的神经解剖回路 食物奖励。目的II：检测VTA、多巴胺和GABA能神经元的神经活动 它们位于DVC或LDTg胰淀素受体激活的下游。目标三：调查 胰淀素受体信号在NAc内表达D1D2受体的神经元中的作用 在控制食物摄入量和调节食物冲动方面。

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.