Defining the neural basis for persistent obesity

项目摘要/摘要。 尽管肥胖症在美国很普遍，但肥胖症是如何加强大脑回路的 目前尚不清楚它们的进食情况。这份K01提案将确定特定的神经回路和子回路机制 增加喂食和增加肥胖的人。虽然之前的研究主要集中在与肥胖相关的适应上 在驱动动态平衡进食的大脑区域，参与享乐的大脑区域的适应，动机 肥胖患者的进食可能会失调，并导致持续的觅食和体重增加。例如, 伏隔核(NAC)是一个大脑区域，负责调节摄食和奖励，人类和啮齿动物 文献显示，肥胖症患者NAC活性发生改变，同时NAC突触可塑性受损 机械装置。这项提案中的初步数据表明，NAC活性在 肥胖小鼠已知的刺激奖赏的神经元亚群--D1受体表达神经元(D1SPN) 在寻找食物的时候。此外，抑制NAC D1SPN的输出减少了对食物的寻找，并防止了饮食诱导 体重增加。增强的D1SPN活性是由增加的内在兴奋性和突触前 谷氨酸能驱动力。总而言之，这些数据表明了一种模型，在该模型中，增强的兴奋性NAC输入推动了食物 寻求肥胖。然而，目前还不清楚哪些因素(S)是肥胖患者NAC活动增加的原因 小鼠，无论是所有的NAC D1SPN被异常激活，还是如果精选的群体驱动觅食，最后， 这些适应背后的突触机制是什么。这项提议的中心假设是 NAC D1SPN的兴奋性输入增强通过弱化突触驱动寻食和肥胖 谷氨酸能输入抑制。这里概述的实验将使用活体光遗传学， 电生理学，基因操作，新的可操作的行为模式，以及饮食的小鼠模型- 诱导肥胖在以下目标中验证这一假说：目标1将确定哪种NAC输入(S)将驱动食物 肥胖小鼠的寻找和体重增加。AIM 2将调查如何选择NAC D1SPN集合 在寻找食物的过程中被激活，会在肥胖时促进进食。目标3将定义一个潜在的机制 肥胖小鼠NAC可塑性的潜在变化，并确定这种可塑性如何为寻找食物奠定基础 体重也增加了。总而言之，这些实验代表着朝着理解如何 肥胖会改变大脑回路，这也是为什么人们很难减肥并保持体重的原因。

Project Summary/Abstract. Despite the prevalence of obesity in the United States, how obesity strengthens brain circuits that reinforce feeding is not known. This K01 proposal will identify specific neural circuits and subcircuit mechanisms that enhance feeding and are co-opted in obesity. While prior research has focused on obesity-linked adaptations in brain regions that drive homeostatic feeding, adaptations in brain regions involved in hedonic, motivated feeding may be dysregulated in obesity and contribute to ongoing food seeking and weight gain. For instance, the nucleus accumbens (NAc) is a brain region that regulates feeding and reward, and human and rodent literature have revealed alterations in NAc activity in obesity, along with disrupted NAc synaptic plasticity mechanisms. Preliminary data in this proposal demonstrates that NAc activity was selectively increased in a subpopulation of neurons known to invigorate reward, D1-receptor expressing neurons (D1SPNs), in obese mice during food seeking. Further, inhibiting NAc D1SPNs output decreased food seeking and prevented diet-induced weight gain. Enhanced D1SPN activity was driven by increased intrinsic excitability and pre-synaptic glutamatergic drive. Together these data suggest a model in which enhanced excitatory NAc inputs drive food seeking in obesity. Yet it remains unclear which input(s) is/are responsible for increased NAc activity in obese mice, whether all NAc D1SPNs are aberrantly activated or if select ensembles drive food seeking, and lastly, what synaptic mechanisms underlie these adaptations. The central hypothesis of this proposal is that enhanced excitatory input to NAc D1SPNs drives food seeking and obesity through attenuated synaptic depression of glutamatergic inputs. The experiments outlined here will use in vivo optogenetics, electrophysiology, genetic manipulations, novel operant behavioral paradigms, and a mouse model of diet- induced obesity to test this hypothesis in the following Aims: Aim 1 will determine which NAc input(s) drive food seeking and weight gain in obese mice. Aim 2 will investigate how select ensembles of NAc D1SPNs that are activated during food seeking drive enhanced feeding in obesity. Aim 3 will define a potential mechanism underlying changes in NAc plasticity in obese mice, and determine how such plasticity underlies food seeking and weight gain. Together, these experiments represent a major step forward towards understanding how obesity alters brain circuits, and why it so difficult for people to lose weight and keep it off.