Defining the neural basis for persistent obesity

项目概要/摘要。 尽管肥胖在美国很普遍，但肥胖如何加强大脑回路， 喂养是未知的。这个K 01提案将确定特定的神经回路和子回路机制， 增加进食量并导致肥胖。虽然之前的研究集中在与肥胖相关的适应性上， 在驱动自我平衡进食的大脑区域， 进食可能在肥胖症中失调，并导致持续的食物寻求和体重增加。比如说， 丘脑核（NAc）是调节进食和奖励的大脑区域，人类和啮齿动物 文献揭示了肥胖者NAc活性的改变，沿着伴有NAc突触可塑性的破坏 机制等该提案中的初步数据表明，NAc活性在一个特定的时间段内选择性地增加。 肥胖小鼠中已知能激发奖赏的神经元亚群，D1受体表达神经元（D1 SPNs） 在寻找食物的过程中。此外，抑制NAc D1 SPNs的输出减少了食物寻求，并防止了饮食诱导的 体重增加.增强的D1 SPN活性是由增加的内在兴奋性和突触前神经元激活所驱动的。 超自然动力总之，这些数据表明了一个模型，其中增强的兴奋性NAc输入驱动食物 寻找肥胖症。然而，目前尚不清楚哪些输入是肥胖患者NAc活性增加的原因。 小鼠，无论所有NAc D1 SPN是否被异常激活，或者是否选择集合驱动食物寻找，最后， 这些适应背后的突触机制这一提议的核心假设是， 增强的NAc D1 SPNs兴奋性输入通过减弱的突触传递驱动食物寻求和肥胖。 脑电输入的抑制。这里概述的实验将使用体内光遗传学， 电生理学，遗传操作，新的操作行为范例，以及饮食的小鼠模型， 目的1将确定哪种NAc输入驱动食物 肥胖小鼠的体重增加。目的2将研究如何选择NAc D1 SPN的集合， 在肥胖症中，食物寻求驱动增强进食过程中激活。目标3将确定一种潜在的机制 肥胖小鼠NAc可塑性的潜在变化，并确定这种可塑性如何成为食物寻求的基础 体重增加总之，这些实验代表着朝着理解 肥胖改变了大脑回路，以及为什么人们很难减肥并保持体重。

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.