Investigating the persistent effects of obesity on effortful behavior and underlying neural circuits

项目摘要/摘要 在这个国家，肥胖是可预防的死亡的主要原因。然而，尽管人们普遍知道 与慢性肥胖症有关的患病率和健康差距，有效的治疗仍然难以捉摸-大多数人 减肥的人体重会重新增加。尽管先前的研究经常探索代谢或能量适应 解释体重重新增加，这并没有解决已证实的享乐式喂养机制对体重的贡献。 肥胖后再次增加。人类和啮齿动物的研究表明，肥胖后的体重减轻会增加动力 食用美味的食物，以及大脑中与食物动机有关的区域的活动--即大脑的内侧 前额叶皮质(MPFC)和伏隔核(NAC)--随着肥胖而改变。然而，这两个增强功能 据报道，肥胖期间mPFC和NAC之间的突触连接减少，呈现 关于享乐喂养回路如何随着肥胖而改变的结论很难得出，因此具有挑战性 以潜在的治疗方法为靶点。这里提出的实验的长期目标是定义 控制mPFC-NAC回路中与肥胖相关的慢性食物动机变化的神经机制。我 建议通过研究NAC神经群中调谐到寻找食物的活动是如何受到 肥胖和随后的体重减轻。我假设肥胖增加了mPFC-NAC在离散的 NAC在寻找食物的过程中受到调节，而且在减肥后这种情况会持续下去。在此，我建议 为了在三个目标中检验这个假设：目标1)我将确定体重增加和体重减少如何改变NAC整体 寻找食物时的活动，目标2)我将确定遗传识别的NAC神经元子集的活动如何 在寻找食物的过程中，由于体重增加和随后的体重减轻，与奖励的变化有关，以及 目的3)我将研究肥胖后的体重减轻如何破坏突触可塑性机制。这些目标将 使用新的行为技术进行研究，活体记录单个神经元的活动，以及光遗传学 刺激以诱导和研究皮质纹状体突触连接机制。来自这些的数据 实验将阐明一种持久的神经机制，肥胖通过这种机制增加食物动机和 最终允许产生与肥胖作斗争的有针对性的疗法。

Project Summary/Absract Obesity is a leading cause of preventable death in this country. However, despite widespread knowledge of the prevalence and health disparities linked to chronic obesity, effective treatments remain elusive – most people who lose weight will re-gain it. Though prior research has often explored metabolic or energy adaptations to explain weight re-gain, this does not address the proven contribution of hedonic feeding mechanisms to weight re-gain after obesity. Human and rodent studies show that weight loss after obesity causes increased motivation to consume palatable foods, and that activity in brain areas involved in food motivation – namely the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc) – is altered with obesity. Yet both enhancements and reductions in synaptic connectivity between mPFC and NAc during obesity have been reported, rendering conclusions about how hedonic feeding circuits change with obesity difficult to draw, and therefore challenging to target with potential therapies. The long-term objective of the experiments proposed here is to define the neural mechanisms governing chronic, obesity-linked changes in food motivation in the mPFC-NAc circuit. I propose to do this by investigating how activity in NAc neural ensembles tuned to food seeking is affected by obesity and subsequent weight loss. I hypothesize that obesity increases mPFC-NAc connectivity onto discrete NAc neural ensembles modulated during food seeking, and that this persists after weight loss. Here I propose to test this hypothesis in three aims: Aim 1) I will identify how weight gain and weight loss alter NAc ensemble activity during food seeking, Aim 2) I will identify how activity of a genetically identified subset of NAc neurons associated with reward changes during food seeking as a result of weight gain and subsequent weight loss, and Aim 3) I will investigate how weight loss after obesity disrupts synaptic plasticity mechanisms. These aims will be investigated using novel behavioral techniques, in vivo recording of single neuron activity, and optogenetic stimulation to induce and study corticostriatal synaptic connectivity mechanisms. The data from these experiments will elucidate a persistent neural mechanism through which obesity increases food motivation and ultimately allow for the generation of targeted therapies to combat obesity.