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

项目概要/摘要 肥胖是这个国家可预防死亡的主要原因。然而，尽管人们普遍知道， 与慢性肥胖相关的患病率和健康差异，有效的治疗仍然难以捉摸-大多数人 尽管先前的研究经常探索代谢或能量适应， 解释体重再增加，这并没有解决享乐喂养机制对体重的贡献 肥胖后的恢复。人类和啮齿动物的研究表明，肥胖后体重减轻会导致动力增加 消费可口的食物，以及大脑中与食物动机有关的区域的活动-即中间 前额叶皮层（mPFC）和脑桥核（NAc）-随着肥胖而改变。然而，这两种增强 肥胖时mPFC和NAc之间的突触连接减少， 关于快乐进食回路如何随着肥胖而变化的结论很难得出，因此具有挑战性 以潜在的治疗方法为目标。这里提出的实验的长期目标是确定 在mPFC-NAc回路中控制慢性肥胖相关食物动机变化的神经机制。我 我建议通过研究NAc神经系统中调节食物寻找的活动如何受到 肥胖和随后的体重减轻。我假设肥胖增加了mPFC-NAc连接到离散的 NAc神经系统在寻找食物的过程中受到调制，并且在体重减轻后仍然存在。在这里我提议 为了检验这一假设，我有三个目标：目标1）我将确定体重增加和体重减轻如何改变NAc系综 在寻找食物时的活动，目标2）我将确定一个遗传上确定的NAc神经元子集的活动如何 与由于体重增加和随后的体重减轻而导致的食物寻求期间的奖励变化相关，以及 目的3）我将研究肥胖后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，在体内记录单个神经元活动， 刺激以诱导和研究皮质纹状体突触连接机制。这些数据 实验将阐明一种持久的神经机制，通过这种机制，肥胖增加了食物动力， 最终允许产生对抗肥胖的靶向疗法。

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.