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

研究肥胖对努力行为和潜在神经回路的持续影响

基本信息

批准号：
10468004
负责人：
Bridget Matikainen-Ankney
金额：
$ 4.68万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10468004
关键词：
Affect Animals Area Behavior Behavioral Body Weight decreased Brain Calcium Chronic Clinical Consumption Country Cues Data Exhibits Fiber Food Functional disorder Generations Goals Human Individual Knowledge Lead Life Style Link Liquid substance Maintenance Medial Metabolic Motivation Mus Neurons Nose Nucleus Accumbens Obese Mice Obesity Opioid Receptor Output Palate Pathway interactions Persons Pharmacology Photometry Pilot Projects Population Prefrontal Cortex Preparation Prevalence Reporting Research Research Personnel Rewards Risk Rodent Signal Transduction Structure Synapses Synaptic plasticity System Techniques Testing Thinness Training United States Weight Weight Gain Work awake cohort combat craving diet and exercise diet-induced obesity effective therapy experience experimental study feeding health disparity hedonic human imaging imaging study in vivo metabolic rate mind control neural circuit neuroimaging marker neuromechanism neuroregulation novel obesity treatment optogenetics preventable death receptor relating to nervous system reward circuitry skills synaptic depression targeted treatment

项目摘要

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.

项目概要/摘要然而，尽管人们普遍认识到肥胖是该国可预防死亡的主要原因。与慢性肥胖相关的患病率和健康差异，有效的治疗方法仍然难以捉摸——大多数人尽管之前的研究经常探索新陈代谢或能量的适应，但减肥后体重会重新增加。解释体重重新增加，这并没有解决享乐喂养机制对体重的已证实的贡献人类和啮齿动物研究表明，肥胖后体重减轻会增加动力。吃可口的食物，以及涉及食物动机的大脑区域的活动，即内侧区域前额皮质（mPFC）和伏隔核（NAc）——都会随着肥胖而改变。据报道，肥胖期间 mPFC 和 NAc 之间的突触连接减少，这使得关于享乐喂养回路如何随肥胖而变化的结论很难得出，因此具有挑战性此处提出的实验的长期目标是确定潜在疗法的目标。控制 mPFC-NAc I 回路中与肥胖相关的慢性食物动机变化的神经机制。建议通过研究 NAc 神经元的活动如何影响寻找食物来做到这一点我认为肥胖会增加 mPFC-NAc 与离散的连接。 NAc 神经元在寻找食物时受到调节，并且这种情况在减肥后仍然存在。为了测试这个假设的三个目标：目标 1) 我将确定体重增加和体重减轻如何改变 NAc 整体寻找食物期间的活动，目标 2) 我将确定基因鉴定的 NAc 神经元子集的活动如何与体重增加和随后体重减轻导致的食物寻找过程中的奖励变化有关，以及目标 3）我将研究肥胖后的减肥如何破坏突触可塑性机制。使用新颖的行为技术、单个神经元活动的体内记录和光遗传学进行研究刺激来诱导和研究皮质纹状体突触连接机制。实验将阐明一种持久的神经机制，肥胖通过该机制增加食物动机最终可以产生对抗肥胖的靶向疗法。