Defining the neural basis for persistent obesity

定义持续性肥胖的神经基础

基本信息

批准号：
10735128
负责人：
Bridget Matikainen-Ankney
金额：
$ 15.3万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735128
关键词：
Adult Affect American Amygdaloid structure Attenuated Behavior Behavioral Paradigm Brain Brain region Calcium Cells Clustered Regularly Interspaced Short Palindromic Repeats Code Data Development Diet Disease Dopamine D1 Receptor Electrophysiology (science)Food Functional disorder Glutamates Goals Head Hippocampus Human Image Impairment Individual Lead Link Literature Long-Term Depression Malignant Neoplasms Mediating Mental disorders Mentors Mentorship Metabolic Diseases Microscope Mission Modeling Molecular Motivation Mus National Institute of Diabetes and Digestive and Kidney Diseases Neurons Nucleus Accumbens Obese Mice Obesity Opioid Receptor Output Persons Population Postdoctoral Fellow Prevalence Property Public Health Research Research Support Research Training Rewards Rodent Source Subgroup Synapses Synaptic plasticity System Technical Expertise Testing Thalamic structure Thinness Training United States Virus Weight Weight Gain brain based career cell type diet-induced obesity effective therapy experience experimental study feeding genetic manipulation heart disease risk hedonic in vivo in vivo calcium imaging interest knock-down member metabolic rate mouse model mu opioid receptors multidisciplinary neural neural circuit neuroimaging neuromechanism novel obesity treatment optogenetics presynaptic prevent programs receptor reward processing synaptic depression targeted treatment

项目摘要

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.

项目摘要/摘要。尽管肥胖在美国盛行，但肥胖如何增强大脑回路，从而强化喂养未知。该 K01 提案将确定特定的神经回路和子电路机制，加强喂养并增选肥胖。虽然之前的研究重点是与肥胖相关的适应在驱动稳态进食的大脑区域中，涉及享乐、动机的大脑区域的适应肥胖症患者的喂养可能会失调，并导致持续的食物寻求和体重增加。例如，伏隔核 (NAc) 是调节进食和奖赏的大脑区域，人类和啮齿动物文献揭示了肥胖中 NAc 活性的变化以及 NAc 突触可塑性的破坏机制。该提案中的初步数据表明，NAc 活性在已知可激活肥胖小鼠奖赏的神经元亚群，即表达 D1 受体的神经元 (D1SPN) 在寻找食物的过程中。此外，抑制 NAc D1SPN 输出可减少食物寻找并防止饮食诱发的体重增加。 D1SPN 活性增强是由内在兴奋性和突触前增强驱动的谷氨酸能驱动。这些数据共同提出了一个模型，其中增强的兴奋性 NAc 输入驱动食物寻找肥胖。然而，目前尚不清楚哪些输入导致肥胖者 NAc 活性增加小鼠，是否所有 NAc D1SPN 都被异常激活，或者是否选择群体驱动食物寻找，最后，这些适应背后的突触机制是什么？该提案的中心假设是 NAc D1SPN 的兴奋性输入增强，通过减弱的突触驱动食物寻找和肥胖谷氨酸能输入的抑制。这里概述的实验将使用体内光遗传学，电生理学、基因操作、新颖的操作行为范式和饮食小鼠模型诱导肥胖，以在以下目标中检验这一假设：目标 1 将确定哪些 NAc 输入驱动食物肥胖小鼠的寻求和体重增加。目标 2 将研究如何选择 NAc D1SPN 的集合在寻找食物期间被激活，促进肥胖症的进食。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成为食物寻求的基础和体重增加。总之，这些实验代表着在理解如何肥胖会改变大脑回路，这也是人们减肥和保持体重如此困难的原因。