Nucleus Accumbens RAGE and Diet-Induced Anhedonia

伏核愤怒和饮食引起的快感缺失

基本信息

批准号：
10054550
负责人：
Kenneth D Carr
金额：
$ 46.61万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-02 至 2023-06-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10054550
关键词：
Adult Advanced Glycosylation End Products Affinity Anhedonia Behavior Behavioral Biological Assay Body Weight Brain Clinical Consumption Data Dextroamphetamine Diet Dietary Sugars Dopamine Dopamine Receptor Energy Intake Fatty acid glycerol esters Female Food Gene Activation Glucose Health Homeostasis Human Inflammation Inflammatory Infusion procedures Insulin Insulin Receptor Insulin Resistance Investigation Link Major Depressive Disorder Measurement Measures Mediating Mental Depression Nervous System Physiology Neuraxis Non-Insulin-Dependent Diabetes Mellitus Nucleus Accumbens Palate Periodicity Plasma Population Prediabetes syndrome Proteins Protocols documentation Rattus Receptor Inhibition Rewards Signal Transduction Source Testing Type 2 diabetic Western Blotting Work behavior measurement comorbidity conditioned place preference inhibitor/antagonist male molecular targeted therapies novel prevent putamen receptor receptor expression receptor for advanced glycation endproducts receptor function receptor sensitivity small molecule sugar ventricular system western diet

项目摘要

Project Summary Nearly half of the US adult population are type 2 diabetic (T2D) or pre-diabetic, and there is increasing evidence of a link between T2D and depression, particularly the core clinical feature of anhedonia. A known mechanistic overlap between T2D and major depression is increased inflammatory activity. In the case of T2D, a key role has been established for advanced glycation end products (AGEs) and their receptor (RAGE) in pro-inflammatory gene activation and insulin resistance. AGEs form endogenously, but also originate exogenously, with dietary sugar and high fat foods being rich sources. We have previously observed that a high fat, high sugar diet decreases evoked dopamine (DA) release in nucleus accumbens (NAc) and induces NAc insulin receptor (InsR) subsensitivity. Although RAGE is expressed in brain, there has been very little investigation of diet effects on brain RAGE expression, and almost nothing is known about brain RAGE effects on CNS function and behavior. New preliminary data indicate that the high fat, high sugar diet, found previously to diminish DA and InsR function, increases expression of RAGE and its key intracellular signaling effector molecule, DIAPH1 in NAc but not caudate putamen. We propose to investigate whether diet-induced RAGE expression and signaling in the NAc induce behavioral signs of anhedonia in rats. We predict that a high-fat, high-sugar diet elevates circulating levels of AGEs, increases expression of RAGE and DIAPH1 in the NAc, and induces behavioral signs of anhedonia in brain stimulation reward and conditioned place preference assays. To assess the causal connection between brain RAGE and behavioral changes, a recently available small-molecule high-affinity RAGE inhibitor will be continuously infused into the brain ventricular system. Our findings might identify a mechanistic basis for the link between T2D and depression and, perhaps, diet-induced anhedonic effects that drive escalating consumption of energy-dense palatable food aimed at achieving reward homeostasis.

项目概要近一半的美国成年人患有 2 型糖尿病 (T2D) 或糖尿病前期，并且越来越多的证据表明， T2D 和抑郁症之间的联系，特别是快感缺失的核心临床特征。已知的机制 T2D 和重度抑郁症之间的重叠之处在于炎症活动增加。就 T2D 而言，关键作用是已在促炎基因中建立晚期糖基化终末产物 (AGE) 及其受体 (RAGE) 激活和胰岛素抵抗。 AGEs 是内源性形成的，但也可以是外源性的，与膳食糖和高脂肪食物是丰富的来源。我们之前观察到，高脂肪、高糖饮食会降低诱发伏核 (NAc) 中多巴胺 (DA) 释放并诱导 NAc 胰岛素受体 (InsR) 不敏感。尽管RAGE在大脑中表达，但饮食对大脑RAGE影响的研究却很少表达，而关于大脑 RAGE 对中枢神经系统功能和行为的影响几乎一无所知。新的初步数据表明，先前发现的高脂肪、高糖饮食会降低 DA 和 InsR 功能，增加 NAc 中 RAGE 及其关键细胞内信号传导效应分子 DIAPH1 的表达，但不增加尾状核中的表达壳门。我们建议研究饮食诱导的 NAc 中的 RAGE 表达和信号传导是否会诱导大鼠快感缺乏的行为迹象。我们预测高脂肪、高糖饮食会提高血液循环水平 AGEs，增加 NAc 中 RAGE 和 DIAPH1 的表达，并诱导快感缺乏的行为体征大脑刺激奖励和条件性位置偏好测定。评估之间的因果关系大脑 RAGE 和行为变化，最近推出的一种小分子高亲和力 RAGE 抑制剂将源源不断地注入脑室系统。我们的研究结果可能会确定这种现象的机制基础 T2D 与抑郁症之间的联系，或许还有饮食引起的快感缺失效应，导致快感缺失效应升级消费高能量的美味食物，旨在实现奖赏稳态。