Nucleus Accumbens RAGE and Diet-Induced Anhedonia

项目摘要 近一半的美国成年人是2型糖尿病（T2D）或糖尿病前期，越来越多的证据表明， 2型糖尿病和抑郁症之间的联系，特别是快感缺乏的核心临床特征。已知的机械 T2D和重度抑郁症之间的重叠是炎症活动增加。在T2D的情况下， 已经建立了晚期糖基化终产物（AGEs）及其受体（AGEs）在促炎基因中的表达， 激活和胰岛素抵抗。AGEs是内源性的，但也是外源性的，与膳食中的糖和 高脂肪食物是丰富的来源。我们以前已经观察到高脂肪，高糖饮食减少诱发 多巴胺（DA）在丘脑腹外侧核（NAc）内释放，并诱导NAc胰岛素受体（InsR）的亚敏感性。 虽然脑内表达着神经递质，但关于饮食对脑神经递质影响的研究却很少 表达，并且几乎不知道大脑对CNS功能和行为的影响。新 初步数据表明，高脂肪、高糖饮食，以前发现会降低DA和InsR功能， 增加NAc而非尾状核中NAc及其关键细胞内信号传导效应分子DIAPH1的表达 壳核我们建议研究饮食诱导的NAc中的BMP1表达和信号传导是否诱导了NAc中的BMP1表达和信号传导。 大鼠快感缺乏的行为体征。我们预测，高脂肪、高糖饮食会提高血液循环中的 AGEs，增加NAc中NAH和DIAPH1的表达，并诱导 大脑刺激奖励和条件位置偏好分析。评估以下因素之间的因果关系 脑损伤和行为改变，最近可用的小分子高亲和力的神经元特异性抑制剂将被 持续注入脑室系统我们的研究结果可能会确定一个机械的基础， T2D和抑郁症之间的联系，也许，饮食引起的快感缺失效应， 消耗能量密集的可口食物，旨在实现奖励稳态。

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.