Cross sensitization of diet and alcohol on binge behaviors and metabolic dysfunction

项目总结/摘要 肥胖和酗酒是美国最常见的两种慢性病。这两种疾病 可能与肥胖和酗酒有着共同的行为特征有关，如暴饮暴食， 被认为利用了重叠的神经机制此外，肥胖和酗酒会导致 胰岛素和葡萄糖代谢，II型糖尿病的早期预测因子。这个项目的目标是了解 高脂肪饮食如何与酒精相互作用，使酒精中毒和 饮食诱导的肥胖相关的代谢功能障碍的小鼠模型。具体来说，我们将研究如何吃 模式可以产生暴饮暴食型高脂肪饮食食物摄入， 在小鼠共病饮食和乙醇相互作用的新行为模型中，然后我们将 检查参与这些暴饮暴食模式的神经回路，并确定其机制， 高脂肪饮食和酒精调节重要的脑细胞群。根据我们的初步数据，我们建议 高脂肪饮食和酒精摄入增加了杏仁核中央核的神经元激活 通过调节神经免疫细胞的功能。最后，我们将研究共病高脂肪饮食的影响 饮酒对胰岛素和葡萄糖功能及代谢的影响。在此过程中，我们将确定 参与胰岛素释放中枢控制的关键神经回路被高血糖改变的机制。 脂肪饮食和酒精。具体来说，我们将研究高脂肪饮食和酒精 消耗抑制迷走神经背侧运动核中的神经元群的活性， 以及这些细胞群是如何被中央杏仁核的输入所调节的。这些研究 问题将通过电生理学、免疫组织化学、光- 化学遗传学、行为学和整体动物生理学方法通常不会在单个 应用和检查饮食和酒精的变化，从细胞水平到整个动物的功能。这些 这些研究将对国家酒精滥用和酒精中毒研究所的使命产生重大兴趣， 并且与FOA PA-17-211具有重要相关性。成功完成这些研究将提供新的 了解肥胖和酗酒疾病进展的机制， 发现治疗这两种疾病的新的潜在靶点，无论是单一的还是共病的情况。

Project Summary/Abstract Obesity and alcoholism are two of the most prevalent chronic diseases in the United States. These two diseases may be linked as obesity and alcoholism share common behavioral characteristics, such as binge intake, and are thought to utilize overlapping neural mechanisms. Additionally, obesity and alcoholism promote deficits in insulin and glucose metabolism, early predictors of Type II diabetes. The goal of this project is to understand how diets high in fat may interact with alcohol to worsen development and progression of both alcoholism and diet-induced obesity related metabolic dysfunction in mouse models. Specifically, we will examine how eating patterns can produce binge-type high fat diet food intake that may cross-sensitize to binge alcohol consumption in a novel behavioral model of co-morbid diet and ethanol interactions in mice. We will then examine the neurocircuitry involved in these binge intake patterns and determine the mechanisms by which high fat diets and alcohol modulate critical brain cell populations. Based on our preliminary data, we propose that high fat diet and alcohol consumption increase neuronal activation in the central nucleus of the amygdala via modulation of neuroimmune cell function. Finally, we will examine the impact of co-morbid high fat diet and alcohol consumption on insulin and glucose function and metabolism. In doing so, we will determine the mechanisms by which key neurocircuitry involved in the central control on insulin release are altered by high fat diet and alcohol. Specifically, we will be examining the mechanisms by which high fat diet and alcohol consumption inhibit the activity of neuronal populations in the dorsal motor nucleus of the vagus nerve that project to the pancreas and how this cell population is modulated by central amygdala inputs. These research questions will be tested with a novel combination of electrophysiologic, immunohistochemical, opto- and chemo- genetic, behavioral, and whole-animal physiology methods not typically seen within a single application and examine diet and alcohol changes from the cellular level to whole animal function. These studies will be of significant interest to the mission of the National Institute of Alcohol Abuse and Alcoholism, and are of important relevance to FOA PA-17-211. Successful completion of these studies will provide new understanding of the mechanisms involved in the disease progression of obesity and alcoholism as well as uncover new potential targets for the treatment of both disorders, both singularly and in co-morbid situations.