(PQA3) The gut-brain axis: a novel target for treating behavioral alterations in

描述（由申请人提供）：我们的提案解决了NCI的挑衅性问题#3（A组）：我们设计了一种改变致癌饮食习惯的策略，该策略基于拯救超重/肥胖个体脑回路中的正常神经活动。流行病学研究证实，采取更健康的饮食习惯可以预防多种癌症，高达20%的癌症相关死亡可能仅归因于肥胖。在 无论是啮齿动物还是人类，过量摄入膳食脂肪都会导致背侧纹状体神经元功能失调。这种饮食来源的纹状体缺陷导致学习一个人的行为的负面结果的能力受损，这反过来又导致冲动行为的表达，如过量的热量摄入。我们的策略建立在以前的动物研究基础上，这些研究表明，长时间接触高脂肪饮食会大大减少肠道中调节食欲的脂质信使的合成。由于我们先前的工作已经确定肠-脑信号调节背侧纹状体的神经化学活性，因此我们确立了中心假设，即拯救肠-脑通信将恢复纹状体功能。作为推论，我们预测，拯救肠-脑交流将提高学习负面结果的能力，从而降低冲动行为评分，提高对低热量饮食的依从性。因此，我们的具体目标如下：具体目标1（机制研究）：确定哪种肠道N-酰基乙醇胺可挽救高脂喂养小鼠的纹状体功能并降低其冲动性，并确定其作用的神经和分子机制;（翻译研究）：确定肠道N-酰基乙醇胺前体是否能挽救超重/肥胖人类受试者的纹状体功能并降低冲动评分。因此，我们提出肠-脑轴是治疗肥胖者行为改变的新靶点，其正常化可能极大地有助于减少与癌症相关的饮食习惯。

DESCRIPTION (provided by applicant): Our proposal addresses NCI's Provocative Question #3 (Group A): We designed a strategy to change cancer- inducing dietary habits, which is based on rescuing normal neural activity in brain circuits of overweight/obese individuals. The relevance of our proposal to cancer prevention is demonstrated by epidemiological studies establishing that several forms of cancer could be prevented by the adoption of healthier dietary habits, with up to 20% of cancer-related deaths being potentially attributable to obesity alone. In both rodents and humans, excessive intake of dietary fats leads to dysregulated neuronal function in dorsal striatum. This diet-derived striatal deficiency leads to an impaired ability to learn about the negative outcomes of one's actions which, in turn, results in the expression of impulsive behaviors such as excessive caloric intake. Our strategy builds on previous animal studies demonstrating that prolonged exposure to a high-fat diet substantially reduces the intestinal synthesis of appetite-regulating lipid messengers. Since our previous work had established that gut- brain signals regulate neurochemical activity in dorsal striatum, we set fort the central hypothesis that rescuing gut-brain communication will restore striatal function. As a corollary, we predict that rescuing gut-brain communication will enhance the ability to learn about negative outcomes, thereby reducing impulsivity behavioral scores and increasing compliance with a low-calorie diet. Accordingly, our Specific Aims are as follows: Specific Aim 1 (Mechanistic studies): To identify which gut N-acylethanolamines rescue striatal function and reduce impulsivity in high-fat fed mice, and to determine the neural and molecular mechanisms of their action; Specific Aim 2 (Translational studies): To determine whether gut N-Acylethanolamines precursors rescue striatal function and reduce impulsivity scores in overweight/obese human subjects. We thus propose that the gut-brain axis is a novel target for treating behavioral alterations in the obese, the normalization of which may greatly contribute to reducing cancer-related dietary habits.