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

(PQA3) 肠-脑轴：治疗行为改变的新目标

基本信息

批准号：
8875640
负责人：
Dana M Small
金额：
$ 66.14万
依托单位：
JOHN B. PIERCE LABORATORY, INC.
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8875640
关键词：
Address Adoption Animal Model Animals Behavioral Body Weight decreased Brain Catecholamines Cessation of life Communication Corpus striatum structure Desire for food Diet Diet Habits Dietary Fats Disease Dopamine Dorsal Eating Energy Intake Epidemiologic Studies Epidemiology Exposure to Fatty acid glycerol esters Food Habits Health Human Impulsive Behavior Impulsivity Incidence Individual Ingestion Intake Intestines Investigation Lead Learning Link Lipids Malignant Neoplasms Mediating Molecular Morbidity - disease rate Mus Neurons Neurotransmitters Obesity Organism Outcome Overweight Pattern Peroxisome Proliferator-Activated Receptors Physiological Rodent Signal Transduction Vagus nerve structure Work base behavioral outcome cancer prevention design feeding gastrointestinal healthy lifestyle human subject improved neurochemistry neurotransmission novel prevent relating to nervous system response translational study

项目摘要

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.

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，该策略的基础是挽救超重/肥胖个体脑回路中的正常神经活动。流行病学研究证明了我们的建议与癌症预防的相关性，这些研究表明，通过采取更健康的饮食习惯可以预防多种形式的癌症，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。这种由饮食引起的纹状体缺陷会导致了解自己行为的负面结果的能力受损，进而导致冲动行为的表达，例如摄入过多的热量。我们的策略建立在之前的动物研究的基础上，该研究表明，长期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。由于我们之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动，因此我们提出了一个中心假设：拯救肠-脑通讯将恢复纹状体功能。作为推论，我们预测拯救肠脑沟通将增强了解负面结果的能力，从而减少冲动行为评分并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）：确定哪些肠道 N-酰基乙醇胺可挽救高脂喂养小鼠的纹状体功能并降低冲动性，并确定其作用的神经和分子机制；具体目标 2（转化研究）：确定肠道 N-酰基乙醇胺前体是否可以挽救超重/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。