Metabolic therapy to modulate brain dopaminergic systems

调节大脑多巴胺能系统的代谢疗法

• 批准号: 10439082
• 负责人: David Nathaniel Ruskin
• 金额: $ 45.85万
• 依托单位: TRINITY COLLEGE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10439082
• 关键词: ADORA2A gene; Acute; Adenosine; Adipose tissue; Adult; Alzheimer' s disease brain; Animals; Anticonvulsants; Anxiety; Authorship; Behavior; Behavioral; Biological Models; Brain; Burn injury; Carbohydrates; Cells; Child; Chronic; Clinical Research; Cocaine; Collaborations; Complement; Data; Diabetes Mellitus; Diet; Dietary Fats; Disease; Dopamine; Dopamine Receptor; Electrophysiology (science); Environment; Epilepsy; Epileptogenesis; Event; Faculty; Fatty acid glycerol esters; Female; Functional disorder; Glucose; Grant; Impaired cognition; In Vitro; Inflammation; Investigation; Ischemic Preconditioning; Ketone Bodies; Knowledge; Link; Literature; Locomotion; Macronutrients Nutrition; Malignant neoplasm of brain; Mental Depression; Mentors; Metabolic; Metabolism; Mitochondria; Motor; Mus; Neurobiology; Neuromodulator; Neurons; Outcome; Pain; Paper; Pharmacology; Play; Predisposition; Proteins; Publications; Publishing; Purinergic P1 Receptors; Rattus; Receptor Signaling; Regulation; Research; Research Proposals; Rewards; Role; Seizures; Seminal; Sex Differences; Signal Transduction; Stereotyped Behavior; Stimulant; Students; System; Testing; Training; Transgenic Mice; Translational Research; Weight Gain; Wild Type Mouse; Work; addiction; adenosine receptor activation; autism spectrum disorder; base; behavioral sensitization; cardiometabolism; comorbidity; conditioned place preference; dopamine system; experimental study; in vivo; insight; ketogenic diet; ketogentic; male; novel; prevent; stereotypy; student training; undergraduate student

PROJECT SUMMARY A ketogenic diet is an established metabolic therapy that is highly effective in treating seizures. Emerging evidence shows it may impact disorders as diverse as diabetes, autism spectrum disorder, Alzheimer’s disease and brain cancer. The diet is high in fat and low in carbohydrate, forcing a switch from glucose-based to ketone body-based metabolism. Nearly 10 years ago we proposed increased adenosine as a key mechanism underlying its efficacy and since then we published numerous studies testing the ketogenic diet/ adenosine hypothesis. Adenosine is a powerful anticonvulsant and neuroprotective neuromodulator, linking metabolism to neuronal activity. Adenosine also interfaces directly with dopaminergic signaling, and a diverse body of behavioral and neurobiological evidence suggests the metabolic switch mobilized by ketogenic diet could reduce dopamine-related behaviors such as stereotypies, sensitization, and reward as well as addiction- related comorbidities such as anxiety, depression, impaired cognition inflammation, and pain. Despite this the relationship among ketogenic diet, adenosine and dopamine-related behaviors has not been tested directly. Multiple mechanisms mobilized by ketogenic diet would be predicted as beneficial in preventing dopamine- related dysfunctions. The central hypothesis is that a ketogenic diet will reduce dopamine-related behaviors via adenosine receptor activation. Published literature and preliminary data support this hypothesis. Here, in an ongoing collaboration among faculty and students, this hypothesis will be tested comprehensively in male and female mice. Wild type mice and mice lacking either adenosine A1 or adenosine A2A receptor subtypes will be fed a control versus ketogenic diet for three weeks and undergo behavioral and metabolic testing to correlate adenosine receptor signaling with behavioral with metabolic effects of the diet. Dopamine-induced stereotypies (Aim 1), dopamine-induced behavioral sensitization (Aim 2), and dopamine-induced conditioned place preference (Aim 3) will be quantified to determine the impact of a ketogenic diet in each paradigm and quantify the role of adenosine receptor activation in this impact. The expected outcome is that expression of dopamine- related behaviors will be reduced in mice fed a ketogenic diet and that adenosine receptors will play a key role. Proposed experiments represent a broad-based approach to test the novel hypothesis that the ketogenic diet, a well-established metabolic therapy, will reduce dopamine-related behaviors via adenosine receptors. Accordingly we determine classes of behavior sensitive to metabolic therapy and gather important initial mechanistic evidence. Each Aim is feasible and independent, testing a separate and established class of dopamine-related behavior. Consistent with our track record, completion of proposed studies will result in publications that include undergraduate coauthors. Throughout the duration of this grant enthusiastic and collaborative faculty, each with a strong track record, will mentor, train and integrate students in all aspects of the proposal and into a rich, diverse and interdisciplinary scientific environment.

项目概要 生酮饮食是一种既定的代谢疗法，对于治疗新发癫痫症非常有效。 有证据表明它可能影响糖尿病、自闭症谱系障碍、阿尔茨海默氏症等多种疾病 疾病和脑癌的饮食脂肪含量高，碳水化合物含量低，迫使人们放弃以葡萄糖为基础的饮食。 近十年前，我们提出增加腺苷作为关键。 其功效背后的机制，从那时起我们发表了大量测试生酮饮食的研究/ 腺苷假说是一种强大的抗惊厥剂和神经保护性神经调节剂。 腺苷还直接与多巴胺能信号传导和多种神经元活动相互作用。 大量行为和神经生物学证据表明生酮饮食可促进代谢转变 可以减少与多巴胺相关的行为，如刻板印象、敏感化、奖励以及成瘾—— 尽管如此，相关的合并症如焦虑、抑郁、认知受损、炎症和疼痛。 生酮饮食、腺苷和多巴胺相关行为之间的关系尚未得到直接测试。 生酮饮食调动的多种机制预计有助于预防多巴胺- 相关的功能障碍是生酮饮食会通过减少多巴胺相关的行为。 已发表的文献和初步数据支持了这一假设。 通过教师和学生之间的持续合作，这一假设将在男性和学生中进行全面测试 野生型小鼠和缺乏腺苷 A1 或腺苷 A2A 受体亚型的小鼠将是雌性小鼠。 喂食对照饮食与生酮饮食三周，并进行行为和代谢测试以关联 腺苷受体信号传导与多巴胺诱导的刻板行为的代谢作用。 （目标 1）、多巴胺诱导的行为敏化（目标 2）和多巴胺诱导的条件性场所 偏好（目标 3）将被量化，以确定生酮饮食在每个范式中的影响并量化 腺苷受体激活在这种影响中的作用，预期的结果是多巴胺的表达。 喂食生酮饮食的小鼠的相关行为将会减少，而腺苷受体将发挥关键作用。 所提出的实验代表了一种基础广泛的方法来检验生酮饮食的新假设 饮食是一种行之有效的代谢疗法，将通过腺苷受体减少与多巴胺相关的行为。 因此，我们确定对代谢治疗敏感的行为类别并收集重要的初始信息 每个目标都是可行且独立的，测试单独且已建立的类别。 与我们的记录一致，完成拟议的研究将导致 包括本科生合著者在内的出版物在整个资助期间都充满热情和热情。 每位教师都拥有良好的合作记录，他们将在各个方面指导、培训和整合学生 提案并融入丰富、多样化和跨学科的科学环境。