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.

项目摘要 生酮饮食是一种已建立的代谢疗法，在治疗癫痫发作方面非常有效。新兴 有证据表明，这可能会影响像糖尿病，自闭症谱系障碍，阿尔茨海默氏病这样的潜水疾病 疾病和脑癌。饮食较高脂肪，碳水化合物低，迫使基于葡萄糖的转换 基于酮体的代谢。大约10年前，我们提议将腺苷作为关键增加 其有效性的机制，从那时起，我们发表了许多研究生酮饮食/的研究 腺苷假设。腺苷是一种强大的抗惊厥药和神经保护神经调节剂，链接 神经元活性的代谢。腺苷还直接与多巴胺能信号接口，潜水员 行为和神经生物学证据的身体表明，生酮饮食动员的代谢转换 可以减少与多巴胺相关的行为，例如刻板印象，灵敏度和奖励以及成瘾 - 相关的合并症，例如焦虑，抑郁，认知注射受损和疼痛。尽管如此 生酮饮食，腺苷和多巴胺相关行为之间的关系尚未直接测试。 通过生酮饮食动员的多种机制将被预测有益于防止多巴胺 相关功能障碍。中心假设是，生酮饮食将通过 腺苷受体激活。发表的文献和初步数据支持了这一假设。在这里 教师和学生之间正在进行的合作，该假设将在男性和 雌鼠。野生型小鼠和缺乏腺苷A1或腺苷A2A受体亚型的小鼠将是 喂养控制与生酮饮食三周，并经过行为和代谢测试以相关 腺苷受体信号传导具有饮食的代谢作用的行为。多巴胺引起的刻板印象 （AIM 1），多巴胺诱导的行为敏感性（AIM 2）和多巴胺诱导的条件位置 优先（目标3）将被量化以确定每个范式中生酮饮食的影响并量化 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 相关行为将减少喂养生酮饮食的小鼠，并且腺苷受体将发挥关键作用。 拟议的实验代表了一种基于广泛的方法，用于检验新的假设 饮食是一种良好的代谢疗法，将通过腺苷受体降低与多巴胺相关的行为。 根据我们确定对代谢疗法敏感的行为类别并收集重要的初始 机械证据。每个目标都是可行和独立的 多巴胺相关的行为。与我们的记录一致，拟议研究的完成将导致 包括本科合着者在内的出版物。在这笔赠款的期限里， 协作教师，每个人都有很强的记录，将在心理，培训和融合学生的各个方面 该提议以及富裕，潜水和跨学科的科学环境。