Metabolic therapy to modulate brain dopaminergic systems

项目总结 生酮饮食是一种公认的代谢疗法，在治疗癫痫方面非常有效。新兴 有证据表明，它可能会影响糖尿病、自闭症谱系障碍、阿尔茨海默氏症等各种疾病 疾病和脑癌。这种饮食是高脂肪、低碳水化合物的，迫使人们从以葡萄糖为基础的饮食转向 以酮体为基础的代谢。大约10年前，我们提出将增加腺苷作为关键 从那时起，我们发表了许多测试生酮饮食的研究。 腺苷假说。腺苷是一种强大的抗惊厥和神经保护性神经调节剂， 新陈代谢转化为神经元活动。腺苷也直接与多巴胺能信号相互作用，并有不同的 大量行为和神经生物学证据表明，生酮饮食调动了代谢开关 可以减少与多巴胺相关的行为，如刻板印象、敏感化、奖励和成瘾- 相关的并发症，如焦虑、抑郁、认知受损、炎症和疼痛。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得到直接测试。 生酮饮食调动的多种机制将被预测为有益于预防多巴胺- 相关功能障碍。中心假设是生酮饮食将通过以下途径减少与多巴胺相关的行为 腺苷受体激活。已发表的文献和初步数据支持这一假设。在这里，在一个 教师和学生之间正在进行的合作，这一假说将在男性和 雌性老鼠。野生型小鼠和缺乏腺苷A1或腺苷A2A受体亚型的小鼠将是 喂食对照组和生酮饮食三周，并接受行为和代谢测试以确定 腺苷受体信号转导与行为与饮食代谢的影响。多巴胺诱导的刻板印象 (目标1)、多巴胺诱导的行为敏感化(目标2)和多巴胺诱导的条件位置 偏好(目标3)将被量化，以确定生酮饮食在每个范例中的影响，并量化 腺苷受体激活在这种影响中的作用。预期结果是多巴胺的表达- 饲喂生酮饮食的小鼠的相关行为将会减少，腺苷受体将发挥关键作用。 拟议的实验代表了一种广泛的方法来检验新的假设，即生酮 饮食是一种成熟的代谢疗法，它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 机械证据。每个目标都是可行的和独立的，测试一个单独的和确定的类别 与多巴胺相关的行为。与我们的过往记录一致，完成建议的研究将导致 包括本科生合著者的出版物。在这笔赠款的整个期间，热情和 合作教员，每个人都有良好的记录，将指导，培训和整合学生在各个方面的 这项提议将成为一个丰富、多样和跨学科的科学环境。

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.