Effects of a ketogenic diet on regional brain energy and plasticity

描述(申请人提供)：高脂肪、低碳水化合物(生酮)饮食是治疗儿童癫痫的有效方法。虽然这种饮食的临床应用已经很好地建立并不断发展，但其作用机制(S)仍然是推定的，更重要的是，这种饮食的认知效应还知之甚少。已发表的假说表明，生酮饮食的临床效果源于大脑线粒体生物能量学和/或抑制性神经递质或神经调节剂的增加，包括GABA和腺苷。增强的中枢抑制预计会影响正常的突触可塑性并改变认知/行为结果，饮食诱导的突触和生物能量变化的幅度可能因年龄而不同。在幼年和成年大鼠中，我们建议量化不同脑区的线粒体功能，确定生酮饮食相关生物能量变化的区域选择性(特定目标1)，并研究清醒自由活动大鼠一个选定脑区(海马体)的突触传递，并确定突触可塑性是否受到饮食的影响(特定目标2)。我们的假设是，生酮饮食将导致癫痫发作关键脑区线粒体功能的区域性变化，并将降低在体内海马区测量的突触可塑性的大小。我们的初步数据支持我们的假设，显示在生酮饮食维持三周的大鼠海马区长时程增强显著减弱。这项建议是神经科学计划与工程系和心理学系之间的跨学科合作，它促进了具有电生理和生化专业知识的实验室之间的互利互动。这些拟议的实验的可行性非常高：标准的生化方法学在我们的初步研究中得到了证明，并在文献中得到了很好的描述。在体电生理学方法学已经在我们的实验室中被广泛应用于多种物种和大小范围，导致在过去的十年中发表了许多出版物。本科生的参与和培训是明确的，因为受过培训的、受监督的学生参与了所有拟议实验的所有步骤。临床意义包括更好地了解基于酮的代谢的局部大脑反应，以及当前儿童癫痫治疗对海马突触可塑性的影响的急需的表征。 公共卫生相关性：生酮饮食是一种高脂肪/极低碳水化合物的饮食，成功地用于治疗儿童癫痫。尽管饮食疗法在儿童中使用，但人们对饮食疗法如何影响大脑能量、学习或记忆知之甚少。根据已发表的和初步的工作，我们假设大脑能量和活动将在癫痫发作影响的大脑区域发生变化。利用动物模型(大鼠)，我们将测试生酮饮食疗法对大脑能量的影响，以及对学习和记忆至关重要的生物机制的影响。

DESCRIPTION (provided by applicant): A high-fat, low-carbohydrate (ketogenic) diet is an effective treatment for pediatric epilepsy. Though clinical use of this diet is well established and growing, its mechanism(s) of action remain putative, and, more importantly, cognitive effects of this diet are poorly understood. Published hypotheses suggest that clinical effects of a ketogenic diet stem from increased brain mitochondrial bioenergetics and/or inhibitory neurotransmitters or neuromodulators, including GABA and adenosine. Enhanced central inhibition would be predicted to influence normal synaptic plasticity and alter cognitive/behavioral outcomes, and the magnitude of diet-induced synaptic and bioenergetic changes may differ with age. In both juvenile and adult rats, we propose to quantify mitochondrial function in a variety of brain areas and determine the regional selectivity of ketogenic diet-related bioenergetic changes (Specific Aim 1), and to investigate synaptic transmission in one selected brain region (the hippocampus) in awake freely-moving rats and determine if synaptic plasticity is affected by the diet (Specific Aim 2). Our hypothesis is that the ketogenic diet will cause regional changes in mitochondrial function in brain areas critical for seizures, and will decrease the magnitude of synaptic plasticity measured in the in vivo hippocampus. Our Preliminary Data support our hypothesis by showing strikingly diminished hippocampal long-term potentiation in rats maintained on the ketogenic diet for three weeks. This proposal is an interdisciplinary collaboration among the Neuroscience Program and the Departments of Engineering and Psychology, and it promotes mutually beneficial interactions between laboratories with electrophysiological and biochemical expertise. The feasibility of these proposed experiments is extremely high: The standard biochemical methodology is demonstrated in our preliminary studies and well-characterized in the literature. The in vivo electrophysiological methodology has been used extensively in our laboratory in multiple species and size ranges, leading to a number of publications over the last decade. The undergraduate participation and training is clear, as trained, supervised students are involved in all steps of all proposed experiments. The clinical relevance includes a better understanding of the regional brain responses to a ketone-based metabolism, and a much-needed characterization of the influence of a current therapy for pediatric epilepsy on hippocampal synaptic plasticity. PUBLIC HEALTH RELEVANCE: The ketogenic diet is a high fat/very-low carbohydrate diet used successfully to treat pediatric epilepsy. Despite its use in children, little is known about how diet therapy affects brain energy, learning or memory. Based on published and preliminary work, we hypothesize that brain energy and activity will change in areas of the brain affected by seizures. Using an animal model (rat) we will test the effects of ketogenic diet therapy on brain energy and on the biological mechanisms that are important for learning and memory.