Effects of a ketogenic diet on regional brain energy and plasticity

生酮饮食对区域大脑能量和可塑性的影响

• 批准号: 7881879
• 负责人: SUSAN A MASINO
• 金额: $ 23.07万
• 依托单位: TRINITY COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7881879
• 关键词: ATP Synthesis Pathway; Acute; Adenosine; Adolescent; Adult; Adverse effects; Affect; Age; Anesthetics; Animal Model; Area; Behavioral; Biochemical; Bioenergetics; Biological; Biological Models; Brain; Brain region; Carbohydrates; Cerebellum; Child; Childhood; Chronic; Clinical; Cognitive; Corpus striatum structure; Data; Development; Diet; Diet therapy; Disease; Electron Transport; Engineering Psychology; Enzymes; Epilepsy; Equilibrium; Fatty acid glycerol esters; Future; Gene Expression; Glucose; Goals; Growth; Heart; Hippocampus (Brain); Human; Hypoglycemia; Hypothalamic structure; In Vitro; Ischemia; Ketone Bodies; Ketones; Laboratories; Lead; Learning; Link; Literature; Liver; Long-Term Depression; Long-Term Potentiation; Measures; Memory; Mental Depression; Metabolic; Metabolism; Methodology; Methods; Mitochondria; Neocortex; Neuromodulator; Neurons; Neurosciences; Neurotransmitters; Outcome; Output; Patients; Perforant Pathway; Peripheral; Pharmacologic Substance; Plasma; Process; Publications; Publishing; Rattus; Refractory; Research; Rodent; Seizures; Skeletal Muscle; Slice; Students; Study models; Succinate Dehydrogenase; Synapses; Synaptic Transmission; Synaptic plasticity; Techniques; Testing; Tissues; Training; Traumatic Brain Injury; Work; awake; base; clinical effect; clinically relevant; dentate gyrus; effective therapy; gamma-Aminobutyric Acid; high standard; in vivo; interdisciplinary collaboration; juvenile animal; ketogenic diet; prevent; programs; public health relevance; relating to nervous system; research study; response; stem; success; synaptic function; weanling animal

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.

描述（由申请人提供）：高脂肪、低碳水化合物（生酮）饮食是治疗小儿癫痫的有效方法。尽管这种饮食的临床应用已经很好地建立起来并在不断增长，但其作用机制仍然是假定的，更重要的是，人们对这种饮食的认知效果知之甚少。已发表的假设表明，生酮饮食的临床效果源于增加脑线粒体生物能量和/或抑制性神经递质或神经调节剂，包括GABA和腺苷。预计中枢抑制增强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随年龄而异。在幼鼠和成年大鼠中，我们建议量化各种脑区的线粒体功能，并确定生酮饮食相关生物能量变化的区域选择性（Specific Aim 1），并研究清醒自由运动大鼠一个选定脑区（海马）的突触传递，并确定突触可塑性是否受到饮食的影响（Specific Aim 2）。我们的假设是，生酮饮食会导致癫痫发作关键脑区线粒体功能的区域性变化，并会降低体内海马中测量到的突触可塑性的大小。我们的初步数据支持我们的假设，表明在维持生酮饮食三周的大鼠中，海马体长期增强显著减弱。该提案是神经科学项目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。这些实验的可行性是非常高的：标准的生化方法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表征。体内电生理方法在我们的实验室中广泛应用于多种物种和大小范围，在过去十年中发表了许多出版物。本科生的参与和训练是明确的，因为受过训练和监督的学生参与了所有拟议实验的所有步骤。临床相关性包括更好地理解脑区域对酮类代谢的反应，以及当前儿科癫痫治疗对海马突触可塑性影响的急需表征。