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Metabolic therapy to modulate brain dopaminergic systems

调节大脑多巴胺能系统的代谢疗法

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目总结