Metabolic therapy to modulate brain dopaminergic systems

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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.