Fiscal Year 2018 Topic Area of Encouragement: This research will advance the understanding of the biological and environmental factors that influence Eating Disorders. Eating disorders are one of the most highly stigmatized psychiatric illnesses and as such are often underdiagnosed. Binge eating disorders (BED) and bulimia nervosa (BN) are two eating disorders that are reported to be overrepresented in military personnel and Veterans, especially in females. Active military Service members are significantly more likely to report binge-type eating (consuming unusually large volumes of food) in conjunction with intermittent fasting or extreme physical activity. These behaviors derive from the strict body weight and fitness standards enforced by the military. Because eating disorders are both persistent and resistant to current medications, they represent lifelong health issues. While the role of psychological stress and combat-related trauma have a known influence on BED and BN, the influence of dietary factors or habits on BED and BN are poorly understood. Indeed, a history of dieting is a risk factor for developing an eating disorder. Thus, research strategies designed to investigate the mechanisms sustaining bingeing behaviors, especially as it pertains to the addictive nature of highly palatable rewarding foods would provide a stronger foundation for developing clinically effective treatment strategies for improving the quality of life for military Service members and Veterans afflicted with eating disorders. This proposal will investigate the central nervous system mechanism(s) by which prior caloric restriction and dieting contribute to the development of persistent eating disorders such as BED and BN.The brain controls food intake. Within the brain, ventral tegmental area (VTA) dopamine projections to the nucleus accumbens drive intake of rewarding foods. The lateral hypothalamic area (LH) orexin neurons activate VTA dopamine neurons. LH orexin neurons are also glucose-inhibited (GI) neurons. We found that food restriction reduces glucose inhibition of orexin-GI neurons, thus increasing neuronal activity. This suggests that after food restriction, orexin-GI neurons may be activated to a greater extent in normal and/or pre-prandial (before meal) glucose levels. We further show that decreased glucose persistently enhances excitatory glutamatergic input onto VTA dopamine neurons in an orexin-dependent manner. This would reinforce VTA reward pathways and sustain the drive to seek rewarding food. In support of this, increasing LH glucose level reduces reward-based feeding after food restriction. Moreover, in a novel model of binge-type eating in rodents, we found that prior food restriction enhances binge eating behavior and renders it resistant to drug therapy. Based on our data, we hypothesize that intermittent caloric restriction alters the activity and glucose sensitivity of LH orexin-GI neurons. This change in glucose sensitivity persistently enhances glutamate transmission onto VTA dopamine neurons, leading to robust and intractable binge eating of palatable rewarding foods.In this partnered proposal, we will use the above rodent model of binge-type eating developed by Dr. Nicolas Bello, an expert in feeding behavior. Dr. Vanessa Routh, an expert in electrophysiological techniques, will measure the glucose sensitivity of LH orexin GI neurons and glutamate transmission in VTA dopamine neurons in this model. We will determine whether orexin inhibition during caloric restriction blocks the increased glutamate transmission in VTA dopamine neurons as well as diminishing and restoring drug sensitivity to binge-type eating. We will also determine whether orexin activation mimics the neuronal and behavioral effects of food restriction. Thus, this partnership is unique and ideal to test our hypothesis in the following three specific aims:Specific Aim I: Determine whether the development of binge-type eating is associated with enhanced glutamate transmission onto VTA dopamine neurons and whether this effect is mediated by orexin (Routh).Specific Aim II: Determine whether the development of binge-type eating is associated with increased activation of LH orexin-GI neurons in low glucose (Routh).Specific Aim III: Determine whether orexin inhibition during caloric restriction diminishes and restores drug sensitivity to binge-type eating and whether orexin activation mimics the effects of food restriction (Bello).Impact: These studies are novel because they are the first to demonstrate that changes in the glucose sensitivity of orexin-GI neurons resulting from food restriction could lead to persistent and drug-resistant adaptive changes in downstream neurocircuitry, which contribute to binge eating behavior. The concepts put forward in this proposal, if proven feasible, provide a transformative line of thinking with regard to BED and BN. Our short-term goal is to test the feasibility of this interesting and transformative concept. If our hypothesis is correct, then the long-term goal is to develop therapies that prevent the enhanced activity of orexin-GI neurons in low glucose following caloric restriction. This could be very beneficial for individuals susceptible to the development of eating disorders.
Area; base; Behavior; Behavioral; Binge Eating; Binge eating disorder; binge type behavior; Biological Factors; Body Weight; Brain; Bulimia; Caloric Restriction; Clinical; combat; Consumption; Data; design; Development; Diet; Diet Habits; Dietary Factors; Dietary History; Dopamine; dopaminergic neuron; Drug resistance; drug sensitivity; Eating; Eating Behavior; Eating Disorders; effective therapy; Electrophysiology (science); Environmental Risk Factor; feeding; Feeding behaviors; Female; fitness; Food; food restriction; Foundations; Glucose; Glutamates; Goals; Health; hypocretin; Hypothalamic structure; improved; Individual; Intake; Intermittent fasting; Lateral; Lateral Hypothalamic Area; Lead; Measures; Mediating; Mental disorders; Military Personnel; mind control; Modeling; Names; Nature; Neuraxis; Neurons; novel; Nucleus Accumbens; Palate; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Physical activity; prevent; Psychological Stress; Quality of life; Reporting; Research; Resistance; Rewards; Risk Factors; Rodent; Rodent Model; Role; service member; Stigmatization; Techniques; Testing; therapy development; Thinking; transmission process; Trauma; treatment strategy; Ventral Tegmental Area; Veterans