Dissecting corticostriatal circuitry underlying chronic binge eating

剖析慢性暴饮暴食背后的皮质纹状体回路

• 批准号: 10226723
• 负责人: Britny Hildebrandt
• 金额: $ 3.32万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226723
• 关键词: Acute; Address; Anorexia Nervosa; Area; BRAIN initiative; Behavior; Behavior Disorders; Behavioral Paradigm; Binge Eating; Binge eating disorder; Biological Pharmacology; Brain; Bulimia; Chronic; Color; Compulsive Behavior; Consumption; Control Groups; Corpus striatum structure; Dependence; Development; Diagnosis; Diagnostic; Disease model; Eating; Eating Behavior; Eating Disorders; Equilibrium; Etiology; Evolution; Extinction (Psychology); Feeling; Feeling suicidal; Fiber; Food; Functional disorder; Goals; Habits; Human; Intervention; Lead; Link; Lithium Chloride; Maintenance; Mediating; Medical; Mental Health; Mental disorders; Methods; Modeling; Mus; National Research Service Awards; Neurons; Neurosciences; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obsessive-Compulsive Disorder; Outcome; Palate; Pathway interactions; Pattern; Pharmacological Treatment; Pharmacology; Photometry; Physiological; Rattus; Research; Resistance; Structure; Substance Use Disorder; Techniques; Testing; Therapeutic Intervention; Time; Training; cost; designer receptors exclusively activated by designer drugs; disability burden; effective therapy; flexibility; in vivo; insight; mortality; mouse model; neural circuit; optogenetics; pre-doctoral; psychologic; psychosocial; relating to nervous system; repetitive behavior; severe mental illness; severe psychiatric disorder

ABSTRACT Eating disorders are severe psychiatric conditions with a significant worldwide cost and disability burden. Binge eating (BE) is a behavior that cuts across nearly all eating disorder diagnoses. Unfortunately, psychological treatments for eating disorders/BE are limited, and targeted biological/pharmacological treatments have not yet been effective. In order to develop more effective targeted treatments, it is critical to understand the neural circuit abnormalities that contribute to the onset, expression, and maintenance of BE. Specifically, studies targeting the neural underpinnings of chronic and repetitive BE will substantially deepen our understanding of the behavior. Other severe psychiatric conditions involving repetitive behaviors (e.g., obsessive compulsive disorder [OCD], substance use disorders) are associated with differences in neural activity within corticostriatal circuitry. Recent models of these disorders have highlighted dysfunction in the balance between goal-directed and habitual behavior, suggesting more reliance on habit related pathways with more chronic duration of illness. However, whether overreliance on habit related circuitry exists in chronic stages of BE, compared to more goal-directed/habitual flexibility at acute stages of BE, has yet to be investigated. The central hypotheses of this project are that BE is associated with 1) increased neural activity in pathways associated with goal- directed behavior (prelimbic cortex [PL], dorsomedial striatum [DMS], PLàDMS projections) at acute stages of BE; and 2) increased activity in structures associated with habit (infralimbic cortex [IL], dorsolateral striatum [DLS]) as BE becomes more chronic, suggesting an evolution from dependence on goal-directed to habitual circuits in BE over time. In order to dissect circuitry underlying BE, a mouse model of binge-like eating will be used. Behavioral paradigms will characterize the propensity to use goal-directed and habitual behavior by examining differences in rates of habitual responding to palatable food using lithium chloride devaluation (Aim 1a) and outcome devaluation (Aim 1b) across duration of BE. The impact of optogenetic inhibition of the IL during outcome devaluation (Aim 1b) will also be assessed. In addition, dual color in vivo fiber photometry will be used to quantify neural activity patterns in goal-directed and habit related networks during the development of BE (Aim 2). In this Aim, neural activity will also be time-locked to specific BE related behaviors that are translatable to human BE (e.g., approach, consumption), which may provide information regarding optimal specific behaviors for therapeutic intervention. Finally, inhibitory designer receptors exclusively activated by designer drugs (DREADDs) will be used to determine if habit related circuitry is necessary for the maintenance of chronic BE (Aim 3). Together, the Aims proposed in this study will lead to a dramatic increase our understanding of neural circuit function underlying BE, which could lead to more specific and targeted treatments for this chronic and severe behavior.

摘要