Dissecting circuits underlying loss of control relevant to binge eating

剖析与暴饮暴食相关的失控回路

• 批准号: 10722697
• 负责人: Britny Hildebrandt
• 金额: $ 16.25万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10722697
• 关键词: Acceleration; Acute; Animal Model; Area; Behavior; Behavior Control; Behavior assessment; Behavioral; Behavioral Paradigm; Binge Eating; Calcium; Cells; Chronic; Clinical Research; Complex; Corpus striatum structure; Data; Development; Diagnostic; Eating; Eating Behavior; Ensure; Event; Feeding behaviors; Fiber; Food; Food Access; Foundations; Future; General Population; Goals; Health; Hyperphagia; Image; Impairment; Intervention; Investigation; Learning; Link; Measurement; Mediating; Mediation; Medical; Mission; Morbidity - disease rate; Motor Cortex; Mus; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathologic; Pattern; Photometry; Physiological; Population; Pre-Clinical Model; Protocols documentation; Public Health; Research; Resolution; Rewards; Role; Scientist; Specificity; Statistical Data Interpretation; System; Technical Expertise; Techniques; Training; Weight Gain; Work; behavior measurement; career; cell type; feeding; food consumption; improved; in vivo; in vivo calcium imaging; loss of control over eating; maladaptive behavior; mortality; neural; neural correlate; neuromechanism; novel; obesity risk; optogenetics; prevent; programs; skills; translational impact

ABSTRACT Obesity is a critical public health problem associated with substantial morbidity and mortality. Binge eating (BE), a compulsive episodic overeating behavior, is associated with increased rates of obesity and weight gain. Despite the negative impact of BE on physiological health and obesity risk, the underlying neural mechanisms contributing to BE are largely unknown. Loss of control (LOC) over eating - i.e., being unable to control the quantity of food consumed - is a core feature of BE and a significant predictor of obesity. However, there have been no mechanistic investigations of in vivo neural activity patterns underlying LOC during BE, limiting development of new treatments. LOC is associated with difficulties disengaging from eating (i.e., feeding offset), and pre-clinical models are an optimal system to precisely measure this behavioral event. In this set of integrated training and scientific Aims, the candidate will identify neural correlates of feeding offset using an animal model for BE to understand the underlying neural substrates of LOC. Data in mice show that activity in dorsolateral striatum (DLS), a key region associated with behavior cessation, is blunted at feeding offset after chronic BE. Preliminary data also suggest that activity in secondary motor cortex (M2) to DLS projecting cells is reduced prior to feeding offset. This project will examine the role of DLS and M2 to DLS projecting cells in feeding offset using a robust behavioral paradigm for binge eating in mice. The overarching hypotheses are: 1) D1 and D2 spiny projection neurons in DLS will differentially contribute to feeding offset in BE vs. non-BE mice; 2) reversing blunted DLS activity in BE mice via closed-loop stimulation will improve pathologic behavior; 3) specific ensembles of M2 to DLS projecting cells tuned to feeding offset will be less active in BE mice; and 4) increasing activity of M2 to DLS specific neurons will improve maladaptive feeding behavior. Cellular resolution in vivo calcium imaging will be used to identify neural activity patterns in specific DLS cell populations during feeding offset (Aim 1). Closed-loop optogenetics will be used determine whether manipulation of neural activity in DLS cell populations facilitates changes in feeding offset (Aim 2). Finally, in vivo calcium imaging and optogenetics will be used to identify, track, and manipulate M2 to DLS projecting cells at feeding offset in BE and non-BE mice to investigate a potential cortical treatment target for non-invasive treatment of BE (Aim 3). The integrated training plan will ensure the candidate achieves her career goal of developing an independent program in translational BE and obesity research. The candidate will expand her training in 4 core areas: 1) learn cellular resolution in vivo calcium imaging; 2) develop statistical analysis skills applicable to complex neural data aligned to behavioral events; 3) apply circuit manipulation techniques to inform future treatment interventions; and 4) refine measurement of novel BE behaviors to maximize translational impact. Completion of this K08 will contribute to a program of research that will increase our understanding of how core circuits underlying BE can be manipulated to minimize maladaptive feeding that contributes to obesity risk.

摘要