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.

抽象的 肥胖是与大量发病率和死亡率相关的关键公共卫生问题。暴饮暴食 （BE）是一种强迫性的暴饮暴食行为，与肥胖和体重增加的率提高有关。 尽管BE对生理健康和肥胖风险产生了负面影响，但基本的神经机制 做出贡献在很大程度上是未知的。饮食失去控制（LOC） - 即无法控制 食用食物的数量 - 是BE的核心特征，也是肥胖的重要预测指标。但是，那里有 在BE期间LOC下的体内神经活动模式没有机械调查，限制 开发新疗法。 LOC与脱离进食的困难有关（即进食 偏移），临床前模型是精确衡量此行为事件的最佳系统。在这套 综合培训和科学目的，候选人将使用一种 动物模型是要了解LOC的基础神经底物。小鼠中的数据显示 背外侧纹状体（DLS）是与行为停止相关的关键区域，在进食后会钝化 慢性。初步数据还表明，次级运动皮层（M2）的活性对DLS投射细胞 在进食偏移之前减少。该项目将检查DLS和M2对DLS投射细胞的作用 使用强大的行为范式进食偏移，以在小鼠中进行暴饮暴食。总体假设是：1） DLS中的D1和D2棘投射神经元将有不同的贡献有助于喂食与非贝生小鼠的进食。 2）通过闭环刺激逆转BE小鼠中钝的DLS活性将改善病理行为； 3） M2对DLS投射细胞的特定集合在小鼠中的活性较低。和4） M2对DLS特定神经元的活性增加将改善适应不良的进食行为。细胞分辨率 体内钙成像将用于识别特定DLS细胞群体中的神经活动模式 进食偏移（AIM 1）。将使用闭环光遗传学确定是否操纵神经活动 在DLS中，细胞种群有助于进食偏移的变化（AIM 2）。最后，体内钙成像和 光遗传学将用于识别，跟踪和操纵M2到DLS投射细胞的进料偏移时 和非贝生小鼠研究非侵入性治疗的潜在皮质治疗靶标（AIM 3）。 综合培训计划将确保候选人实现她的职业目标，以发展独立 翻译和肥胖研究的计划。候选人将在4个核心领域扩大培训：1） 学习体内钙成像中的细胞分辨率； 2）开发适用于复杂的统计分析技能 神经数据与行​​为事件一致； 3）应用电路操纵技术为未来的治疗提供信息 干预措施； 4）精炼新型行为的测量，以最大程度地提高翻译影响。完成 该K08将有助于一项研究计划，这将增加我们对核心电路的理解 可以操纵潜在的基础，以最大程度地减少适应不良的喂养，从而导致肥胖风险。