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 肥胖是一个严重的公共卫生问题，与相当大的发病率和死亡率有关。暴饮暴食 (BE)，一种强制性的间歇性暴食行为，与肥胖率和体重增加有关。 尽管BE对生理健康和肥胖风险有负面影响，但潜在的神经机制 对BE的贡献在很大程度上是未知的。对进食失去控制(LOC)--即无法控制 食物消耗量-是BE的核心特征，也是肥胖的重要预测指标。然而，有一些 在BE期间，没有对LOC潜在的体内神经活动模式进行机制研究，限制了 开发新的治疗方法。LOC与脱离进食(即进食)的困难有关 偏移量)，临床前模型是精确测量这种行为事件的最佳系统。在这套 综合培训和科学目标，候选人将识别神经相关的喂养补偿使用 BE的动物模型以了解LOC的潜在神经基础。在老鼠身上的数据显示，在 背外侧纹状体(DLS)是与行为停止相关的关键区域，在行为停止后的摄食偏移时变钝 慢性病就是。初步数据还表明，次级运动皮质(M2)对DLS投射细胞的活动 在进给偏移量之前减少。本项目将研究DLS和M2在DLS投射细胞中的作用 在老鼠暴饮暴食中使用健壮的行为范式进行摄食补偿。主要假设如下：1) DLS内的D1和D2棘突投射神经元对BE小鼠和非BE小鼠的摄食补偿有不同的贡献； 2)通过闭环刺激逆转BE小鼠迟钝的DLS活性将改善病理行为；3) 调节到摄食偏移的M2到DLS投射细胞的特定集合在BE小鼠中将不那么活跃；以及4) 增加M2对DLS特异性神经元的活动将改善不良适应的摄食行为。细胞分辨率 体内钙成像将用于识别特定DLS细胞群中的神经活动模式 进给偏移(目标1)。将使用闭环光遗传学来确定是否操纵神经活动 DLS细胞种群的变化有助于改变摄食补偿(目标2)。最后，体内钙成像和 光遗传学将被用来识别、跟踪和操纵BE中饲养偏移的M2到DLS投射细胞 和非BE小鼠研究非侵入性治疗BE的潜在皮质治疗靶点(目标3)。 综合培训计划将确保应聘者实现她的职业目标，即发展独立的 翻译BE和肥胖症研究计划。候选人将在4个核心领域扩大她的培训：1) 学习体内细胞分辨率钙成像；2)开发适用于复合体的统计分析技能 神经数据与行为事件一致；3)应用电路操作技术，为未来的治疗提供信息 干预措施；以及4)改进对新的商务英语行为的测量，以最大限度地提高翻译效果。完成 将有助于一个研究计划，该计划将增加我们对核心电路如何 潜在的BE可以被操纵，以最大限度地减少导致肥胖风险的不适应喂养。