Dissecting circuits underlying loss of control relevant to binge eating

摘要 肥胖是一个严重的公共卫生问题，与高发病率和死亡率相关。暴食 (BE)强迫性间歇性暴饮暴食行为，与肥胖和体重增加率增加有关。 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。饮食失控（英语：Loss of control），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因素。然而， 在BE期间，没有对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。食欲不振与进食困难有关（即，喂养 偏移），并且临床前模型是精确测量该行为事件的最佳系统。的此集合中 综合培训和科学的目标，候选人将确定神经相关的喂养偏移使用 BE的动物模型，以了解潜在的神经基板的神经。小鼠的数据显示， 背外侧纹状体（DLS），一个与行为停止相关的关键区域，在进食补偿后变钝。 慢性BE。初步数据还表明，次级运动皮层（M2）中DLS投射细胞的活动 在进给偏移之前减小。本项目将研究DLS和M2对DLS投射细胞在 喂养补偿使用了一个强大的行为模式，在小鼠暴饮暴食。总体假设是：1） DLS中的D1和D2棘状投射神经元将差异地有助于BE与非BE小鼠的摄食偏移; 2)通过闭环刺激逆转BE小鼠中钝化的DLS活性将改善病理行为; 3） M2至DLS投射细胞的特定集合被调谐到进食偏移，在BE小鼠中活性较低;以及4） 增加M2对DLS特异性神经元的活性将改善适应不良的摄食行为。细胞分辨率 体内钙成像将用于鉴定特定DLS细胞群中的神经活动模式， 进给偏移（目标1）。闭环光遗传学将用于确定是否操纵神经活动 在DLS细胞群中促进摄食偏移的变化（目的2）。最后，体内钙成像和 光遗传学将用于识别、跟踪和操纵BE中摄食偏移时的M2至DLS投射细胞 和非BE小鼠以研究用于BE的非侵入性治疗的潜在皮质治疗靶标（目的3）。 综合培训计划将确保候选人实现其职业目标，即发展独立的 翻译BE和肥胖研究项目。候选人将在4个核心领域扩展她的培训：1） 学习体内钙成像细胞分辨率; 2）发展适用于复杂的统计分析技能 神经数据与行为事件一致; 3）应用电路操作技术，为未来的治疗提供信息 干预措施; 4）完善新的BE行为的测量，以最大限度地提高翻译的影响。完成 这K 08将有助于一个研究计划，将增加我们对核心电路的理解 潜在的BE可以被操纵以最小化导致肥胖风险的适应不良喂养。

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.