Dissecting corticostriatal circuitry underlying chronic binge eating

摘要 进食障碍是一种严重的精神疾病，在全球范围内造成巨大的成本和残疾负担。狂欢 进食(BE)是一种行为，几乎贯穿了所有饮食失调的诊断。不幸的是，心理上的 饮食失调/BE的治疗是有限的，而有针对性的生物/药物治疗还没有 很有效。为了开发更有效的靶向治疗，了解神经是至关重要的 与BE的发病、表达和维持有关的回路异常。具体地说，研究 针对慢性和重复性BE的神经基础将极大地加深我们对 他的行为。涉及重复行为的其他严重精神疾病(例如，强迫症 障碍[强迫症]，物质使用障碍)与皮质纹状体内神经活动的差异有关 电路。最近这些障碍的模型强调了目标导向型之间的平衡障碍。 和习惯性行为，表明更多地依赖与习惯相关的途径，具有更长的慢性持续时间 生病了。然而，与BE的慢性阶段相比，是否存在对习惯相关回路的过度依赖 在BE的急性阶段，更多的目标导向/习惯性灵活性还有待研究。中心假说 这个项目的特点是，BE与1)与目标相关的通路中神经活动的增加有关- 急性发作期的定向行为(前脑皮质、背内侧纹状体、背内侧纹状体投射) BE；2)与习惯有关的结构(边缘下皮质[IL]、背外侧纹状体)活动增加 随着BE变得更加长期，暗示着从依赖目标到习惯性的演变 随着时间的推移，电路会变得越来越多。为了剖析BE背后的电路，将建立一个暴饮暴食的小鼠模型 使用。行为范式将通过以下方式描述使用目标导向和习惯性行为的倾向 使用氯化锂贬值检查对美味食物的习惯性反应率的差异(目的 A)和结果贬值(目标1b)。光遗传抑制对白介素2的影响 在结果贬值期间(目标1b)也将进行评估。此外，双色活体纤维光度法将 用于量化发育过程中目标导向网络和习惯相关网络中的神经活动模式 目标2)。在这个目标中，神经活动也将被时间锁定到特定的BE相关行为，这些行为是 可翻译为人类BE(例如，方法、消费)，其可以提供关于最优 治疗干预的具体行为。最后，抑制性设计者受体仅由 将使用特制药物(DREADD)来确定维护是否需要与习惯相关的电路 慢性BE(目标3)。总而言之，这项研究中提出的目标将导致我们的 了解BE背后的神经回路功能，这可能会导致更具体和有针对性的 治疗这种慢性和严重的行为。

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], PLàDMS 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.