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费用和残疾负担。狂欢 进食（BE）是一种几乎贯穿所有进食障碍诊断的行为。不幸的是，心理上 进食障碍/BE的治疗是有限的，并且靶向生物/药理学治疗还没有 有效。为了开发更有效的靶向治疗方法，了解神经系统至关重要 导致BE发作、表达和维持的回路异常。具体而言，研究 针对慢性和重复性BE的神经基础将大大加深我们对 行为其他涉及重复行为的严重精神疾病（例如，强迫 物质使用障碍）与皮质纹状体内神经活动的差异有关。 电路这些疾病的最新模型强调了目标导向和目标导向之间的平衡功能障碍。 和习惯性行为，这表明更多的依赖于习惯相关的途径， 病然而，是否过度依赖习惯相关的电路存在于慢性阶段的BE，相比， 在BE急性期，更多的目标导向/习惯性灵活性，还有待研究。核心假设 BE与1）与目标相关的通路中的神经活动增加有关， 定向行为（前边缘皮层[PL]，背内侧纹状体[DMS]，PLàDMS投射）在急性期 BE;和2）与习惯相关的结构（边缘下皮层[IL]，背外侧纹状体 [DLS]），因为BE变得更加慢性，这表明从依赖目标导向到习惯性的演变 随着时间的推移，BE的电路。为了剖析BE背后的电路，将建立一个暴食的小鼠模型。 采用行为范式将描述使用目标导向和习惯行为的倾向， 使用氯化锂贬值法检查对可口食物习惯性反应率的差异（Aim 1a）和结果贬值（目标1b）在整个BE的持续时间。光遗传学抑制对IL-10的影响 在结果贬值（目标1b）期间也将进行评估。此外，双色在体内光纤测光将 用于量化发展过程中目标导向和习惯相关网络中的神经活动模式 目标2（Aim 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， 可转化为人类BE（例如，方法、消耗），其可以提供关于最佳的 治疗干预的具体行为。最后，抑制性设计受体只被 将使用特制药物（DREADDs）来确定与习惯相关的电路是否是维持所必需的 慢性BE（目标3）。总之，本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], PLàDMS 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.