Excessive grooming of Sapap3-KO mice has been used as a model of obsessive-compulsive disorder (OCD). Previous studies suggest that dysregulation of cortico-striatal circuits is critically important in the generation of compulsive behaviors, and it has been proposed that the alteration in the activity patterns of striatal circuitry underlies the excessive grooming observed in Sapap3-KO mice. To test this hypothesis, we used in-vivo calcium imaging of individual cells to record striatal activity in these animals and optogenetic inhibition to manipulate this activity. We identified striatal neurons that are modulated during grooming behavior and found that their proportion is significantly larger in Sapap3-KO mice compared to wild-type littermates. Inhibition of striatal cells in Sapap3-KO mice increased the number of grooming episodes observed. Remarkably, the specific inhibition of indirect pathway neurons decreased the occurrence of grooming events. Our results indicate that there is striatal neural activity related to excessive grooming engagement in Sapap3-KO mice. We also demonstrate, for the first time, that specific inhibition of striatal indirect pathway neurons reduces this compulsive phenotype, suggesting that treatments that alleviate compulsive symptoms in OCD patients may exert their effects through this specific striatal population.

Sapap3-KO 小鼠的过度梳理已被用作强迫症 (OCD) 的模型。先前的研究表明，皮质-纹状体回路的失调在强迫行为的产生中至关重要，并且有人提出，纹状体回路活动模式的改变是在 Sapap3-KO 小鼠中观察到的过度梳理的基础。为了检验这一假设，我们使用单个细胞的体内钙成像来记录这些动物的纹状体活动，并使用光遗传学抑制来操纵这种活动。我们确定了在梳理行为期间受到调节的纹状体神经元，并发现与野生型同窝小鼠相比，它们在 Sapap3-KO 小鼠中的比例明显更大。Sapap3-KO 小鼠中纹状体细胞的抑制增加了观察到的梳理次数。值得注意的是，间接通路神经元的特异性抑制减少了梳理事件的发生。我们的结果表明，在 Sapap3-KO 小鼠中存在与过度梳理相关的纹状体神经活动。我们还首次证明，对纹状体间接通路神经元的特异性抑制会减少这种强迫性表型，这表明减轻强迫症患者强迫症状的治疗可能会通过这种特定的纹状体群体发挥作用。