Convergent functional neuroimaging findings implicate hyperactivity across the prefrontal cortex (PFC) and striatum in the neuropathology of obsessive compulsive disorder (OCD). The impact of cortico-striatal circuit hyperactivity on executive functions subserved by these circuits is unclear, because impaired recruitment of PFC has also been observed in OCD patients during paradigms assessing cognitive flexibility. To investigate the relationship between cortico-striatal circuit disturbances and cognitive functioning relevant to OCD, Sapap3 knockout mice (KOs) and littermate controls were tested in an instrumental reversal-learning paradigm to assess cognitive flexibility. Cortical and striatal activation associated with reversal learning was assessed via quantitative analysis of expression of the immediate early gene cFos and generalized linear mixed-effects models. Sapap3-KOs displayed heterogeneous reversal-learning performance, with almost half (n = 13/28) failing to acquire the reversed contingency, while the other 15/28 had similar acquisition as controls. Notably, reversal impairments were not correlated with compulsive grooming severity. cFos analysis revealed that reversal performance declined as medial PFC (mPFC) activity increased in Sapap3-KOs. No such relationship was observed in controls. Our studies are among the first to describe cognitive impairments in a transgenic OCD-relevant model, and demonstrate pronounced heterogeneity among Sapap3-KOs. These findings suggest that increased neural activity in mPFC is associated with impaired reversal learning in Sapap3-KOs, providing a likely neural basis for this observed heterogeneity. The Sapap3-KO model is thus a useful tool for future mechanistic studies to determine how mPFC hyperactivity contributes to OCD-relevant cognitive dysfunction.

中文翻译：

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在 Sapap3 基因敲除小鼠强迫行为模型中，工具逆转学习受损与内侧前额叶皮层活动增加有关。

聚合功能神经影像学发现表明，强迫症（OCD）的神经病理学中存在前额皮质（PFC）和纹状体的过度活跃。皮质纹状体环路过度活跃对这些环路所支持的执行功能的影响尚不清楚，因为在评估认知灵活性的范例中，在强迫症患者中也观察到 PFC 募集受损。为了研究皮质纹状体回路紊乱与强迫症相关认知功能之间的关系，在仪器逆转学习范式中测试了 Sapap3 敲除小鼠 (KO) 和同窝对照小鼠，以评估认知灵活性。通过立即早期基因 cFos 表达的定量分析和广义线性混合效应模型来评估与逆转学习相关的皮质和纹状体激活。Sapap3-KO 显示出异质的逆向学习性能，几乎一半 (n = 13/28) 未能获得逆向偶发事件，而另外 15/28 则与对照组具有类似的获取。值得注意的是，逆转损伤与强迫性梳理行为的严重程度无关。cFos 分析显示，随着 Sapap3-KO 中内侧 PFC (mPFC) 活性的增加，逆转性能下降。在对照中没有观察到这种关系。我们的研究是最早描述转基因强迫症相关模型中认知障碍的研究之一，并证明了 Sapap3-KO 之间存在明显的异质性。这些发现表明，mPFC 中神经活动的增加与 Sapap3-KO 中逆转学习受损有关，为这种观察到的异质性提供了可能的神经基础。因此，Sapap3-KO 模型是未来机制研究的有用工具，可用于确定 mPFC 过度活跃如何导致强迫症相关认知功能障碍。