Background

Patients with obsessive-compulsive disorder (OCD) display disrupted performance and abnormal lateral orbitofrontal cortex (LOFC) activity during reversal learning tasks. However, it is unknown whether compulsions and reversal learning deficits share a common neural substrate. To answer this question, we measured neural activity with in vivo calcium imaging in LOFC during compulsive grooming and reversal learning before and after fluoxetine treatment.

Methods

Sapap3 knockout (KO) mice were used as a model for OCD-relevant behaviors. Sapap3 KOs and control littermates were injected with a virus encoding GCaMP6f and implanted with gradient-index lenses to visualize LOFC activity using miniature microscopes. Grooming, reversal learning, and neural activity were measured pre- and post-fluoxetine treatment (18 mg/kg, 4 weeks).

Results

Baseline compulsive grooming and reversal learning impairments in KOs improved after fluoxetine treatment. In addition, KOs displayed distinct patterns of abnormal LOFC activity during grooming and reversal learning, both of which normalized after fluoxetine. Finally, reversal learning–associated neurons were distributed randomly among grooming-associated neurons (i.e., overlap is what would be expected by chance).

Conclusions

In OCD, LOFC is disrupted during both compulsive behaviors and reversal learning, but whether these behaviors share common neural underpinnings is unknown. We found that LOFC plays distinct roles in compulsive grooming and impaired reversal learning and their improvement with fluoxetine. These findings suggest that LOFC plays separate roles in pathophysiology and treatment of different perseverative behaviors in OCD.

中文翻译：

---

氟西汀后强迫梳理和逆转学习正常化期间外侧眶额叶皮质活动的不同模式

背景

强迫症 (OCD) 患者在逆转学习任务中表现出异常的表现和异常的外侧眶额叶皮层 (LOFC) 活动。然而，尚不清楚强迫症和逆转学习缺陷是否具有共同的神经基质。为了回答这个问题，我们在氟西汀治疗前后的强迫梳理和逆转学习期间用体内钙成像测量了 LOFC 中的神经活动。

方法

Sapap3基因敲除 (KO) 小鼠被用作强迫症相关行为的模型。Sapap3 KO 和对照同窝仔被注射了一种编码 GCaMP6f 的病毒，并植入了梯度折射率透镜，以使用微型显微镜观察 LOFC 活动。在氟西汀治疗（18 mg/kg，4 周）前后测量梳理、逆转学习和神经活动。

结果

氟西汀治疗后，KOs 的基线强迫梳理和逆转学习障碍得到改善。此外，KOs 在梳理和逆转学习过程中表现出明显的异常 LOFC 活动模式，这两种模式在氟西汀后均正常化。最后，逆向学习相关神经元随机分布在梳理相关神经元中（即，重叠是偶然发生的）。

结论

在 OCD 中，LOFC 在强迫行为和逆向学习期间都被破坏，但这些行为是否具有共同的神经基础尚不清楚。我们发现 LOFC 在强迫性梳理和受损的逆转学习以及使用氟西汀改善它们方面发挥着独特的作用。这些发现表明，LOFC 在病理生理学和 OCD 不同顽固行为的治疗中起着不同的作用。