Successfully navigating dynamic environments requires balancing the decision to stay at an optimal choice with that to switch to an alternative to acquire new knowledge. However, the genetic factors and cellular activity shaping this "stay or switch" action decision remains largely unidentified. Here we find that mice carrying a deletion of the exchange protein directly activated by cAMP 2 (Epac2) gene, a putative autism locus, exhibit perseverative "stay" behavior in a dynamic foraging task. Anatomical analysis found that the loss of Epac2 resulted in a significant decrease in the density of PV-expressing interneurons in the ventrolateral orbitofrontal cortex (OFC) and dorsal striatum (dSTR). Further, in vitro whole cell patch clamp recordings of PV + GABAergic interneurons in the dSTR revealed altered neural activity in Epac2 KO mice in response to dopamine. Our findings highlight a potential role of Epac2 in structural changes and neural responses of PV-expressing GABAergic interneurons in the ventrolateral OFC and dSTR during value-based reinforcement learning and link Epac2 function to abnormal decision-making processes and perseverative behaviors seen in autism.

中文翻译：

---

Epac2 KO 小鼠在基于奖励的决策任务中的持续刻板行为

成功地驾驭动态环境需要在保持最佳选择的决定与转换为获取新知识的替代方案的决定之间取得平衡。然而，形成这种“停留或转换”行动决定的遗传因素和细胞活动在很大程度上仍未确定。在这里，我们发现携带由 cAMP 2 (Epac2) 基因（一种推定的自闭症基因座）直接激活的交换蛋白缺失的小鼠在动态觅食任务中表现出持续的“停留”行为。解剖学分析发现，Epac2 的缺失导致腹外侧眶额皮质 (OFC) 和背侧纹状体 (dSTR) 中表达 PV 的中间神经元密度显着降低。更多，dSTR 中 PV + GABA 能中间神经元的体外全细胞膜片钳记录揭示了 Epac2 KO 小鼠响应多巴胺的神经活动改变。我们的研究结果强调了 Epac2 在基于价值的强化学习期间在腹外侧 OFC 和 dSTR 中表达 PV 的 GABA 能中间神经元的结构变化和神经反应中的潜在作用，并将 Epac2 功能与自闭症中看到的异常决策过程和坚持行为联系起来。