Fetal alcohol spectrum disorder (FASD) is the most common preventable form of developmental and neurobehavioral disability. Animal models have demonstrated that even low to moderate prenatal alcohol exposure (PAE) is sufficient to impair behavioral flexibility in multiple domains. Previously, utilizing a moderate limited access drinking in the dark paradigm, we have shown that PAE 1) impairs touchscreen pairwise visual reversal in male adult offspring 2) leads to small but significant decreases in orbitofrontal (OFC) firing rates 3) significantly increases dorsal striatum (dS) activity and 4) aberrantly sustains OFC-dS synchrony across early reversal. In the current study, we examined whether optogenetic stimulation of OFC-dS projection neurons would be sufficient to rescue the behavioral inflexibility induced by PAE in male C57BL/6J mice. Following discrimination learning, we targeted OFC-dS projections using a retrograde adeno-associated virus (AAV) delivered to the dS which expressed channel rhodopsin (ChR2). During the first four sessions of reversal learning, we delivered high frequency optogenetic stimulation to the OFC via optic fibers immediately following correct choice responses. Our results show that optogenetic stimulation significantly reduced the number of sessions, incorrect responses, and correction errors required to move past the early perseverative phase for both PAE and control mice. In addition, OFC-dS stimulation during early reversal learning reduced the increased sessions, correct and incorrect responding seen in PAE mice during the later learning phase of reversal but did not significantly alter later performance in control ChR2 mice. Taken together these results suggest that stimulation of OFC-dS projections can improve early reversal learning in PAE and control mice, and these improvements can persist even into later stages of the task days later. These studies provide an important foundation for future clinical approaches to improve executive control in those with FASD.

中文翻译：

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皮质纹状体回路的光遗传学刺激可改善产前酒精暴露小鼠的行为灵活性

胎儿酒精谱系障碍 (FASD) 是最常见的可预防的发育和神经行为障碍。动物模型已经证明，即使是低至中度的产前酒精暴露（PAE）也足以损害多个领域的行为灵活性。此前，利用黑暗范式中适度有限的饮酒，我们已经证明 PAE 1) 损害雄性成年后代的触摸屏成对视觉逆转 2) 导致眶额 (OFC) 放电率小幅但显着降低 3) 显着增加背侧纹状体(dS) 活动和 4) 在早期逆转过程中异常维持 OFC-dS 同步。在当前的研究中，我们检查了 OFC-dS 投射神经元的光遗传学刺激是否足以挽救雄性 C57BL/6J 小鼠中由 PAE 引起的行为僵化。在辨别学习之后，我们使用逆行腺相关病毒（AAV）将 OFC-dS 预测作为目标，将逆行腺相关病毒（AAV）传递到表达通道视紫红质（ChR2）的 dS。在逆转学习的前四节中，我们在正确的选择反应后立即通过光纤向 OFC 提供高频光遗传学刺激。我们的结果表明，光遗传学刺激显着减少了 PAE 和对照小鼠度过早期持续阶段所需的会话次数、错误反应和纠正错误。此外，早期逆转学习期间的 OFC-dS 刺激减少了 PAE 小鼠在逆转的后期学习阶段所见的增加的会话、正确和错误反应，但没有显着改变对照 ChR2 小鼠的后期表现。综上所述，这些结果表明，刺激 OFC-dS 投射可以改善 PAE 和对照小鼠的早期逆转学习，并且这些改善甚至可以持续到几天后任务的后期阶段。这些研究为未来改善 FASD 患者执行控制的临床方法奠定了重要基础。