Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, USA; New Mexico Alcohol Research Center, UNM Health Sciences Center, Albuquerque, NM, USA.
Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, USA.
Neuropharmacology. 2024 Apr 1;247:109860. doi: 10.1016/j.neuropharm.2024.109860. Epub 2024 Feb 7.
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. This article is part of the Special Issue on "PFC circuit function in psychiatric disease and relevant models".
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。动物模型表明，即使是低至中等水平的产前酒精暴露（PAE）也足以损害多个领域的行为灵活性。以前，我们利用适度的限时黑暗饮酒范式，发现 PAE 会：1）损害雄性成年后代的触摸屏成对视觉反转；2）导致眶额皮层（OFC）放电率小但显著降低；3）显著增加背侧纹状体（dS）的活动；4）异常维持 OFC-dS 的同步性，跨越早期反转。在目前的研究中，我们检查了光遗传学刺激 OFC-dS 投射神经元是否足以挽救 PAE 诱导的雄性 C57BL/6J 小鼠的行为灵活性障碍。在辨别学习之后，我们使用逆行腺相关病毒（AAV）靶向 dS 中的 OFC-dS 投射，该病毒表达通道视蛋白（ChR2）。在反转学习的前四个阶段中，我们通过光纤在正确选择反应后立即向 OFC 传递高频光遗传学刺激。我们的结果表明，光遗传学刺激显著减少了 PAE 和对照组小鼠通过早期坚持阶段所需的阶段数、错误反应和校正错误。此外，在早期反转学习期间，OFC-dS 刺激减少了 PAE 小鼠在反转后期学习阶段出现的阶段数增加、正确和错误反应，但对对照组 ChR2 小鼠的后期表现没有显著影响。总的来说，这些结果表明，刺激 OFC-dS 投射可以改善 PAE 和对照组小鼠的早期反转学习，并且这些改善甚至可以在任务的后期阶段持续几天。这些研究为未来改善 FASD 患者的执行控制的临床方法提供了重要基础。本文是“精神疾病相关模型中的 PFC 回路功能”特刊的一部分。
