Alcohol exposure in utero disrupts cortico-striatal coordination required for behavioral flexibility
Alcohol exposure in utero disrupts cortico-striatal coordination required for behavioral flexibility
复制标题
DOI：
10.1016/j.neuropharm.2019.107832
复制
发表时间：
2020-01-01
影响因子：
4.7
通讯作者：
Brigman, Jonathan L.
中科院分区：
文献类型：
--
作者：
Marquardt, Kristin;Cavanagh, James F.;Brigman, Jonathan L.
行为灵活性缺陷是多种精神、神经和物质使用障碍的标志。这些缺陷通常表现为前额皮质（PFC）功能下降；然而，这种行政赤字的起源仍未得到充分研究。在这里，我们报告了最可预防的发育障碍原因，子宫内暴露于酒精，如何改变皮质纹状体回路活动，导致成年后行为灵活性受损。我们利用平移式触屏任务结合体内电生理学，在成年小鼠中检测了灵活行为时外侧眶额皮质（OFC）和背外侧纹状体（DS）的单个和协调活动。产前酒精暴露（PAE）降低了OFC，增加了DS，逆转学习期间的单单位活动，并改变了两个区域的选择反应神经元的数量。通过振荡场活动和改变的峰场耦合测量，PAE还降低了OFC和DS内的协调活性。此外，PAE导致区域之间的持续连通性超过了对照动物。这些发现表明，PAE导致OFC和DS内部和之间的协调改变，促进了不适应的持续。我们的模型表明，在功能最佳的小鼠中，OFC与DS分离并更新新改变的奖励偶发，而在PAE动物中，异常和持续的OFC与DS信号在早期逆转过程中驱动行为不灵活性。总之，这些发现证明了发育暴露如何改变导致行为缺陷的回路水平活动，并提出了在需要执行功能的行为中协调神经时间的关键作用。
Deficits in behavioral flexibility are a hallmark of multiple psychiatric, neurological, and substance use disorders. These deficits are often marked by decreased function of the prefrontal cortex (PFC); however, the genesis of such executive deficits remains understudied. Here we report how the most preventable cause of developmental disability, in utero exposure to alcohol, alters cortico-striatal circuit activity leading to impairments in behavioral flexibility in adulthood. We utilized a translational touch-screen task coupled with in vivo electrophysiology in adult mice to examine single unit and coordinated activity of the lateral orbital frontal cortex (OFC) and dorsolateral striatum (DS) during flexible behavior. Prenatal alcohol exposure (PAE) decreased OFC, and increased DS, single unit activity during reversal learning and altered the number of choice responsive neurons in both regions. PAE also decreased coordinated activity within the OFC and DS as measured by oscillatory field activity and altered spike-field coupling. Furthermore, PAE led to sustained connectivity between regions past what was seen in control animals. These findings suggest that PAE causes altered coordination within and between the OFC and DS, promoting maladaptive perseveration. Our model suggests that in optimally functioning mice OFC disengages the DS and updates the newly changed reward contingency, whereas in PAE animals, aberrant and persistent OFC to DS signaling drives behavioral inflexibility during early reversal sessions. Together, these findings demonstrate how developmental exposure alters circuit-level activity leading to behavioral deficits and suggest a critical role for coordination of neural timing during behaviors requiring executive function.