Dysregulation of Cortico-Striatal Function in Prenatal Alcohol-Exposed Mice

越来越多的证据表明，在发育过程中适度饮酒会导致行为和认知缺陷，这种缺陷可能会持续一生。与胎儿酒精谱系障碍（FASDs）相关的认知障碍包括学习和记忆、执行控制和社会行为方面的异常，通常以过度专注于某一特定任务或任务的某一方面为特征，损害了其他重要行为。在啮齿动物的发育过程中，皮质介导的认知测量已被证明对高剂量乙醇（EtOH）暴露敏感，但对与FASD相关的执行功能改变的机制知之甚少。我们建议通过整合高度可翻译的触摸屏行为测量，研究产前乙醇暴露对皮质纹状体介导的行为和学习相关的皮质和纹状体生理的影响，这些行为测量先前被证明可以调动背纹状体和眶额皮质，并结合在体内和离体电生理，在产前暴露和对照小鼠中进行。我们假设，适度的产前ettoh暴露会降低眶额皮质（OFC）神经元回路的激活，损害执行控制行为，并释放皮层控制的背纹状体（dS），导致过度集中，不受调节的学习。为了验证这一假设，我们提出了三个具体目标。首先，我们将通过使用触摸屏范式测量青春期小鼠在适度产前酒精暴露后的选择学习和转移，来研究适度产前酒精暴露是否会损害反转学习。接下来，我们将通过在体内进行多电极阵列电生理记录来检测选择学习和转移过程中dS神经元的放电活动，并利用体外切片电生理技术来检测选择学习和转移后dS神经元的突触传递和可塑性，来研究乙醇暴露是否会损害dS神经元回路的功能。最后，我们将通过在体内记录OFC神经元在选择学习和移动过程中的放电活动，并在体外进行切片电生理测量选择学习和移动后OFC的突触传递和AMPAR/NMDAR比值，来研究PAE是否会损害反转学习过程中OFC神经元回路的功能。综上所述，这些目标的完成将使我们更好地理解FASD中认知障碍的机制，并为开发更有效的执行功能障碍治疗提供重要工具。

There is growing evidence that moderate exposure to alcohol during development can lead to behavioral and cognitive deficits that can persist throughout the lifespan. The cognitive impairments associated with Fetal Alcohol Spectrum Disorders (FASDs) include abnormalities in learning and memory, executive control and social behaviors^"^ and are often characterized by a hyper-focus on one particular task or aspect of a task, to the detriment of other important behaviors. Measures of cortically-mediated cognition have been shown to be sensitive to high dose ethanol (EtOH) exposure during development in rodents, but little is known regarding the mechanisms responsible for executive function alterations associated with FASD. We propose to investigate the impact of prenatal ethanol exposure on corticostriatal-mediated behavior and learning related cortical and striatal physiology by integrating highly translatable touch-screen behavioral measures previously shown to recruit dorsal striatum and orbitofrontal cortex with in vivo and ex vivo electrophysiology in prenatally exposed and control mice. We hypothesize that moderate prenatal EtOH exposure will decrease activation of neuronal circuits in the orbito-frontal cortex (OFC) impairing executive control behavior and releasing the dorsal striatal (dS) from cortical control, resulting in hyper-focused, unregulated learning. In order to test this hypothesis we propose three specific aims. First, we will investigate whether moderate prenatal ethanol exposure impairs reversal learning by measuring choice learning and shifting in adolescent mice after moderate prenatal alcohol exposure using touch screen paradigm. Next, we will examine whether this ethanol exposure impairs the function of dS neuronal circuits by both performing in vivo multi-electrode array electrophysiological recording to examine dS neuronal firing activity during choice learning and shifting and utilizing in vitro slice electrophysiological techniques to examine synaptic transmission and plasticity in the dS after choice learning and shifting. Finally, we will investigate whether PAE impairs the function of OFC neuronal circuits during reversal learning by performing in vivo recording of OFC neuronal firing activity during choice learning and shifting and performing in vitro slice electrophysiology to measure synaptic transmission and AMPAR/NMDAR ratios in the OFC after choice learning and shifting. Taken together, the completion of these aims will allow us to better understand the mechanisms of cognitive impairment in FASD and provide an important tool for developing more effective therapies for executive dysfunction.