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

越来越多的证据表明，在发育过程中适度接触酒精会导致行为和认知缺陷，这种缺陷会持续整个生命周期。与胎儿酒精谱系障碍（FASD）相关的认知障碍包括学习和记忆、执行控制和社会行为的异常，并且通常以过度关注一个特定任务或任务的一个方面为特征，从而损害其他重要行为。皮质介导的认知的措施已被证明是敏感的高剂量乙醇（EtOH）暴露在啮齿动物的发展过程中，但鲜为人知的机制，负责与FASD相关的执行功能改变。我们建议调查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学的影响，通过整合高度可翻译的触摸屏行为措施，以前显示招募背侧纹状体和眶额皮质与产前暴露和对照小鼠的体内和体外电生理学。我们假设，适度的产前EtOH暴露将减少眶额皮质（OFC）中神经元回路的激活，从而损害执行控制行为并从皮质控制中释放背侧纹状体（dS），导致超集中，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，我们将调查是否适度的产前酒精暴露损害逆转学习，通过测量选择学习和转移后，适度的产前酒精暴露使用触摸屏范例青春期小鼠。接下来，我们将研究这种乙醇暴露是否会损害dS神经元回路的功能，通过在体内进行多电极阵列电生理记录来检查选择学习和移位过程中的dS神经元放电活动，并利用体外切片电生理技术来检查选择学习和移位后dS中的突触传递和可塑性。最后，我们将研究PAE是否损害OFC神经元回路的功能，通过在选择学习和移位过程中进行OFC神经元放电活动的体内记录，并进行体外切片电生理学测量选择学习和移位后OFC中的突触传递和AMPAR/NMDAR比率。总之，这些目标的完成将使我们能够更好地了解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方法提供重要工具。

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.