DEFICIENT RESPONSE INHIBITION AND CORTICAL ALTERATIONS AFTER PRENATAL ALCOHOL EXPOSURE IN THE MOUSE

摘要 胎儿酒精谱系障碍（FASD）的一个共同特征是无法适当地集中注意力 并抑制对刺激的反应，这些刺激类似于但不同于那些可靠地导致积极反应的刺激。 结果。连续的表现任务已经被用来测量注意力和反应抑制， 人类受试者和五个选择连续性能任务（5C-CPT）被开发来检查这些 在啮齿动物中以类似的方式进行。我们最近与合作者一起验证了这一点 在小鼠和人类受试者的任务行为，我们目前的数据表明，5C-CPT招募类似 来自啮齿动物和健康人类受试者的额叶和顶叶皮层的EEG信号。在这里，我们建议测试 在妊娠的第一和第二个三个月期间，适度的乙醇暴露是否会损害注意力， 触摸屏5C-CPT上的响应抑制。接下来，我们将进行同步脑电图一样的硬脑膜休息 局部场电位（LFP）和额叶和顶叶皮层的深度记录，以检查中度PAE是否 显著改变额叶和顶叶信号，如果这种信号与神经元放电的改变有关， 模式或时间。这些方法的结合将使我们能够看到单个单元的发射， 区域活动，并将其与临床相关的大脑活动测量进行比较。最后，有证据表明， LFP振荡信号由快速尖峰小清蛋白阳性（FS-PV+）的活性控制 因此，我们将进行FS-PV+神经元的靶向体内记录，免疫组织化学和离体 电生理学检查认知控制缺陷是否由中间神经元的改变介导 数字和兴奋音。我们的假设是，PAE导致不适当的顶叶振荡音通过损失 的中间神经元信号，与整体的结果是受损的认知控制。总的来说， 这些目标的完成将使我们能够更好地了解长期损害的机制， FASD中的认知控制，并为执行功能障碍的更有效治疗提供了目标。

Abstract A common feature in Fetal Alcohol Spectrum Disorders (FASD) is an inability to focus attention appropriately and inhibit responding to stimuli that are similar to, but distinct from, those that reliably lead to positive outcomes. Continuous performance tasks have been used to measure both attention and response inhibition in human subjects and the Five Choice Continuous Performance task (5C-CPT) was developed to examine these processes in an analogous manner in rodents. Together with our collaborators, we have recently validated this task behaviorally in mice and human subjects and our current data shows that the 5C-CPT recruits similar EEG signal from frontal and parietal cortex in rodents and healthy human subjects. Here, we propose to test whether moderate ethanol exposure during the first and second trimester equivalents impairs attention and response inhibition on the touch-screen 5C-CPT. Next, we will perform simultaneous EEG-like dura-resting local field potential (LFP) and depth recording of frontal and parietal cortex to examine whether moderate PAE significantly alters frontal and parietal signaling, and if this signaling is related to alteration in neuronal firing pattern or timing. The combination of these approaches will allow us to look at both individual unit firing and regional activity and compare it to a clinically relevant measure of brain activity. Finally, given evidence that LFP oscillatory signaling is controlled by the activity of fast-spiking parvalbumin positive (FS-PV+) interneurons, we will perform targeted in vivo recording of FS-PV+ neurons, immunohistochemistry and ex vivo electrophysiology to examine whether deficits in cognitive control are mediated by alterations in interneuron number and excitatory tone. Our hypothesis is that PAE leads to inappropriate parietal oscillatory tone via loss of interneuron signaling, with the overall outcome being impaired cognitive control. Taken together, the completion of these aims will allow us to better understand the mechanisms of the long-lasting impairments in cognitive control seen in FASD and provide targets for more effective therapies for executive dysfunction.