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

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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.