Gestational day 12 moderate prenatal alcohol exposure produces sex-specific social impairments and attenuates prelimbic excitability and amygdala-cortex modulation of adult social behavior

Lifelong social impairments are common in individuals with prenatal alcohol exposure (PAE), and preclinical studies have identified gestational day (G)12 as a vulnerable timepoint for producing social deficits following binge-level PAE. While moderate (m)PAE also produces social impairments, the long-term neuroadaptations underlying them are poorly understood. Activity of the projection from the basolateral amygdala to the prelimbic cortex (BLA→PL) leads to social avoidance, and the PL alone is implicated in negative social behaviors, making each of these potential candidates for the neuroadaptations underlying mPAE-induced social impairments. To examine this, we first established that G12 mPAE produced sex-specific social impairments lasting into adulthood. We then chemogenetically inhibited the BLA→PL using Clozapine N-Oxide (CNO) during adult social testing. This revealed that CNO reduced social investigation in control males, but had no effect on mPAE males or females of either exposure, indicating that mPAE attenuated the role of this projection in regulating male social behavior and highlighting one potential mechanism by which mPAE affects male social behavior more severely. Using whole-cell electrophysiology, we also examined mPAE-induced changes to PL pyramidal cell physiology and determined that mPAE reduced the excitability of these cells, likely due to increased suppression by inhibitory interneurons. Overall, this work identified two mPAE-induced neuroadaptations that last into adulthood and which may underlie the sexspecific vulnerability to mPAE-induced social impairments. Future research is necessary to expand upon how these circuits modulate both normal and pathological social behavior, and to identify sex-specific mechanisms leading to differential vulnerability in males and females.