Transcranial alternating current stimulation reverses adolescent alcohol-induced cellular and behavioral deficits.

BACKGROUND: Alcohol is commonly consumed by adolescents in a binge-like pattern that can produce persistent cognitive impairments. Previous work found that adolescent intermittent ethanol (AIE) exposure reduces parvalbumin expressing (PV+) interneurons and increases perineuronal net (PNN) expression in brain regions critical for cognition. Transcranial alternating current stimulation (tACS), a noninvasive neuromodulation technique, has shown promise for treating psychiatric disorders associated with cognitive dysfunction. Here, we examined whether AIE exposure alters PV+ interneurons and PNN expression in the medial prefrontal cortex (mPFC) and impairs cognition, and whether mPFC-targeted gamma tACS can reverse these effects. METHODS: Sprague Dawley rats (N=139, 50% female) underwent AIE or control exposure during adolescence and received Active or Sham mPFC-targeted gamma tACS treatment for three consecutive days in adulthood. Following stimulation, rats either underwent immunohistochemical assessment of PV+ and PNN expression or behavioral testing using the novel object recognition (NOR) task. RESULTS: AIE exposure reduced PV+ cell counts in the prelimbic cortex, an effect that was reversed by active tACS. In contrast, AIE exposure did not alter PNN measures. Interestingly, active tACS affected the prelimbic and infralimbic cortices more than the anterior cingulate cortex. AIE exposure also reduced recognition memory of a novel object, and this deficit was ameliorated by active tACS when assessed one week after stimulation. Additionally, active stimulation decreased anxiety-like behavior in the open-field test. CONCLUSIONS: Together, these results confirm that adolescent alcohol exposure produces lasting cellular and cognitive alterations and supports mPFC-targeted gamma tACS as a potential intervention for alcohol-induced dysfunction.