Rationale <p>Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) frequently co-occur, leading to significant impairments in learning and memory. Despite the prevalence of these disorders, existing treatment strategies remain inadequate, necessitating novel approaches targeting underlying neural circuits.</p> Objectives <p>This study investigated whether optogenetic stimulation of medial prefrontal cortex subregions could rescue fear extinction deficits in a preclinical model of comorbid PTSD/AUD. We examined the differential roles of the infralimbic (IL) and prelimbic (PL) cortices in modulating extinction learning following combined stress and chronic alcohol exposure.</p> Methods <p>Male and female Wistar rats underwent restraint stress (RS) and chronic intermittent ethanol exposure (CIE), followed by fear conditioning and extinction training. Animals received optogenetic stimulation (ChR2 or eYFP control) targeting either IL or PL cortex immediately prior to each extinction session. Extinction learning rates, days to criterion, and long-term memory retention (21-day spontaneous recovery) were assessed.</p> Results <p>Combined stress and alcohol exposure significantly impaired extinction learning compared to controls. IL-ChR2 stimulation recovered these extinction deficits in the RS + CIE group, accelerating extinction rates and reducing spontaneous recovery. Conversely, PL-ChR2 stimulation impaired extinction learning in control animals but produced no additional deficits in the already-impaired RS + CIE group, suggesting a ceiling effect.</p> Conclusions <p>This study identifies the IL cortex as a critical regulator of fear extinction learning following stress and alcohol exposure, demonstrating that targeted circuit activation can overcome extinction deficits characteristic of comorbid PTSD and AUD. These region-specific effects provide important insights into the prefrontal mechanisms governing fear memory processes in pathological states.</p>