Abstract
BACKGROUND: Alcohol use disorder (AUD) is a chronically relapsing condition marked by a pathological shift in behaviour, where excessive motivational drive predominates over cognitive control. Brodmann area 6 (BA6) is a key cortical region that integrates cognitive control with motor output and striatal circuits. Cellular alterations in the BA6 can shift from flexible, goal-directed planning to habitual, compulsive behaviours. METHOD: Here, we examined cellular changes in the human post-mortem cortex from AUD cases (n = 9) and age-matched controls (n = 10). The density of parvalbumin (PV) neurons and perineuronal nets (PNN) was analysed from immunofluorescent-stained sections. The number of PV neurons, PNN-positive cells, and PV neurons colocalised with PNN across cortical layers II-VI in BA6 regions was quantified. RESULTS: Across layers II/VI, the density of PV neurons and PNN was similar in the control and AUD groups, indicative of no cellular loss in the BA6. Analysis of the colocalisation of PV neurons with PNN revealed no effect in layers II/III (p = 0.720). However, there was a significant increase in colocalisation of PV neurons with PNN in layers IV (p = 0.043) and V/VI (p = 0.025) in the AUD compared to the control group. CONCLUSION: This study reveals layer-specific remodelling of PNN and PV networks in the human cortex in AUD cases, suggesting shifts in AUD behaviours are potentially attributed to PV neuronal activity regulated by PNN in specific cortical layers. Together, this study identifies AUD-related neuropathology and provides insight into the mechanisms underlying persistent alcohol-seeking behaviour.