# Cortical Layer‐Specific Remodelling of Parvalbumin and Perineuronal Net Networks in Alcohol Use Disorder

## TL;DR

This study shows that alcohol use disorder causes changes in specific brain layers, which may explain compulsive behaviors.

## Contribution

First evidence of cortical perineuronal net remodelling in human alcohol use disorder.

## Key findings

- Increased colocalisation of PV neurons with PNN in layers IV and V/VI in AUD cases.
- No cellular loss in BA6 cortex of AUD patients compared to controls.
- Suggests reduced plasticity in cortical output circuits driving habitual behavior in AUD.

## Abstract

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.

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.

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.

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.

First evidence of cortical perineuronal net remodelling in human alcohol use disorder.Increased perineuronal net and parvalbumin colocalisation selectively in layers IV–VI in AUD.Suggests reduced plasticity in cortical output circuits driving habitual behaviour.

First evidence of cortical perineuronal net remodelling in human alcohol use disorder.

Increased perineuronal net and parvalbumin colocalisation selectively in layers IV–VI in AUD.

Suggests reduced plasticity in cortical output circuits driving habitual behaviour.

Remodelling of perineuronal nets on cortical parvalbumin neurons in layers IV–VI occurs in human alcohol use disorder, suggests reduced plasticity in cortical output circuits driving habitual behaviour.