Hyper-oligodendrogenesis at the vascular niche and reduced blood-brain barrier integrity in the prefrontal cortex during protracted abstinence

- Protracted abstinence from chronic alcohol enhances the proximity of oligodendrocytes with endothelial cells.
- Enhanced oligo-vasculature proximity is associated with enhanced blood-brain barrier permeability.
- Wheel running during abstinence prevents oligo-vascular maladaptations and normalizes blood-brain barrier permeability.

Alcoholism is a relapsing disorder with limited treatment options, in part due to our limited understanding of the disease etiology. We have recently shown that increased ethanol-seeking in a behavioral model of relapse in a rat model of alcoholism was associated with increased oligodendrogenesis which was positively correlated with platelet/endothelial cell adhesion molecule (PECAM-1) expression in the medial prefrontal cortex (mPFC). The current study investigated whether newly born oligodendrocytes form close physical associations with endothelial cells expressing PECAM-1 and whether these changes were accompanied by altered blood-brain barrier (BBB) integrity. Colableling and confocal analysis demonstrate that newly born oligodendroglia were always located in close physical proximity to PECAM-1 in the mPFC of rats that were ethanol dependent and demonstrated high propensity for relapse. Notably, the endothelial proximity of new oligodendrocytes was associated with reduced expression of endothelial barrier antigen (SMI-71), a marker for BBB integrity. Furthermore, voluntary wheel running during abstinence enhanced SMI-71 expression in endothelial cells, indicating protection against abstinence-induced reduction in BBB integrity. Taken together, these results suggest that ethanol experience and abstinence disrupts homeostasis in the oligo-vascular niche in the mPFC. Reversing these mechanisms may hold the key to reducing propensity for relapse in individuals with moderate to severe alcohol use disorder.