Neurogliovascular unit adaptations following chronic distress predict motivational deficits in mice

Abstract

The neurogliovascular unit (NGVU) reflects the complex interplay between neural tissue and blood flow. Dysfunction in this NGVU system is involved in neuropsychiatric disorders, however, whether the alterations are a cause or consequence of these conditions remains unclear. This study investigates the role of NGVU adaptations in motivational deficits associated with depressive episodes, focusing on blood vessel structural changes and blood-brain barrier (BBB) permeability. We used brain samples from adult male C57BL/6jRj mice that were chronically treated with corticosterone (CORT), and which presented severe motivational deficits in an operant progressive ratio task, along with altered neural activation in brain regions involved in motivational processing (anterior insular cortex, basolateral amygdala, bed nucleus of the stria terminalis and ventral tegmental area), as assessed by FosB expression. NGVU modifications were first evaluated through immunofluorescence staining for microglia (IBA-1), endothelial tight junctions (ZO-1), and astrocytes (GFAP). BBB permeability was assessed using intravenous perfusion of fluorescent 40 kDa Dextran. Principal component analysis revealed that NGVU alterations in the ventral tegmental area and basolateral amygdala predicted motivational deficits in CORT-treated mice. Specifically, ZO-1 expression was downregulated, and Dextran extravasation was increased in these regions. These findings suggest that NGVU adaptations induced by chronic CORT exposure impact BBB integrity and are integral to understanding behavioural performance. In conclusion, NGVU modifications may play a key role in the cognitive and behavioural dysfunction seen in neuropsychiatric disorders, highlighting their relevance in the biological substrate of these conditions.