The neurovascular unit (NVU) represents the structural and functional relationship between the neural tissue and the blood. Neurovascular dysfunction has been highlighted in neuropsychiatric afflictions, but it is still unclear whether it is a cause or a consequence of the pathology. Studying how NVU components associate might clarify its role on the emergence of emotional-cognitive dysfunction. This study aims at investigating whether the development of depressive-related loss of motivation is grounded on NVU modifications impacting the permeability of the blood-brain barrier (BBB) and in particular, of the structural scaffolding of microvessels. Adult male C57BL/6jRj mice chronically treated with corticosterone (CORT) and showing severe motivational deficits in an operant progressive ratio (PR) schedule of reinforcement task, presented altered neural activation assessed through FosB expression in key brain regions involved in appetitive and consummatory motivational processing (anterior insular cortex, basolateral amygdala, bed nucleus of the stria terminalis and ventral tegmental area). We evaluated NVU modifications through immunofluorescence staining targeting specific markers of microglia (IBA-1), endothelial tight junctions (ZO-1) and astrocytes (GFAP). The BBB permeability was evaluated in CORT-treated mice through perfusion of fluorescent 40 kDa Dextran. Our results show that where neuronal activation failed, NVU modifications predict behavioural deficits in CORT-treated animals. Notably, our analyses indicate that ZO-1, key element of microvessels’ tight junctions, plays a preponderant role on motivation-related behavioural output. Therefore, our results shed light into the relationship between NVU alterations and emotional-cognitive dysfunction relevant in the context of neuropsychiatric disorders.