Neurovascular unit adjustments following chronic distress explain motivational deficits in mice

Abstract

Background. 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 whether it is a cause or a consequence of the pathology remains to be elucidated. Thus, to elucidate the role of the NVU on the emergence of emotional-cognitive dysfunction, it is necessary to study how its individual components associate. This study therefore aims at investigating whether the development of depressive-related loss of motivation is grounded on NVU adjustments impacting the permeability of the blood-brain barrier (BBB) and in particular, of the structural scaffolding of microvessels. Methods. 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 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 effect of chronic CORT administration on mice BBB permeability was evaluated through in vivo perfusion of fluorescent 40 kDa Dextran. Results. Our results highlight that where sustained neuronal activation failed, NVU modifications predict behavioural deficits in CORT-treated animals. Notably, our analyses show that NVU modifications within the ventral tegmental area are essential to understand effort-based related behavioural performance in mice, and most particularly, that the key element of microvessels' tight junctions ZO-1 plays a pivotal role on motivation-related behavioural output. Conclusions. Our results confirm a direct role of neurovascular adaptations on emotional and cognitive behavioural performance in mice, and therefore place the NVU in a key position in the research of the biological substrate at the origin of neuropsychiatric disorders.