Astrocytic Cannabinoid Receptor 1 Promotes Resilience by Dampening Stress-Induced Blood-Brain Barrier Alterations

Abstract Blood-brain barrier (BBB) alterations contribute to stress vulnerability and development of depressive behaviors. In contrast, neurovascular adaptations underlying stress resilience remain unexplored. Here, we report that high expression of astrocytic cannabinoid receptor 1 (CB1) in the nucleus accumbens (NAc) shell, particularly in the endfeet ensheathing blood vessels, is associated with resilience despite chronic social stress exposure. Viral-mediated overexpression of Cnr1 in astrocytes of the NAc shell has baseline anxiolytic effects and dampened stress-induced anxiety- and depression-like behaviors. It also reduced astrocyte inflammatory response and morphological changes following an immune challenge with the cytokine interleukin-6, linked to stress susceptibility and mood disorders. At the preventive and therapeutic level, physical exercise and antidepressant treatment increased perivascular astrocytic Cnr1 in mice. Loss of CNR1 was confirmed in the NAc astrocytes of depressed individuals. These findings suggest a role for the astrocytic endocannabinoid system in stress responses and possibly, human depression, via BBB modulation.