ADOLESCENT STRESS INDUCES A DEPRESSIVE-LIKE PHENOTYPE ACCOMPANIED BY METABOLIC AND NEUROIMMUNE DISRUPTIONS

Adolescence confers a higher vulnerability to stress and thus a higher risk of developing stress-related psychiatric disorders. Chronic stress has been linked to neuroinflammation, which is partly mediated by glial cell dysfunction. Nevertheless, the mechanisms that operate glial cell dysfunction upon stress remain unclear. We hypothesize that disruptions in the kynurenine pathway in glial cells, which metabolizes tryptophan and is upregulated by inflammatory signals, could explain the impact of adolescent chronic stress on behavior. To model adolescent stress, we used a double hit model consisting of a chronic stress protocol (Postnatal day (PD)30 - PD58) in male and female mice, which combines social isolation with oral administration of corticosterone. Behavioral assessment revealed that chronic stressed male and female mice presented depressive-like behavior and anhedonia, as measured by the Forced Swimming Test and the Sucrose Splash Test, respectively. Interestingly, depressive-like behavior score correlated with changes in Kynurenine metabolites concentration, quantified by Liquid-Chromatography Mass Spectrometry. Moreover, immunostaining analysis revealed that adolescent stress induced microglial activation in the dorsal hippocampus CA1 of male mice.To test whether glial IDO-1 activity causally contributes to stress-induced behavioral alterations, we generated GFAP/IDO-1-cKO and Cx3Cr1/IDO-1-cKO mouse lines. Tamoxifen was administered prior to the chronic stress protocol to selectively delete IDO-1 in astrocytes or microglia during adolescence, allowing assessment of the impact of astrocytic or microglial IDO-1 loss on behavior and neuroimmune function. Overall, our results provide new evidence of glial-related mechanisms underlying the behavioral consequences of adolescent stress.