Prolonged 5-week and 12-week chronic stress differentially modulates CNS expression of pro- and anti-neuroinflammatory biomarkers, brain monoamines and affective behavior in adult zebrafish.

Chronic stress is a major cause of affective pathogenesis, such as anxiety and depression. Experimental animal models, including rodents and zebrafish, are a valuable tool for translational neuroscience research focusing on stress-related brain disorders. Here, we examined the effects of 5- and 12-week chronic unpredictable stress (CUS5 and CUS12) on zebrafish behavior, whole-body cortisol and neuroinflammation-related biomarker gene expression, including markers of pro-inflammatory microglia (NOS2a, COX2, P75NTR) and astroglia (C3, GBP), and markers of anti-inflammatory microglia (ARG-1, CD206) and astroglia (S100a10, PTX). We also assessed stress-induced changes in brain monoamine levels and brain-blood-barrier permeability. Overall, CUS5 induced anxiety-like behavior, accompanied by elevated CNS pro-inflammatory marker gene expression, cortisol signaling and norepinephrine levels. In contrast, CUS12 induced depression-like behavior, accompanied by lowered cortisol levels, impaired serotonin turnover and activated anti-inflammatory biomarker gene expression, as well as upregulated histone deacetylase 4 gene (suggesting the involvement of epigenetic regulation). Collectively, this confirms the importance of stress duration as a key factor in the development of stress-related disorders in zebrafish models, and further implicates pro- and inti-inflammatory neuroglia in affective pathogenesis.