Modeling consequences of prolonged strong unpredictable stress in zebrafish: Complex effects on behavior and physiology.

Abstract

Chronic stress is the major pathogenetic factor of human anxiety and depression. Zebrafish (Danio rerio) have become a novel popular model species for neuroscience and CNS drug discovery. The utility of zebrafish for mimicking human affective disorders is also rapidly growing. Here, we develop a new zebrafish model of clinically relevant, prolonged unpredictable chronic stress (PUCS). The 5-week PUCS induced overt anxiety-like and motor retardation-like behaviors in adult zebrafish, also elevating whole-body cortisol and proinflammatory cytokines interleukins IL-1β and IL-6. PUCS also elevated whole-body levels of the anti-inflammatory cytokine IL-10 and increased the density of dendritic spines in telencephalic neurons. Chronic treatment with an antidepressant fluoxetine (0.1mg/L for 8days) normalized the behavioral and endocrine phenotypes, as well as stress-elevated IL-1β and IL-6 levels, similar to clinical and rodent data. The CNS expression of the bdnf gene, the two genes of its receptors (trkB, p75), and the gfap gene of glia biomarker, the glial fibrillary acidic protein, was unaltered in all three groups. However, stress elevated whole-body BDNF levels and telencephalic dendritic spine density (which were corrected by fluoxetine), thereby somewhat differing from the effects of chronic stress in rodents. Together, these findings support zebrafish as a useful in-vivo model of chronic stress, also calling for further cross-species studies of both shared and distinct neurobiological responses to chronic stress.