Anxiety and depression are major chronic mood disorders, and the etiopathology for each appears to be repeated exposure to
diverse unpredictable stress factors. Most of the studies on anxiety and related mood disorders are performed in rodents,
and a good model is chronic unpredictable stress (CUS). In this study, we have attempted to understand the molecular basis
of the neuroglial and behavioral changes underlying CUS-induced mood disorders in the simplest vertebrate model, the zebrafish,
Danio rerio. Zebrafish were subjected to a CUS paradigm in which two different stressors were used daily for 15 days, and
thorough behavioral analyses were performed to assess anxiety and related mood disorder phenotypes using the novel tank test,
shoal cohesion and scototaxis. Fifteen days of exposure to chronic stressors appears to induce an anxiety and related mood
disorder phenotype. Decreased neurogenesis, another hallmark of anxiety and related disorders in rodents, was also observed
in this zebrafish model. The common molecular markers of rodent anxiety and related disorders, corticotropin-releasing factor
(CRF), calcineurin (ppp3r1a) and phospho cyclic AMP response element binding protein (pCREB), were also replicated in the
fish model. Finally, using 2DE FTMS/ITMSMS proteomics analyses, 18 proteins were found to be deregulated in zebrafish anxiety
and related disorders. The most affected process was mitochondrial function, 4 of the 18 differentially regulated proteins
were mitochondrial proteins: PHB2, SLC25A5, VDAC3 and IDH2, as reported in rodent and clinical samples. Thus, the zebrafish
CUS model and proteomics can facilitate not only uncovering new molecular targets of anxiety and related mood disorders but
also the routine screening of compounds for drug development.