Abstract
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.
Highlights
Stress, which is becoming more prevalent in daily human life, has dual impacts on brain and body physiology
Knowing that the initial response to chronic stress is anxiety followed by depression and that the co-morbidity of these mental disorders is an undeniable risk factor for other bodily diseases, such as inflammatory bowel disease [6,8,9], it is imperative that we develop simpler models to study the effects of chronic stress on the brain and to identify associated molecular markers that can be effectively used for central nervous system (CNS) drug screening
The total duration of shoal cohesion increased significantly in the Chronic unpredictable stress (CUS) group compared to non-stressed control group
Summary
Stress, which is becoming more prevalent in daily human life, has dual impacts on brain and body physiology. Within limits, it has positive effects, such as improved memory performance [1] and increased alertness, focus, and energy; it can help people to cope with unfavorable situations. During the last few decades, researchers using animal models have found that chronic stress can induce depression, anxiety and related mood disorders [2,3,6]. Chronic unpredictable stress (CUS), one of the most clinically relevant stress paradigms in rodents, mimics a number of behavioral characteristics observed in patients with anxiety, depression and related mood disorders [6,7]. Knowing that the initial response to chronic stress is anxiety followed by depression and that the co-morbidity of these mental disorders is an undeniable risk factor for other bodily diseases, such as inflammatory bowel disease [6,8,9], it is imperative that we develop simpler models to study the effects of chronic stress on the brain and to identify associated molecular markers that can be effectively used for CNS drug screening
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