TY - JOUR
T1 - Delayed behavioral and genomic responses to acute combined stress in zebrafish, potentially relevant to PTSD and other stress-related disorders: Focus on neuroglia, neuroinflammation, apoptosis and epigenetic modulation
AU - Yang, L.E.
AU - Wang, J.T.
AU - Wang, D.M.
AU - Hu, G.J.
AU - Liu, Z.Y.
AU - Yan, D.N.
AU - Serikuly, N.
AU - Alpyshov, E.T.
AU - Demin, K.A.
AU - Strekalova, T.
AU - de Abreu, M.S.
AU - Song, C.
AU - Kalueff, A.V.
N1 - Funding Information:
This study is supported by the Southwest University Zebrafish Platform Construction Funds. AVK is the President of the International Stress and Behavior Society (ISBS, www.stress-and-behavior.com) and the Chair of the International Zebrafish Neuroscience Research Consortium (ZNRC) that coordinated this collaborative project. KAD is supported by the President of Russia Graduate Fellowship and the Special Rector's Productivity Fellowship for SPSU PhD Students. The laboratory is supported by the Russian Science Foundation (RSF) grant 19-15-00053 and St. Petersburg State University budgetary funds. ETA's research is supported by ZNRC; the research is also supported by the budgetary funding for basic research from the Scientific Research Institute of Physiology and Basic Medicine (project AAAA-A16-116021010228-0) and the RSF grant 20-65-46006 to the laboratory of Prof. Tamara G. Amstislavskaya (Novosibirsk State University, Novosibirsk, Russia). The funders had no role in the design, analyses and interpretation of the submitted study, or decision to publish.
Funding Information:
This study is supported by the Southwest University Zebrafish Platform Construction Funds . AVK is the President of the International Stress and Behavior Society (ISBS, www.stress-and-behavior.com ) and the Chair of the International Zebrafish Neuroscience Research Consortium (ZNRC) that coordinated this collaborative project. KAD is supported by the President of Russia Graduate Fellowship and the Special Rector's Productivity Fellowship for SPSU PhD Students. The laboratory is supported by the Russian Science Foundation (RSF) grant 19-15-00053 and St. Petersburg State University budgetary funds. ETA's research is supported by ZNRC; the research is also supported by the budgetary funding for basic research from the Scientific Research Institute of Physiology and Basic Medicine (project AAAA-A16-116021010228-0) and the RSF grant 20-65-46006 to the laboratory of Prof. Tamara G. Amstislavskaya (Novosibirsk State University, Novosibirsk, Russia). The funders had no role in the design, analyses and interpretation of the submitted study, or decision to publish.
Publisher Copyright:
© 2020 Elsevier B.V.
PY - 2020/7/1
Y1 - 2020/7/1
N2 - Stress is a common trigger of stress-related illnesses, such as anxiety, phobias, depression and post-traumatic stress disorder (PTSD). Various animal models successfully reproduce core behaviors of these clinical conditions. Here, we develop a novel zebrafish model of stress (potentially relevant to human stress-related disorders), based on delayed persistent behavioral, endocrine and genomic responses to an acute severe 'combined' stressor. Specifically, one week after adult zebrafish were exposed to a complex combined 90-min stress, we assessed their behaviors in the novel tank and the light-dark box tests, as well as whole-body cortisol and brain gene expression, focusing on genomic biomarkers of microglia, astrocytes, neuroinflammation, apoptosis and epigenetic modulation. Overall, stressed fish displayed persistent anxiety-like behavior, elevated whole-body cortisol, as well as upregulated brain mRNA expression of genes encoding the glucocorticoid receptor, neurotrophin BDNF and its receptors (TrkB and P75), CD11b (a general microglial biomarker), COX-2 (an M1-microglial biomarker), CD206 (an M2-microglial biomarker), GFAP (a general astrocytal biomarker), C3 (an A1-astrocytal biomarker), S100 alpha(10) (an A2-astrocytal biomarker), as well as pro-inflammatory cytokines IL-6, IL-1 beta, IFN-gamma and TNF-alpha. Stress exposure also persistently upregulated the brain expression of several key apoptotic (Bax, Caspase-3, Bcl-2) and epigenetic genes (DNMT3a, DNMT3b, HAT1, HDAC4) in these fish. Collectively, the present model not only successfully recapitulates lasting behavioral and endocrine symptoms of clinical stress-related disorders, but also implicates changes in neuroglia, neuroinflammation, apoptosis and epigenetic modulation in long-term effects of stress pathogenesis in vivo.
AB - Stress is a common trigger of stress-related illnesses, such as anxiety, phobias, depression and post-traumatic stress disorder (PTSD). Various animal models successfully reproduce core behaviors of these clinical conditions. Here, we develop a novel zebrafish model of stress (potentially relevant to human stress-related disorders), based on delayed persistent behavioral, endocrine and genomic responses to an acute severe 'combined' stressor. Specifically, one week after adult zebrafish were exposed to a complex combined 90-min stress, we assessed their behaviors in the novel tank and the light-dark box tests, as well as whole-body cortisol and brain gene expression, focusing on genomic biomarkers of microglia, astrocytes, neuroinflammation, apoptosis and epigenetic modulation. Overall, stressed fish displayed persistent anxiety-like behavior, elevated whole-body cortisol, as well as upregulated brain mRNA expression of genes encoding the glucocorticoid receptor, neurotrophin BDNF and its receptors (TrkB and P75), CD11b (a general microglial biomarker), COX-2 (an M1-microglial biomarker), CD206 (an M2-microglial biomarker), GFAP (a general astrocytal biomarker), C3 (an A1-astrocytal biomarker), S100 alpha(10) (an A2-astrocytal biomarker), as well as pro-inflammatory cytokines IL-6, IL-1 beta, IFN-gamma and TNF-alpha. Stress exposure also persistently upregulated the brain expression of several key apoptotic (Bax, Caspase-3, Bcl-2) and epigenetic genes (DNMT3a, DNMT3b, HAT1, HDAC4) in these fish. Collectively, the present model not only successfully recapitulates lasting behavioral and endocrine symptoms of clinical stress-related disorders, but also implicates changes in neuroglia, neuroinflammation, apoptosis and epigenetic modulation in long-term effects of stress pathogenesis in vivo.
KW - acute restraint stress
KW - acute stress
KW - animal-models
KW - apoptosis
KW - astrocytes
KW - chronic mild stress
KW - depression
KW - epigenetics
KW - hpa axis
KW - microglia
KW - posttraumatic-stress
KW - prefrontal cortex
KW - psychological stress
KW - trauma
KW - vulnerability
KW - zebrafish
KW - PSYCHOLOGICAL STRESS
KW - CHRONIC MILD STRESS
KW - VULNERABILITY
KW - POSTTRAUMATIC-STRESS
KW - ANIMAL-MODELS
KW - DEPRESSION
KW - Acute stress
KW - ACUTE RESTRAINT STRESS
KW - Astrocytes
KW - Zebrafish
KW - PREFRONTAL CORTEX
KW - Microglia
KW - Epigenetics
KW - HPA AXIS
KW - Apoptosis
KW - TRAUMA
U2 - 10.1016/j.bbr.2020.112644
DO - 10.1016/j.bbr.2020.112644
M3 - Article
C2 - 32344037
SN - 0166-4328
VL - 389
JO - Behavioural Brain Research
JF - Behavioural Brain Research
M1 - 112644
ER -