TY - JOUR
T1 - Minocycline reduces neurobehavioral deficits evoked by chronic unpredictable stress in adult zebrafish
AU - Wang, Dongmei
AU - Wang, Jingtao
AU - Yan, Dongni
AU - Wang, Mengyao
AU - Yang, Longen
AU - Demin, Konstantin A.
AU - de Abreu, Murilo S.
AU - Kalueff, Allan V.
N1 - Publisher Copyright:
© 2024 Elsevier B.V.
PY - 2024/12/15
Y1 - 2024/12/15
N2 - Chronic stress-related brain disorders are widespread and debilitating, and often cause lasting neurobehavioral deficits. Minocycline, a common antibiotic and an established inhibitor of microglia, emerges as potential treatment of these disorders. The zebrafish (Danio rerio) is an important emerging model organism in translational neuroscience and stress research. Here, we evaluated the potential of minocycline to correct microglia-mediated behavioral, genomic and neuroimmune responses induced by chronic unpredictable stress (CUS) in adult zebrafish. We demonstrated that CUS evoked overt behavioral deficits in the novel tank, light–dark box and shoaling tests, paralleled by elevated stress hormones (CRH, ACTH and cortisol), and upregulated brain expression of the ‘neurotoxic M1′ microglia-specific biomarker gene (MHC-2) and pro-inflammatory cytokine genes (IL-1β, IL-6 and IFN-γ). CUS also elevated peripheral (whole-body) pro-inflammatory (IL-1β, IFN-γ) and lowered anti-inflammatory cytokines (IL-4 and IL-10), as well as reduced whole-brain serotonin, dopamine and norepinephrine levels, and increased brain dopamine and serotonin turnover. In contrast, minocycline attenuated most of these effects, also reducing CUS-elevated peripheral levels of IL-6 and IFN-γ. Collectively, this implicates microglia in zebrafish responses to chronic stress, and suggests glial pathways as potential evolutionarily conserved drug targets for treating stress-evoked neuropathogenesis. Our findings also support the growing translational value of zebrafish models for understanding complex molecular mechanisms of brain pathogenesis and its therapy.
AB - Chronic stress-related brain disorders are widespread and debilitating, and often cause lasting neurobehavioral deficits. Minocycline, a common antibiotic and an established inhibitor of microglia, emerges as potential treatment of these disorders. The zebrafish (Danio rerio) is an important emerging model organism in translational neuroscience and stress research. Here, we evaluated the potential of minocycline to correct microglia-mediated behavioral, genomic and neuroimmune responses induced by chronic unpredictable stress (CUS) in adult zebrafish. We demonstrated that CUS evoked overt behavioral deficits in the novel tank, light–dark box and shoaling tests, paralleled by elevated stress hormones (CRH, ACTH and cortisol), and upregulated brain expression of the ‘neurotoxic M1′ microglia-specific biomarker gene (MHC-2) and pro-inflammatory cytokine genes (IL-1β, IL-6 and IFN-γ). CUS also elevated peripheral (whole-body) pro-inflammatory (IL-1β, IFN-γ) and lowered anti-inflammatory cytokines (IL-4 and IL-10), as well as reduced whole-brain serotonin, dopamine and norepinephrine levels, and increased brain dopamine and serotonin turnover. In contrast, minocycline attenuated most of these effects, also reducing CUS-elevated peripheral levels of IL-6 and IFN-γ. Collectively, this implicates microglia in zebrafish responses to chronic stress, and suggests glial pathways as potential evolutionarily conserved drug targets for treating stress-evoked neuropathogenesis. Our findings also support the growing translational value of zebrafish models for understanding complex molecular mechanisms of brain pathogenesis and its therapy.
KW - Microglia
KW - Minocycline
KW - Neuroinflammation
KW - Stress-related disorders
KW - Zebrafish
UR - http://www.scopus.com/inward/record.url?scp=85203282234&partnerID=8YFLogxK
U2 - 10.1016/j.brainres.2024.149209
DO - 10.1016/j.brainres.2024.149209
M3 - Article
C2 - 39233136
AN - SCOPUS:85203282234
SN - 0006-8993
VL - 1845
JO - Brain Research
JF - Brain Research
M1 - 149209
ER -