Journal
GLIA
Volume 68, Issue 12, Pages 2674-2692Publisher
WILEY
DOI: 10.1002/glia.23878
Keywords
cognitive impacts; depression; IFN-gamma; microglia; neurogenesis
Categories
Funding
- Department of Science and Technology of Guizhou High-level Innovative Talents [[2018]5638]
- First-class Discipline Construction Projects of Guizhou Province of China [GNYL(2017)008]
- National Natural Science Foundation of China [81571174]
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Neuroinflammation driven by interferon-gamma (IFN-gamma) and microglial activation has been linked to neurological disease. However, the effects of IFN-gamma-activated microglia on hippocampal neurogenesis and behavior are unclear. In the present study, IFN-gamma was administered to mice via intracerebroventricular injection. Mice received intraperitoneal injection of ruxolitinib to inhibit the JAK/STAT1 pathway or injection of minocycline to inhibit microglial activation. During a 7-day period, mice were assessed for depressive-like behaviors and cognitive impairment based on a series of behavioral analyses. Effects of the activated microglia on neural stem/precursor cells (NSPCs) were examined, as was pro-inflammatory cytokine expression by activated microglia. We showed that IFN-gamma-injected animals showed long-term adult hippocampal neurogenesis reduction, behavior despair, anhedonia, and cognitive impairment. Chronic activation with IFN-gamma induces reactive phenotypes in microglia associated with morphological changes, population expansion, MHC II and CD68 up-regulation, and pro-inflammatory cytokine (IL-1 beta, TNF-alpha, IL-6) and nitric oxide (NO) release. Microglia isolated from the hippocampus of IFN-gamma-injected mice suppressed NSPCs proliferation and stimulated apoptosis of immature neurons. Inhibiting of the JAK/STAT1 pathway in IFN-gamma-injected animals to block microglial activation suppressed microglia-mediated neuroinflammation and neurogenic injury, and alleviated depressive-like behaviors and cognitive impairment. Collectively, these findings suggested that priming of microglia with IFN-gamma impairs adult hippocampal neurogenesis and leads to depression-like behaviors and cognitive defects. Targeting microglia by modulating levels of IFN-gamma the brain may be a therapeutic strategy for neurodegenerative diseases and psychiatric disorders.
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