Priming of microglia with IFN-γ impairs adult hippocampal neurogenesis and leads to depression-like behaviors and cognitive defects.
Jinqiang ZhangHui HeYan QiaoTao ZhouHaili HeSaini YiLijuan ZhangLi MoYahui LiWeike JiangZili YouPublished in: Glia (2020)
Neuroinflammation driven by interferon-gamma (IFN-γ) and microglial activation has been linked to neurological disease. However, the effects of IFN-γ-activated microglia on hippocampal neurogenesis and behavior are unclear. In the present study, IFN-γ 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-γ-injected animals showed long-term adult hippocampal neurogenesis reduction, behavior despair, anhedonia, and cognitive impairment. Chronic activation with IFN-γ induces reactive phenotypes in microglia associated with morphological changes, population expansion, MHC II and CD68 up-regulation, and pro-inflammatory cytokine (IL-1β, TNF-α, IL-6) and nitric oxide (NO) release. Microglia isolated from the hippocampus of IFN-γ-injected mice suppressed NSPCs proliferation and stimulated apoptosis of immature neurons. Inhibiting of the JAK/STAT1 pathway in IFN-γ-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-γ impairs adult hippocampal neurogenesis and leads to depression-like behaviors and cognitive defects. Targeting microglia by modulating levels of IFN-γ the brain may be a therapeutic strategy for neurodegenerative diseases and psychiatric disorders.
Keyphrases
- inflammatory response
- cognitive impairment
- dendritic cells
- cerebral ischemia
- neuropathic pain
- immune response
- lipopolysaccharide induced
- lps induced
- nitric oxide
- spinal cord injury
- spinal cord
- signaling pathway
- depressive symptoms
- traumatic brain injury
- high fat diet induced
- rheumatoid arthritis
- cell cycle arrest
- metabolic syndrome
- bipolar disorder
- brain injury
- induced apoptosis
- skeletal muscle
- oxidative stress
- cancer therapy
- functional connectivity
- insulin resistance
- binding protein
- drug induced