Lentivirus-mediated interleukin-1β (IL-1β) knock-down in the hippocampus alleviates lipopolysaccharide (LPS)-induced memory deficits and anxiety- and depression-like behaviors in mice

Abstract

BackgroundRecent evidence has suggested that peripheral inflammatory responses induced by lipopolysaccharides (LPS) play an important role in neuropsychiatric dysfunction in rodents. Interleukin-1β (IL-1β), a pro-inflammatory cytokine, has been proposed to be a key mediator in a variety of behavioral dysfunction induced by LPS in mice. Thus, inhibition of IL-1β may have a therapeutic benefit in the treatment of neuropsychiatric disorders. However, the precise underlying mechanism of knock-down of IL-1β in repairing behavioral changes by LPS remains unclear.MethodsThe mice were treated with either IL-1β shRNA lentivirus or non-silencing shRNA control (NS shRNA) lentivirus by microinjection into the dentate gyrus (DG) regions of the hippocampus. After 7 days of recovery, LPS (1 mg/kg, i.p.) or saline was administered. The behavioral task for memory deficits was conducted in mice by the novel object recognition test (NORT), the anxiety-like behaviors were evaluated by the elevated zero maze (EZM), and the depression-like behaviors were examined by the sucrose preference test (SPT) and the forced swimming test (FST). Furthermore, the levels of malondialdehyde (MDA), superoxide dismutase (SOD), nuclear factor erythroid-derived 2-like 2 (Nrf2), heme oxygenase 1 (HO1), IL-1β, tumor necrosis factor (TNF-α), neuropeptide VGF (non-acronymic), and brain-derived neurotrophic factor (BDNF) were assayed.ResultsOur results demonstrated that IL-1β knock-down in the hippocampus significantly attenuated the memory deficits and anxiety- and depression-like behaviors induced by LPS in mice. In addition, IL-1β knock-down ameliorated the oxidative and neuroinflammatory responses and abolished the downregulation of VGF and BDNF induced by LPS.ConclusionsCollectively, our findings suggest that IL-1β is necessary for the oxidative and neuroinflammatory responses produced by LPS and offers a novel drug target in the IL-1β/oxidative/neuroinflammatory/neurotrophic pathway for treating neuropsychiatric disorders that are closely associated with neuroinflammation, oxidative stress, and the downregulation of VGF and BDNF.

Genetic deletion of xCT attenuates peripheral and central inflammation and mitigates LPS‐induced sickness and depressive‐like behavior in mice

“…In line with this idea, the attenuated activation of microglial cells induced by absence of xCT reduced the hippocampal content of IL-1b after LPS-injection. Worth of note, a recent study from Li et al (2017) demonstrates that IL-1b knock-down in the hippocampus significantly attenuates LPS-induced depressive-like behaviors in mice (Li et al, 2017). As previously discussed, our results strongly point to the involvement of IL-1b in transducing both the acute and chronic effects of LPS.…”

Adeno‐associated virus‐mediated over‐expression of CREB‐regulated transcription coactivator 1 in the hippocampal dentate gyrus ameliorates lipopolysaccharide‐induced depression‐like behaviour in mice

“…However, research has also shown that LPS‐induced depression‐like behaviour, neuroinflammation and down‐regulation of BDNF and VGF are significantly improved by IL‐1β knockdown in the hippocampus of mice (Li et al . ). Thus, CRTC1 might interact with inflammatory factors, and CRTC1 over‐expression might suppress the level of pro‐inflammatory cytokines in a BDNF/VGF‐dependent manner; in turn, the decrease in pro‐inflammatory cytokines may also improve the expression of the CRTC1/BDNF/VGF signalling pathway.…”

“…) and VGF functions in the LPS‐induced depression model (Li et al . ,b). However, whether CRTC1 signalling is involved in LPS‐induced depression‐like behaviour remains unclear.…”

Myalgic encephalomyelitis or chronic fatigue syndrome: how could the illness develop?

“…The resulting neurocognitive dysfunction has much the same origins as microglial activation induced by PICs but there is some evidence to suggest that the adverse effects on adult neurogenesis, memory deposition and recall, synaptic plasticity and long-term potentiation following elevated systemic LPS is primarily mediated by elevated IL-1β in the hippocampus (Abareshi et al 2016; Li et al 2017; Nolan et al 2005). …”