Repeated daily administration of increasing doses of lipopolysaccharide provides a model of sustained inflammation-induced depressive-like behaviour in mice that is independent of the NLRP3 inflammasome

Abstract

Mounting preclinical evidence has implicated the NLRP3 inflammasome in depression-related behaviours elicited by chronic stress or acute lipopolysaccharide (LPS) challenge. However, the relevance of acute LPS as a model of depression has been questioned and behavioural time-courses of its effects can be inconsistent. The aims of this study were (1) to develop a novel protocol for repeated daily LPS administration and (2) to use this model to assess the involvement of NLRP3 inflammasome signalling in sustained inflammation-induced depressive-like behaviour in adult C57BL/6J mice deficient in NLRP3. Acute LPS (0.83mg/kg; i.p.) induced sickness behaviour evident as hypolocomotor activity. However, there was no significant increase in depressive-like behaviour in the forced swim test 24h post-administration. Interestingly, depressive-like behaviours were observed in the female urine sniffing test and in the sucrose preference test at 24h, but not 48h, post-administration of acute LPS. To mimic a period of sustained inflammation, 3-day repeated increasing LPS doses (0.1, 0.42 and 0.83mg/kg; i.p.) was compared to constant LPS doses (0.83mg/kg; i.p.). Sickness behaviour was seen in response to increasing doses, but tolerance developed to repeated constant doses of LPS. Furthermore, 3-day increasing doses of LPS resulted in a significant increase in immobility time in the forced swim test, consistent with depressive-like behaviour. When NLRP3^-/- mice received this 3-day increasing dose regimen of LPS, sickness behaviours were attenuated compared to wild-type mice. The behaviour in the forced swim test was not significantly altered in NLRP3^-/- mice. We propose that this increasing repeated dosing LPS model of inflammation-induced depressive-like behaviour may better model the sustained inflammation observed in depression and may provide a more translationally relevant paradigm to study the inflammatory mechanisms that contribute to depression.

Keywords: C57BL/6J; Depression; Female urine sniffing test; Forced swim test; Neuroinflammation; Sickness.