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 (0.83 mg/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 24 h post-administration. Interestingly, depressive-like behaviours were observed in the female urine sniffing test and in the sucrose preference test at 24 h, but not 48 h, post-administration of acute LPS. To mimic a period of sustained inflammation, 3-day repeated increasing LPS doses (0.1, 0.42 and 0.83 mg/kg; i.p.) was compared to constant LPS doses (0.83 mg/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.
Acute LPS (0.83 mg/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 24 h post-administration. Interestingly, depressive-like behaviours were observed in the female urine sniffing test and in the sucrose preference test at 24 h, but not 48 h, post-administration of acute LPS. To mimic a period of sustained inflammation, 3-day repeated increasing LPS doses (0.1, 0.42 and 0.83 mg/kg; i.p.) was compared to constant LPS doses (0.83 mg/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.
Original language | English |
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Pages (from-to) | 99-108 |
Number of pages | 10 |
Journal | Behavioural Brain Research |
Volume | 352 |
Early online date | 29 Jul 2017 |
DOIs | |
Publication status | Published - 15 Oct 2018 |
Keywords
- Depression
- Inflammation
- Inflammasome
- Forced swim test
- Sickness
- Neuroinflammation
- C57BL/6J
- Female urine sniffing test
ASJC Scopus subject areas
- Behavioral Neuroscience
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Sarah Bailey
- Department of Life Sciences - Senior Lecturer
- Addiction and Mental Health Group (AIM)
Person: Research & Teaching
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Amanda Mackenzie
- Department of Life Sciences - Deputy Head of Department
- Centre for Bioengineering & Biomedical Technologies (CBio)
Person: Research & Teaching, Affiliate staff