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

Robin A. Wickens, Luc Ver Donck, Amanda B. Mackenzie, Sarah J. Bailey

Research output: Contribution to journalArticle

1 Citation (Scopus)
147 Downloads (Pure)

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.
Original languageEnglish
Pages (from-to)99-108
Number of pages10
JournalBehavioural Brain Research
Volume352
Early online date29 Jul 2017
DOIs
Publication statusPublished - 15 Oct 2018

Fingerprint

Inflammasomes
Lipopolysaccharides
Inflammation
Illness Behavior
Depression
Inbred C57BL Mouse
Sucrose

Keywords

  • Depression
  • Inflammation
  • Inflammasome
  • Forced swim test
  • Sickness
  • Neuroinflammation
  • C57BL/6J
  • Female urine sniffing test

ASJC Scopus subject areas

  • Behavioral Neuroscience

Cite this

@article{eb32e47a257f425eb91b6f17d29d429d,
title = "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 (0.83 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.",
keywords = "Depression, Inflammation, Inflammasome, Forced swim test, Sickness, Neuroinflammation, C57BL/6J, Female urine sniffing test",
author = "Wickens, {Robin A.} and {Ver Donck}, Luc and Mackenzie, {Amanda B.} and Bailey, {Sarah J.}",
year = "2018",
month = "10",
day = "15",
doi = "10.1016/j.bbr.2017.07.041",
language = "English",
volume = "352",
pages = "99--108",
journal = "Behavioural Brain Research",
issn = "0166-4328",
publisher = "Elsevier",

}

TY - JOUR

T1 - 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

AU - Wickens, Robin A.

AU - Ver Donck, Luc

AU - Mackenzie, Amanda B.

AU - Bailey, Sarah J.

PY - 2018/10/15

Y1 - 2018/10/15

N2 - 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.

AB - 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.

KW - Depression

KW - Inflammation

KW - Inflammasome

KW - Forced swim test

KW - Sickness

KW - Neuroinflammation

KW - C57BL/6J

KW - Female urine sniffing test

UR - https://doi.org/10.1016/j.bbr.2017.07.041

UR - http://www.scopus.com/inward/record.url?scp=85027235327&partnerID=8YFLogxK

U2 - 10.1016/j.bbr.2017.07.041

DO - 10.1016/j.bbr.2017.07.041

M3 - Article

VL - 352

SP - 99

EP - 108

JO - Behavioural Brain Research

JF - Behavioural Brain Research

SN - 0166-4328

ER -