Post-inflammatory behavioural despair in male mice is associated with reduced cortical glutamate-glutamine ratios, and circulating lipid and energy metabolites
Post-inflammatory behaviours in rodents are widely used to model human depression and to test the efficacy of novel anti-depressants. Mice injected with lipopolysaccharide (LPS) display a depressive-like phenotype twenty-four hours after endotoxin administration. Despite the widespread use of this m...
| Main Authors: | , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Springer Nature
2020
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| _version_ | 1797102680026382336 |
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| author | Chan, SY Probert, F Radford-Smith, D Hebert, J Claridge, T Anthony, D Burnet, P |
| author_facet | Chan, SY Probert, F Radford-Smith, D Hebert, J Claridge, T Anthony, D Burnet, P |
| author_sort | Chan, SY |
| collection | OXFORD |
| description | Post-inflammatory behaviours in rodents are widely used to model human depression and to test the efficacy of novel anti-depressants. Mice injected with lipopolysaccharide (LPS) display a depressive-like phenotype twenty-four hours after endotoxin administration. Despite the widespread use of this model, the mechanisms that underlie the persistent behavioural changes after the transient peripheral inflammatory response remain elusive. The study of the metabolome, the collection of all the small molecule metabolites in a sample, combined with multivariate statistical techniques provides a way of studying biochemical pathways influenced by an LPS challenge. Adult male CD-1 mice received an intraperitoneal injection of either LPS (0.83 mg/kg) or saline, and were assessed for depressive-like behaviour 24 h later. In a separate mouse cohort, pro-inflammatory cytokine gene expression and 1H nuclear magnetic resonance (NMR) metabolomics measurements were made in brain tissue and blood. Statistical analyses included Independent Sample t-tests for gene expression data, and supervised multi-variate analysis using orthogonal partial least squares discriminant analysis for metabolomics. Both plasma and brain metabolites in male mice were altered following a single peripheral LPS challenge that led to depressive-like behaviour in the forced swim test. The plasma metabolites altered by LPS are involved in energy metabolism, including lipoproteins, glucose, creatine, and isoleucine. In the brain, glutamate, serine, and N-acetylaspartate (NAA) were reduced after LPS, whereas glutamine was increased. Serine-modulated glutamatergic signalling and changes in bioenergetics may mediate the behavioural phenotype induced by LPS. In light of other data supporting a central imbalance of glutamate-glutamine cycling in depression, our results suggest that aberrant central glutaminergic signalling may underpin the depressive-like behaviours that result from both inflammation and non-immune pathophysiology. Normalising glutaminergic signalling, rather than seeking to increase serotonergic signalling, might prove to be a more coherent approach to the development of new treatments for mood disorder. |
| first_indexed | 2024-03-07T06:09:25Z |
| format | Journal article |
| id | oxford-uuid:eef4fc43-cd3b-4fd7-8f4b-fe3e208913ef |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:09:25Z |
| publishDate | 2020 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:eef4fc43-cd3b-4fd7-8f4b-fe3e208913ef2022-03-27T11:36:50ZPost-inflammatory behavioural despair in male mice is associated with reduced cortical glutamate-glutamine ratios, and circulating lipid and energy metabolitesJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:eef4fc43-cd3b-4fd7-8f4b-fe3e208913efEnglishSymplectic ElementsSpringer Nature2020Chan, SYProbert, FRadford-Smith, DHebert, JClaridge, TAnthony, DBurnet, PPost-inflammatory behaviours in rodents are widely used to model human depression and to test the efficacy of novel anti-depressants. Mice injected with lipopolysaccharide (LPS) display a depressive-like phenotype twenty-four hours after endotoxin administration. Despite the widespread use of this model, the mechanisms that underlie the persistent behavioural changes after the transient peripheral inflammatory response remain elusive. The study of the metabolome, the collection of all the small molecule metabolites in a sample, combined with multivariate statistical techniques provides a way of studying biochemical pathways influenced by an LPS challenge. Adult male CD-1 mice received an intraperitoneal injection of either LPS (0.83 mg/kg) or saline, and were assessed for depressive-like behaviour 24 h later. In a separate mouse cohort, pro-inflammatory cytokine gene expression and 1H nuclear magnetic resonance (NMR) metabolomics measurements were made in brain tissue and blood. Statistical analyses included Independent Sample t-tests for gene expression data, and supervised multi-variate analysis using orthogonal partial least squares discriminant analysis for metabolomics. Both plasma and brain metabolites in male mice were altered following a single peripheral LPS challenge that led to depressive-like behaviour in the forced swim test. The plasma metabolites altered by LPS are involved in energy metabolism, including lipoproteins, glucose, creatine, and isoleucine. In the brain, glutamate, serine, and N-acetylaspartate (NAA) were reduced after LPS, whereas glutamine was increased. Serine-modulated glutamatergic signalling and changes in bioenergetics may mediate the behavioural phenotype induced by LPS. In light of other data supporting a central imbalance of glutamate-glutamine cycling in depression, our results suggest that aberrant central glutaminergic signalling may underpin the depressive-like behaviours that result from both inflammation and non-immune pathophysiology. Normalising glutaminergic signalling, rather than seeking to increase serotonergic signalling, might prove to be a more coherent approach to the development of new treatments for mood disorder. |
| spellingShingle | Chan, SY Probert, F Radford-Smith, D Hebert, J Claridge, T Anthony, D Burnet, P Post-inflammatory behavioural despair in male mice is associated with reduced cortical glutamate-glutamine ratios, and circulating lipid and energy metabolites |
| title | Post-inflammatory behavioural despair in male mice is associated with reduced cortical glutamate-glutamine ratios, and circulating lipid and energy metabolites |
| title_full | Post-inflammatory behavioural despair in male mice is associated with reduced cortical glutamate-glutamine ratios, and circulating lipid and energy metabolites |
| title_fullStr | Post-inflammatory behavioural despair in male mice is associated with reduced cortical glutamate-glutamine ratios, and circulating lipid and energy metabolites |
| title_full_unstemmed | Post-inflammatory behavioural despair in male mice is associated with reduced cortical glutamate-glutamine ratios, and circulating lipid and energy metabolites |
| title_short | Post-inflammatory behavioural despair in male mice is associated with reduced cortical glutamate-glutamine ratios, and circulating lipid and energy metabolites |
| title_sort | post inflammatory behavioural despair in male mice is associated with reduced cortical glutamate glutamine ratios and circulating lipid and energy metabolites |
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