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The induction of indoleamine 2,3-dioxygenase (IDO) by pro-inflammatory cytokines interferon gamma and tumour necrosis factor α (TNFα) increases kynurenine levels and its downstream metabolites 11, 17. Several mechanisms may underlie how locally expressed cytokines in the central nervous system (CNS) alter neuronal function. While it is clear from previous investigations and our current work that the peripheral administration of LPS results in depressive-like behavioural changes, the underlying mechanisms remain poorly understood. However, brain concentrations of pro-inflammatory cytokines remained elevated 24 h after the LPS administration 16. Inflammation-related behavioural deficits are paralleled by increases in plasma pro-inflammatory cytokines, which peak 2 to 4 h after LPS administration and normalize to control levels 24 h post-LPS. These behavioural deficits are reversed with antidepressants 15. In rodents, intraperitoneal administration of LPS also results in anxiety- and depressive-like behaviour 11, 12, 13, 14. In humans, inducing inflammation with LPS resulted in increased anxiety and depressed mood, and deficits in memory tasks 10.
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In humans, inflammatory biomarkers are associated with depression and depressive symptomology 7, 8, and attenuating this immune activation may be a prerequisite for antidepressant treatment efficacy 9.Ī systemic injection of lipopolysaccharide (LPS) generates a peripheral and central pro-inflammatory response, mimicking the outcomes of stress-induced neuroinflammation. Psychological stress, a key contributor to depression and other psychiatric conditions 2, alters the neuroimmune system, particularly through the induction of a pro-inflammatory state with cytokine signalling initiated by activated microglia 3, 4, 5, 6. Despite a surge in the availability and prescription of antidepressants over the last three decades, the prevalence of the disorder continues to increase, and the global health burden remains substantial 1. 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.ĭepression is a common illness affecting those of all ages and disposition. 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. Serine-modulated glutamatergic signalling and changes in bioenergetics may mediate the behavioural phenotype induced by LPS. In the brain, glutamate, serine, and N-acetylaspartate (NAA) were reduced after LPS, whereas glutamine was increased. The plasma metabolites altered by LPS are involved in energy metabolism, including lipoproteins, glucose, creatine, and isoleucine. 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. 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. 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. 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. 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. Despite the widespread use of this model, the mechanisms that underlie the persistent behavioural changes after the transient peripheral inflammatory response remain elusive. Mice injected with lipopolysaccharide (LPS) display a depressive-like phenotype twenty-four hours after endotoxin administration. Post-inflammatory behaviours in rodents are widely used to model human depression and to test the efficacy of novel anti-depressants.