Post-inflammatory behavioural despair in male mice is associated with reduced cortical glutamate-glutamine ratios, and circulating lipid and energy metabolites

Abstract

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.

Probiotics Bacillus licheniformis Improves Intestinal Health of Subclinical Necrotic Enteritis-Challenged Broilers

“…Membrane transport, a vital pathway for the survival of bacteria in the gut ecosystem ( Lyons et al, 2017 ), was increased in group PA, which may point out an attempt to compensate for the antibiotic effect of enramycin. Regarding energy metabolism pathway, it was enriched in group PC comparing with group PG and PA, showing an energy metabolites disorder in SNE infection broilers ( Chan et al, 2020 ). Cell motility is the determinant step of pathogen bacteria in early local invasion ( Lin et al, 2017 ).…”

Immunomodulatory effects of new phytotherapy on human macrophages and TLR4- and TLR7/8-mediated viral-like inflammation in mice

“…For both cytokines, their release was suppressed by the IP, though the effect of prednisolone was much greater. IL-1β and TNF are inflammatory mediators that have long been associated with the “cytokine storm” caused by SARS-CoV-2 ( 7 , 39 , 40 ). TLRs are strongly expressed in macrophages ( 41 ), and it is seems probable that the IP counteracts their activation caused by LPS ( 42 ).…”

Effects of Remote Immune Activation on Performance in the 5-Choice Serial Reaction Time Task Following Mild Traumatic Brain Injury in Adolescence

“…The microglial phenotype may also change in response to alteration in neurotransmission, with glutamatergic neurotransmission shown to induce hyper-ramification (Fontainhas et al, 2011 ), with increased process number and process extension (Eyo et al, 2014 ). This is in part driven by the expression of glutamatergic receptors on microglia, with inflammation known to increase glutamatergic receptors, like mGlu-5 on microglia (Drouin-Ouellet et al, 2011 ) and LPS to increase glutamatergic signaling (Chan et al, 2020 ). Exposure to a prior inflammatory stimulus, in mTBI (Donat et al, 2017 ), could alter the microglial expression of these receptors and hence increase the response of microglia to later LPS.…”