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Papers of the Week

Papers: 10 Feb 2024 - 16 Feb 2024


Gut Microbes




Repeated (s)-ketamine administration ameliorates the spatial working memory impairment in mice with chronic pain: role of the gut microbiota-brain axis.


Jiang Y, Wang X, Chen J, Zhang Y, Hashimoto K, Yang JJ, Zhou Z


Chronic pain is commonly linked with diminished working memory. This study explores the impact of the anesthetic (s)-ketamine on spatial working memory in a chronic constriction injury (CCI) mouse model, focusing on gut microbiome. We found that multiple doses of (s)-ketamine, unlike a single dose, counteracted the reduced spontaneous alteration percentage (%SA) in the Y-maze spatial working memory test, without affecting mechanical or thermal pain sensitivity. Additionally, repeated (s)-ketamine treatments improved the abnormal composition of the gut microbiome (β-diversity), as indicated by fecal 16S rRNA analysis, and increased levels of butyrate, a key gut – brain axis mediator. Protein analysis showed that these treatments also corrected the upregulated histone deacetylase 2 (HDAC2) and downregulated brain-derived neurotrophic factor (BDNF) in the hippocampi of CCI mice. Remarkably, fecal microbiota transplantation from mice treated repeatedly with (s)-ketamine to CCI mice restored %SA and hippocampal BDNF levels in CCI mice. Butyrate supplementation alone also improved %SA, BDNF, and HDAC2 levels in CCI mice. Furthermore, the TrkB receptor antagonist ANA-12 negated the beneficial effects of repeated ()-ketamine on spatial working memory impairment in CCI mice. These results indicate that repeated (s)-ketamine administration ameliorates spatial working memory impairment in CCI mice, mediated by a gut microbiota – brain axis, primarily through the enhancement of hippocampal BDNF – TrkB signaling by butyrate.