Journal of neuroinflammation
December 18, 2025
Mengqi Han, Bing Xie, Yuan Yu et al.
Chronic stress triggers depression by activating a gut-immune-brain pathway. In mice exposed to chronic restraint stress, gut microbiota changes caused small intestinal γδ T cells to migrate to the brain, where they released interleukin-17A (IL-17A). This IL-17A impaired a mitochondrial cleanup process called mitophagy in the hippocampus, leading to reduced energy production, damaged synapses, and depression-like behavior. Blocking γδ T cell migration, removing a key receptor on these cells, or giving the antidepressant arketamine all restored mitophagy and improved behavior. The findings identify a specific chain from gut microbes to immune cells to brain mitochondria that drives stress-induced depression, and point to arketamine as a potential treatment targeting this pathway.
Neuroscience and biobehavioral reviews
July 1, 2025
Rumi Murayama, Yi Cai, Hiroyuki Nakamura et al.
Loss of myelin sheaths around neuronal axons is increasingly recognized as a key factor in a broad range of psychiatric and neurological disorders, including schizophrenia, major depressive disorder, bipolar disorder, post-traumatic stress disorder, autism spectrum disorder, substance use disorders, Alzheimer's disease, Parkinson's disease, and multiple sclerosis. This review examines core mechanisms driving demyelination, its clinical impact, and emerging therapeutic strategies. Key contributors include genetic predisposition, environmental triggers, immune dysregulation, neuroinflammation, and alterations in the gut-brain axis mediated by the vagus nerve.
Neurobiology of disease
March 1, 2024
Yong Yang, Akifumi Eguchi, Chisato Mori et al.
Depression often accompanies liver cirrhosis, but the underlying reasons are unclear. In mice with cirrhosis induced by common bile duct ligation (CBDL), depression-like behaviors, inflammation, reduced synaptic proteins in the prefrontal cortex, gut microbiota imbalance, and altered blood metabolites were observed. These changes were reversed by severing the subdiaphragmatic vagus nerve, and a single injection of arketamine improved the depression-like behaviors. The findings suggest that the gut-liver-brain axis, via the vagus nerve, mediates depression in cirrhosis, and arketamine may offer a new treatment.
Brain, behavior, and immunity
October 1, 2023
Xinying Zhang, Teng He, Zifeng Wu et al.
In a mouse model of depression induced by lipopolysaccharide, CD38 expression increased in the hippocampus and cortex. Pharmacological inhibition or genetic knockout of CD38 reduced neuroinflammation, microglia activation, synaptic defects, and Sirt1/STAT3 signaling, and improved depression-like behaviors. Optogenetic activation of glutamatergic neurons in the hippocampal CA3 region reduced depression susceptibility and lowered CD38 expression. The antidepressant (R)-ketamine suppressed CD38 expression and reversed synaptic defects. Hippocampal CD38 is closely linked to depressive behaviors in this inflammation model, suggesting it as a potential therapeutic target.
Translational psychiatry
July 25, 2023
Li Ma, Long Wang, Youge Qu et al.
Relapse is common in remitted major depressive disorder. Arketamine, an (R)-enantiomer of ketamine, has prophylactic actions in an inflammatory model of depression, but the mechanisms are unclear. In mice, a single injection of arketamine (10 mg/kg) blocked lipopolysaccharide-induced increases in spleen genes of the heme biosynthesis II pathway (Alas2, Fech, Hmbs). Expression of these genes correlated with spleen weight and pro-inflammatory cytokines. Spleens from depressed patients showed higher ALAS2 and FECH expression. Pretreatment with a heme precursor (5-aminolaevulinic acid) worsened inflammation and depression-like behavior, while a heme inhibitor (succinyl acetone) had prophylactic effects. The heme biosynthesis pathway may be a target for preventing relapse.
Neuropharmacology
May 1, 2023
Xiayun Wan, Akifumi Eguchi, Lijia Chang et al.
A single injection of arketamine (10 mg/kg) reduced anhedonia-like behavior and reversed the loss of femoral neck cortical and total bone mineral density in mice susceptible to chronic social defeat stress. The abundance of certain gut microbiota and plasma metabolites differed between arketamine-treated and saline-treated susceptible mice, and these microbial and metabolite abundances correlated with bone mineral density. The findings suggest arketamine may improve both depressive symptoms and bone density through a gut-microbiota-bone-brain axis, indicating potential as a therapy for depressed patients with low bone mineral density.
Progress in brain research
January 1, 2023
Kenji Hashimoto
Neuroinflammation is central to major depressive disorder (MDD) and treatment-resistant depression (TRD), with patients showing higher inflammatory biomarkers. The gut-microbiota-brain axis, mediated by the vagus nerve, contributes to neuroinflammation. Fecal microbiota transplantation (FMT) from depressed humans or rodents induces depression-like behaviors and systemic inflammation in rodents, effects blocked by subdiaphragmatic vagotomy. Vagotomy also blocks antidepressant effects of serotonergic drugs. The antidepressant arketamine may restore altered gut microbiota in depressed rodents. This chapter reviews the vagus nerve-dependent gut-microbiota-brain axis in depression and discusses FMT, vagus nerve stimulation, and arketamine as potential TRD treatments.