Stress causes changes in neurotransmission in the brain, thereby influencing stress-induced behaviors. However, it is unclear how neurotransmission systems orchestrate stress responses at the molecular and cellular levels. Transient receptor potential vanilloid 1 (TRPV1), a non-selective cation channel involved mainly in pain sensation, affects mood and neuroplasticity in the brain, where its role is poorly understood. Here, we show that Trpv1-deficient (Trpv1) mice are more stress resilient than control mice after chronic unpredictable stress. We also found that glucocorticoid receptor (GR)-mediated histone deacetylase 2 (HDAC) 2 expression and activity are reduced in the Trpv1 mice and that HDAC2-regulated, cell-cycle- and neuroplasticity-related molecules are altered. Hippocampal knockdown of TRPV1 had similar effects, and its behavioral effects were blocked by HDAC2 overexpression. Collectively, our findings indicate that HDAC2 is a molecular link between TRPV1 activity and stress responses.

Ketamine produces rapid antidepressant-like effects in animal assays for depression, although the molecular mechanisms underlying these behavioral actions remain incomplete. Here, we demonstrate that ketamine rapidly stimulates histone deacetylase 5 (HDAC5) phosphorylation and nuclear export in rat hippocampal neurons through calcium/calmodulin kinase II-and protein kinase D-dependent pathways. Consequently, ketamine enhanced the transcriptional activity of myocyte enhancer factor 2 (MEF2), which leads to regulation of MEF2 target genes. Transfection of a HDAC5 phosphorylation-defective mutant (Ser259/Ser498 replaced by Ala259/Ala498, HDAC5-S/A), resulted in resistance to ketamineinduced nuclear export, suppression of ketamine-mediated MEF2 transcriptional activity, and decreased expression of MEF2 target genes. Behaviorally, viral-mediated hippocampal knockdown of HDAC5 blocked or occluded the antidepressant effects of ketamine both in unstressed and stressed animals. Taken together, our results reveal a novel role of HDAC5 in the actions of ketamine and suggest that HDAC5 could be a potential mechanism contributing to the therapeutic actions of ketamine.ketamine | HDAC | depression | hippocampus D epression is a multifaceted illness, characterized by somatic, cognitive, and behavioral changes. All currently available antidepressants primarily act via monoaminergic neurotransmitters, such as serotonin and/or noradrenaline (1). Currently available pharmacotherapies for depression provide some relief for patients, but these agents have significant limitations (1). In this context, new antidepressants with faster onset of action and greater efficacy are needed (2).The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has shown remarkable consistency in rapidly ameliorating depressive symptoms in major depressive disorder (MDD) (3). Preclinical studies have demonstrated that ketamine produces rapid antidepressant responses (within hours) (4, 5). Ketamine's antidepressant effects in rodents are associated with activation of several signaling systems including the mammalian target of rapamycin complex 1 (mTORC1) (4), brain derived neurotrophic factor (BDNF) and elongation factor 2 (EF2) kinase (5). Despite these remarkable effects, the widespread use of ketamine is limited by potential side effects and abuse. Thus, studies are necessary to further elucidate mechanistic actions of ketamine at cellular and network levels.Recent studies have generated evidence that epigenetic regulation is closely involved in the pathophysiology of depression and in the therapeutic mechanisms of typical antidepressants (6, 7). In addition, reports that sodium butyrate, a histone deacetylase (HDAC) inhibitor, has antidepressant effects indicate that HDAC inhibition is sufficient to produce an antidepressant response (8). HDACs are a family of enzymes capable of repressing gene expression by removing acetyl groups from histones to produce a less accessible chromatin structure (9).Previous studies demonstrate that the...

Astrocytes and microglia are brain‐resident glia that can establish harmful inflammatory environments in disease contexts and thereby contribute to the progression of neuronal loss in neurodegenerative disorders. Correcting the diseased properties of glia is therefore an appealing strategy for treating brain diseases. Previous studies have shown that serum/ glucocorticoid related kinase 1 (SGK1) is upregulated in the brains of patients with various neurodegenerative disorders, suggesting its involvement in the pathogenesis of those diseases. In this study, we show that inhibiting glial SGK1 corrects the pro‐inflammatory properties of glia by suppressing the intracellular NFκB‐, NLRP3‐inflammasome‐, and CGAS‐STING‐mediated inflammatory pathways. Furthermore, SGK1 inhibition potentiated glial activity to scavenge glutamate toxicity and prevented glial cell senescence and mitochondrial damage, which have recently been reported as critical pathologic features of and therapeutic targets in Parkinson disease (PD) and Alzheimer disease (AD). Along with those anti‐inflammatory/neurotrophic functions, silencing and pharmacological inhibition of SGK1 protected midbrain dopamine neurons from degeneration and cured pathologic synuclein alpha (SNCA) aggregation and PD‐associated behavioral deficits in multiple in vitro and in vivo PD models. Collectively, these findings suggest that SGK1 inhibition could be a useful strategy for treating PD and other neurodegenerative disorders that share the common pathology of glia‐mediated neuroinflammation.

Sleep is integral to life and sleep duration is important in sleep quality, physical, and psychological health. Disturbances in sleep duration have been associated with increased risk of metabolic disorders, hypertension, and overall mortality. Sleep disturbance has also been linked with various gastrointestinal disorders. However, the association between sleep and peptic ulcer disease (PUD) has not been evaluated. We investigated the association between sleep duration and PUD. Subjects were included from the fifth Korean National Health and Nutrition Examination Survey conducted from 2008–2009. Individuals with PUD were defined as those with a physician diagnosis of PUD. Daily sleep duration was established by asking participants the amount of time that they slept per day. Multiple logistic regression models were used to evaluate the association of PUD and sleep duration. This study included 14,290 participants (8,209 women). The prevalence of PUD was 5.7% and was higher in men (6.8%) than in women (4.9%). Women who slept ≥9 hours were significantly less likely to have PUD compared to women who slept 7 hours. In men, longer sleep duration (≥9 hours) had a tendency toward PUD prevention. Our results suggest that longer sleep duration may play a protective role for PUD development.