Chronic stress-induced aberrant gene expression in the brain and subsequent dysfunctional neuronal plasticity have been implicated in the etiology and pathophysiology of mood disorders. In this ...study, we examined whether altered expression of small, regulatory, noncoding microRNAs (miRNAs) contributes to the depression-like behaviors and aberrant neuronal plasticity associated with chronic stress. Mice exposed to chronic ultra-mild stress (CUMS) exhibited increased depression-like behaviors and reduced hippocampal expression of the brain-enriched miRNA-124 (miR-124). Aberrant behaviors and dysregulated miR-124 expression were blocked by chronic treatment with an antidepressant drug. The depression-like behaviors are likely not conferred directly by miR-124 downregulation because neither viral-mediated hippocampal overexpression nor intrahippocampal infusion of an miR-124 inhibitor affected depression-like behaviors in nonstressed mice. However, viral-mediated miR-124 overexpression in hippocampal neurons conferred behavioral resilience to CUMS, whereas inhibition of miR-124 led to greater behavioral susceptibility to a milder stress paradigm. Moreover, we identified histone deacetylase 4 (HDAC4), HDAC5, and glycogen synthase kinase 3β (GSK3β) as targets for miR-124 and found that intrahippocampal infusion of a selective HDAC4/5 inhibitor or GSK3 inhibitor had antidepressant-like actions on behavior. We propose that miR-124-mediated posttranscriptional controls of HDAC4/5 and GSK3β expressions in the hippocampus have pivotal roles in susceptibility/resilience to chronic stress.
Depressive disorders are a major public health concern worldwide. Although a clear understanding of the etiology of depression is still lacking, chronic stress-elicited aberrant neuronal plasticity has been implicated in the pathophysiology of depression. We show that the hippocampal expression of microRNA-124 (miR-124), an endogenous small, noncoding RNA that represses gene expression posttranscriptionally, controls resilience/susceptibility to chronic stress-induced depression-like behaviors. These effects on depression-like behaviors may be mediated through regulation of the mRNA or protein expression levels of histone deacetylases HDAC4/5 and glycogen synthase kinase 3β, all highly conserved miR-124 targets. Moreover, miR-124 contributes to stress-induced dendritic hypotrophy and reduced spine density of dentate gyrus granule neurons. Modulation of hippocampal miR-124 pathways may have potential antidepressant effects.
Abstract Sirtuins are a family of NAD+-dependent enzymes that regulate cellular functions through deacetylation of various proteins. Although recent reports have suggested an important role of ...deacetylases (i.e., histone deacetylases) in mood disorders and antidepressant action, the involvement of sirtuins in the pathophysiology of mood disorders is largely unknown. In this study, we aimed to determine whether there are alterations in sirtuin mRNA expression in peripheral white blood cells of patients with a mood disorder. Also, to examine whether the altered sirtuin mRNA expression is state- or trait-dependent, mood disorder patients who were in a remissive state were assessed. We used quantitative real-time polymerase chain reaction to measure the mRNA levels of seven sirtuin isoforms (SIRT1–7) in peripheral white blood cells of patients with major depressive disorder (MDD) or bipolar disorder (BPD) during depressive and remissive states and in normal healthy subjects. The SIRT1, 2 and 6 mRNA levels in MDD and BPD patients decreased significantly in those who were in a depressive state compared to healthy controls, whereas the expression of those mRNAs in both MDD and BPD of patients in a remissive state were comparable to those in healthy controls. Thus, our data suggest that altered SIRT1, 2 and 6 expression is state-dependent and might be associated with the pathogenesis and/or pathophysiology of mood disorders.
Nature therapies are gaining attention as non-pharmacological treatments for depressive and anxiety disorders, but research on their effectiveness in patients is limited. This study investigates the ...mood-improving effects of visual stimulation with natural environmental images in patients with depressive and anxiety disorders.
We conducted a randomized crossover comparison trial involving 60 right-handed adult participants with depressive or anxiety disorders and receiving outpatient treatment. Visual stimuli of natural environments consisted of green-themed nature images, while the control stimuli featured urban scenes dominated by buildings. The stimulation lasted for 3 min, during which orbital prefrontal brain activity was measured using a 2-channel Near-infrared Spectroscopy (NIRS) system, and heart rate variability was assessed using fingertip accelerated plethysmography.
Mood enhancement effects were observed in both the depressive and anxiety disorder groups following visual stimulation with nature images. In the depression group, orbital prefrontal oxygenated hemoglobin concentration significantly increased after visual stimulation with nature images, while there were no significant changes in the anxiety group. However, in the anxiety group, a correlation was found between reduced orbital prefrontal oxygenated hemoglobin in response to nature images and increased mood-enhancement. Furthermore, the severity of depressive symptoms did not significantly affect the intervention effects, whereas heightened anxiety symptoms was associated with a smaller mood enhancement effect.
Our study demonstrates the benefits of nature image stimulation for patients with depressive and anxiety disorders. Differential orbital prefrontal brain activity impacts notwithstanding, both conditions exhibited mood enhancement, affirming the value of nature image stimulation.
•We explore visual stimulation by natural images in depression and anxiety patients.•We utilize randomized crossover trials and advanced measurement techniques.•Findings reveal mood improvement and unique brain responses to natural images.•This highlights the therapeutic potential of natural image stimulation for mental health.
Glycosylation is a common posttranslational modification in protein biosynthesis that is implicated in several disease states. It has been reported that specific protein glycan structures are useful ...as biomarkers for cancer and some neuropsychiatric diseases; however, the relationship between plasma protein glycosylation and major depressive disorder (MDD) has not been investigated to date. The aim of this study was to determine whether plasma protein glycan structures are altered in depression using a stress-based mouse model and samples from patients with MDD.
We used chronic ultra-mildly stressed mice that were untreated or treated with imipramine as mouse models of depression and remission, respectively. We also made comparisons between samples from depressed and remitted patients with MDD. Protein glycosylation was analyzed using a lectin microarray that included 45 lectins with binding affinities for various glycan structures.
Sia-alpha2-6Gal/GalNAc was a commonly altered glycan structure in both depression model mice and patients with MDD. Moreover, the expression of ST6GALNAC2 was decreased in leukocytes from patients with MDD.
Our study samples were small and we did not identify specific alpha2-6Gal/GalNAc-sialylated proteins.
The glycan structure Sia-alpha2-6GalNAc in plasma protein and ST6GALNAC2 expression in peripheral leukocytes may have utility as candidate biomarkers for the clinical diagnosis and monitoring of MDD.
•We investigated plasma protein glycosylation in murine and human depression.•Sia-alpha2-6Gal/GalNAc was decreased in the mouse model and in patients.•ST6GALNAC2 expression in leukocytes may be a biological marker of depression.
Abstract Aberrant transcriptional regulation may be one of the key components of the pathophysiology of mood disorders. DNA methylation generally acts as an epigenetic gene silencing mechanism and is ...catalyzed by a group of enzymes known as DNA methyltransferases (DNMTs). Several lines of evidence have suggested aberrant DNA methylation in patients with neuropsychiatric disorders and in animal models for psychiatric disorders. However, the involvement of DNMTs in the pathophysiology of mood disorders is not completely understood. In this study, we aimed to determine whether there are alterations in the expression of DNMTs mRNA in mood disorder patients. We used quantitative real-time PCR to measure the mRNA expression of four DNMT isoforms in the peripheral white blood cells of major depressive disorder (MDD) and bipolar disorder (BPD) patients during a depressive and a remissive episode. We found that the levels of DNMT1 mRNA were significantly decreased in a depressive but not in a remissive state of MDD and BPD. In addition, the levels of DNMT3B mRNA in MDD were significantly increased in a depressive but not in a remissive state. Thus, our data suggest that the altered expression of DNMTs is state dependent and that the aberrant epigenetic gene regulations caused by the altered expression of DNMT1 and DNMT3B may be associated with the pathophysiology of mood disorders.
Abstract Background Depression in old age is an increasing contributor to poor health and accompanying health care costs. Although there is an abundance of literature on later-life depression (LLD), ...the neural correlates have not been clarified. The aim of this study was to determine whether patients with LLD show abnormal gray matter volume (GMV) and white matter integrity by using multiple image analysis methods. Methods The study included 45 patients with LLD and 61 healthy participants who were matched for age, sex, years of education, and vascular risk factors. GMV was examined using voxel-based morphometry, while the white matter integrity was determined by tract-based spatial statistics and tract-specific analysis, which were obtained from high-resolution magnetic resonance images. Results Patients with LLD showed significantly less GMV in the orbitofrontal cortex, anterior cingulate, insula, amygdala, and temporal regions, as well as higher fractional anisotropy in the uncinate fasciculus, compared with healthy participants. Patients with LLD who had reduced orbitofrontal and insular GMV had more severe clinical variables. The reduced orbitofrontal GMV was associated with higher fractional anisotropy in the uncinate fasciculus. Limitation The effects of medication should also be considered when interpreting the results of this study. Conclusion Our results suggest that regional GMV is linked to white matter integrity of the uncinate fasciculus in the orbitomedial prefrontal limbic network, and the disruption of this network may be involved in the pathophysiology of LLD.
Abstract Background Although depression is the leading cause of disability worldwide, its pathophysiology is poorly understood. Recent evidence has suggested that sirtuins (SIRTs) play a key role in ...cognition and synaptic plasticity, yet their role in mood regulation remains controversial. Here, we aimed to investigate whether SIRT function is associated with chronic stress-elicited depression-like behaviors and neuronal atrophy. Methods We measured SIRTs expression and activity in a mouse model of depression. We injected mice with a SIRT1 activator or inhibitor and measured their depression-like behaviors and dendritic spine morphology. To assess the role of SIRT1 directly, we used a viral-mediated gene transfer to overexpress the wild-type SIRT1 or dominant negative SIRT1 and evaluated their depression-like behaviors. Finally, we examined the role of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), a potential downstream target of SIRT1, in depression-like behavior. Results We found that chronic stress reduced SIRT1 activity in the dentate gyrus of the hippocampus. Pharmacological and genetic inhibition of hippocampal SIRT1 function led to an increase in depression-like behaviors. Conversely, SIRT1 activation blocked both the development of depression-related phenotypes and aberrant dendritic structures elicited by chronic stress exposure. Furthermore, hippocampal SIRT1 activation increased the phosphorylation level of ERK1/2 in stressed condition, and viral-mediated activation and inhibition of hippocampal ERK2 led to anti- and pro-depressive behaviors, respectively. Conclusion Our results suggest that the hippocampal SIRT1 pathway contributes to the chronic stress-elicited depression-related phenotype and aberrant dendritic atrophy.
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