Molecular mechanism for stress-induced depression assessed by sequencing miRNA and mRNA in medial prefrontal cortex (miRNA)
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ABSTRACT: Major depressive disorder is a common mood disorder. Chronic stressful life is presumably main etiology that leads to the neuron and synapse atrophies in the limbic system. However, the intermediate molecules from stress to neural atrophy remain elusive. Mice were treated by chronic unpredictable mild stress (CUMS) until demonstrating depression-like behaviors confirmed by the tests of sucrose preference, forced swimming and Y-maze. The sequencings of microRNA and mRNA from the medial prefrontal cortices were performed in CUMS-induced depression mice versus control mice to assess the molecular profiles of major depressive disorder. In the medial prefrontal cortices of depression-like mice, the levels of mRNAs that translated the proteins for the GABAergic synapses, dopaminergic synapses, myelination, synaptic vesicle cycle and neuronal growth were downregulated. miRNAs of regulating these mRNAs are upregulated. The deterioration of GABAergic and dopaminergic synapses as well as axonal growth is associated to CUMS-induced depression.
Project description:Major depressive disorder is a common mood disorder. Chronic stressful life is presumably main etiology that leads to the neuron and synapse atrophies in the limbic system. However, the intermediate molecules from stress to neural atrophy remain elusive. Mice were treated by chronic unpredictable mild stress (CUMS) until demonstrating depression-like behaviors confirmed by the tests of sucrose preference, forced swimming and Y-maze. The sequencings of microRNA and mRNA from the medial prefrontal cortices were performed in CUMS-induced depression mice versus control mice to assess the molecular profiles of major depressive disorder. In the medial prefrontal cortices of depression-like mice, the levels of mRNAs that translated the proteins for the GABAergic synapses, dopaminergic synapses, myelination, synaptic vesicle cycle and neuronal growth were downregulated. miRNAs of regulating these mRNAs are upregulated. The deterioration of GABAergic and dopaminergic synapses as well as axonal growth is associated to CUMS-induced depression.
Project description:Major depressive disorder (MDD) is considered as a neural circuit-based polygene syndrome that is mainly triggered by genetic susceptibility and stress factors. The present study employed the Wistar Kyoto (WKY) rat as an animal model with endogenous depression to further investigate the molecular basis of its genetic susceptibility to depression by performing quantitative protemoics analyses of the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and hippocampus (Hip), respectively.
Project description:Gene expression profiling of blood cells in patients with major depressive disorder (MDD) has been used to identify potential biomarkers and to address the pathophysiology of MDD. However, whether alteration in gene expression in blood cells are reflected in the brain of the same individual is unclear. Here, we used an animal model of depression to investigate intra-subject correlation of gene expression patterns between the whole blood (WB) and the medial prefrontal cortex (mPFC). Ovariectomized mice exposed to the chronic mild stress were used as an animal model of depression.
Project description:In this study, we used chronic restraint stress to establish a mouse model of depression, and differentially expressed proteins in the medial prefrontal cortex of depressive model mice were detected by TMT proteomics. By functional enrichment analysis of the differentially expressed proteins, we found that CRS-induced mice have altered synaptic function and excessive autophagy. In addition, we also demonstrated that CRS may disrupt synaptic plasticity by affecting activation of the Wnt2b/尾-catenin pathway which may help explain the pathogenesis of depression and identify new antidepressant drug targets.
Project description:Major depressive disorder is one of the most common mental health conditions. Meningeal lymphatics are essential for drainage of molecules in the cerebrospinal fluid to the peripheral immune system. Their potential role in depression-like behaviour has not been investigated. Here, we show in mice, sub-chronic variable stress as a model of depression-like behaviour impairs meningeal lymphatics in females but not in males. Manipulations of meningeal lymphatics regulate the sex difference in the susceptibility to stress-induced depression- and anxiety-like behaviors in mice, as well as alterations of the medial prefrontal cortex and the ventral tegmental area, brain regions critical for emotional regulation. Together, our findings suggest meningeal lymphatic impairment contributes to susceptibility to stress in mice, and that restoration of the meningeal lymphatics might have potential for modulation of depression-like behaviour.
Project description:Gene expression profiling of blood cells in patients with major depressive disorder (MDD) has been used to identify potential biomarkers and to address the pathophysiology of MDD. However, whether alteration in gene expression in blood cells are reflected in the brain of the same individual is unclear. Here, we used an animal model of depression to investigate intra-subject correlation of gene expression patterns between the whole blood (WB) and the medial prefrontal cortex (mPFC). Ovariectomized mice exposed to the chronic ultra-mild stress were used as an animal model of depression. The major findings of the current genome-wide microarray analysis are that 1) the expression levels of 467 genes that were expressed in both tissues correlated positively between the two tissues, 2) alterations in the expression of 4,215 genes in the WB of OVX-operated mice compared to the sham-operated mice were concordant with alterations in the corresponding mPFC, 3) the biological terms over-represented in the 4,215 OVX-affected genes were associated with ribosomal function, and 4) the 6 genes that are potentially relevant to depression-like behavior were observed to be differentially expressed in the WB of the model mice. The current findings suggest that alterations in the expression of a subset of genes are significantly correlated between the WB and the mPFC with in the same individual in an experimental model of depression. Female mice were subjected to chronic ultra-mild stress, a bilateral ovariectomy, or both. Sham-operated mice without stress were used as the control. Medial prefrontal cortex and whole blood were obtained from the same individual (n = 6 in each group), and analyzed using an Agilent SurePrint G3 Mouse GE 8×60K Microarray (Design ID: 028005)
Project description:Major depressive disorder (MDD) is a common disorder and is responsible for considerable disability in global functioning, anorexia, and severer medical comorbidity. Recently, some reports showed the relationship between MDD and the metabolic disorders such as diabetes. We examined gene expression profiles in the mice prefrontal cortex using genome-wide microarray technology, and determined gene expression profiles with and without chronic mild stress(CMS) for 4 weeks which was often used to make models of depression. To analyze the candidate genes involved in not only depression but dysfunction of physiological homeostasis like diabetes, we campared the gene expression levels between with and without CMS, then we isolated 494 genes showing a more than 2-fold increase or a less than 1/2-fold decrease, in addition, we chose the isolated genes transcriptional products of both samples were confirmed clearly. The prefrontal cortex of C57Bl/6 N sea mice with and without CMS. We mixed tatal RNA from 7 mice prefrontal cortex per each.
Project description:Chronic stress increases the risk of emotional disorders by altering brain structure and function. Patients with post-traumatic stress disorder (PTSD) or depressions show activity difference between the two hemispheres in the prefrontal cortex (PFC) but molecular targets associated with this laterality remains unclear. Here, we reveal that chronic social defeats later gene-expression profile differentially between the left and right medial prefrontal cortices (mPFC) in mice.
Project description:The serotonergic system and in particular serotonin 1A receptor (5-HT1AR) are critically implicated in major depressive disorder (MDD), although underlying mechanisms remain enigmatic. Here we demonstrated that 5-HT1AR is palmitoylated in human and rodent brains and identified ZDHHC21 as a major palmitoyl-transferase, whose depletion reduced palmitoylation and consequently signaling functions of 5-HT1AR. Two rodent models for depression show reduced brain ZDHHC21 expression in conjunction with attenuated 5-HT1AR palmitoylation. Moreover, selective knock-down of ZDHHC21 in murine forebrain by itself sufficed to provoke depressive symptoms, demonstrating a causal relationship between 5-HT1AR palmitoylation and depression. Regarding the underlying mechanism, we identified the microRNA miR-30e as a negative regulator of Zdhhc21 expression. By analysis of the post-mortem samples from suicide MDD victims we also found ZDHHC21 expression as well as palmitoylation of 5-HT1AR to be specifically reduced within the prefrontal cortex (PFC), a brain area critically involved in the pathogenesis of depressive symptoms. Our study provides evidence for transcriptional downregulation of 5-HT1AR palmitoylation as a central mechanism in the etiology of depression and even suicide, in effect making the restoration of 5-HT1AR palmitoylation a promising clinical strategy for the treatment of major depressive disorder.
Project description:In this study, depressive-like mice induced by chronic unpredictable mild stimulation (CUMS) were used to investigate the impact of psychological stress on reproduction and alterations in sperm sncRNAs. The results showed that CUMS treatments for 4 weeks induced depressive behavior in male mice and significantly affected sperm quality. The results obtained from small RNA sequencing indicated that alterations occurred in the distribution and composition of small non-coding RNAs (sncRNAs), encompassing PIWI-interacting RNAs (piRNAs), rRNA-derived small RNAs (rsRNA), and tRNA-derived small RNAs (tsRNA). Furthermore, the offspring of male mice with depressive-like behavior have a significant reduction in survival rate at 21 days after birth, and those that did survive displayed an increased susceptibility to depression.