scholarly journals Single-cell mass cytometry of microglia in major depressive disorder reveals a non-inflammatory phenotype with increased homeostatic marker expression

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Chotima Böttcher ◽  
Camila Fernández-Zapata ◽  
Gijsje J. L. Snijders ◽  
Stephan Schlickeiser ◽  
Marjolein A. M. Sneeboer ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Single Cell ◽  
Single Cell Analysis ◽  
Cell Mass ◽  
Brain Regions ◽  
Major Depressive ◽  
Immune Effector ◽  
Cytokines And Chemokines ◽  
The Brain

Abstract Stress-induced disturbances of brain homeostasis and neuroinflammation have been implicated in the pathophysiology of mood disorders. In major depressive disorder (MDD), elevated levels of proinflammatory cytokines and chemokines can be found in peripheral blood, but very little is known about the changes that occur directly in the brain. Microglia are the primary immune effector cells of the central nervous system and exquisitely sensitive to changes in the brain microenvironment. Here, we performed the first single-cell analysis of microglia from four different post-mortem brain regions (frontal lobe, temporal lobe, thalamus, and subventricular zone) of medicated individuals with MDD compared to controls. We found no evidence for the induction of inflammation-associated molecules, such as CD11b, CD45, CCL2, IL-1β, IL-6, TNF, MIP-1β (CCL4), IL-10, and even decreased expression of HLA-DR and CD68 in microglia from MDD cases. In contrast, we detected increased levels of the homeostatic proteins P2Y12 receptor, TMEM119 and CCR5 (CD195) in microglia from all brain regions of individuals with MDD. We also identified enrichment of non-inflammatory CD206hi macrophages in the brains of MDD cases. In sum, our results suggest enhanced homeostatic functions of microglia in MDD.

scholarly journals Correlations Among mRNA Expression Levels of ATP7A, Serum Ceruloplasmin Levels, and Neuronal Metabolism in Unmedicated Major Depressive Disorder

2020 ◽  
Vol 23 (10) ◽  
pp. 642-652 ◽  
Author(s):  
Xuanjun Liu ◽  
Shuming Zhong ◽  
Lan Yan ◽  
Hui Zhao ◽  
Ying Wang ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Mrna Expression ◽  
Brain Regions ◽  
Regions Of Interest ◽  
Major Depressive ◽  
Expression Levels ◽  
Neuronal Metabolism ◽  
The Brain ◽  
Mrna Expression Levels

Abstract Background Previous studies have found that elevated copper levels induce oxidation, which correlates with the occurrence of major depressive disorder (MDD). However, the mechanism of abnormal cerebral metabolism of MDD patients remains ambiguous. The main function of the enzyme ATPase copper-transporting alpha (ATP7A) is to transport copper across the membrane to retain copper homeostasis, which is closely associated with the onset of mental disorders and cognitive impairment. However, less is known regarding the association of ATP7A expression in MDD patients. Methods A total of 31 MDD patients and 21 healthy controls were recruited in the present study. Proton magnetic resonance spectroscopy was used to assess the concentration levels of N-acetylaspartate, choline (Cho), and creatine (Cr) in brain regions of interest, including prefrontal white matter (PWM), anterior cingulate cortex (ACC), thalamus, lentiform nucleus, and cerebellum. The mRNA expression levels of ATP7A were measured using polymerase chain reaction (SYBR Green method). The correlations between mRNA expression levels of ATP7A and/or ceruloplasmin levels and neuronal biochemical metabolite ratio in the brain regions of interest were evaluated. Results The decline in the mRNA expression levels of ATP7A and the increase in ceruloplasmin levels exhibited a significant correlation in MDD patients. In addition, negative correlations were noted between the decline in mRNA expression levels of ATP7A and the increased Cho/Cr ratios of the left PWM, right PWM, and right ACC in MDD patients. A positive correlation between elevated ceruloplasmin levels and increased Cho/Cr ratio of the left PWM was noted in MDD patients. Conclusions The findings suggested that the decline in the mRNA expression levels of ATP7A and the elevated ceruloplasmin levels induced oxidation that led to the disturbance of neuronal metabolism in the brain, which played important roles in the pathophysiology of MDD. The decline in the mRNA expression levels of ATP7A and the elevated ceruloplasmin levels affected neuronal membrane metabolic impairment in the left PWM, right PWM, and right ACC of MDD patients.

scholarly journals Mendelian randomization integrating GWAS and eQTL data revealed genes pleiotropically associated with major depressive disorder

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Huarong Yang ◽  
Di Liu ◽  
Chuntao Zhao ◽  
Bowen Feng ◽  
Wenjin Lu ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Mendelian Randomization ◽  
Brain Regions ◽  
Specific Gene ◽  
Genome Wide Association Studies ◽  
Major Depressive ◽  
Eqtl Data ◽  
The Brain ◽  
Summary Data

AbstractPrevious genome-wide association studies (GWAS) have identified potential genetic variants associated with the risk of major depressive disorder (MDD), but the underlying biological interpretation remains largely unknown. We aimed to prioritize genes that were pleiotropically or potentially causally associated with MDD. We applied the summary data-based Mendelian randomization (SMR) method integrating GWAS and gene expression quantitative trait loci (eQTL) data in 13 brain regions to identify genes that were pleiotropically associated with MDD. In addition, we repeated the analysis by using the meta-analyzed version of the eQTL summary data in the brain (brain-eMeta). We identified multiple significant genes across different brain regions that may be involved in the pathogenesis of MDD. The prime-specific gene BTN3A2 (corresponding probe: ENSG00000186470.9) was the top hit showing pleiotropic association with MDD in 9 of the 13 brain regions and in brain-eMeta, after correction for multiple testing. Many of the identified genes are located in the human major histocompatibility complex (MHC) region on chromosome 6 and are mainly involved in the immune response. Our SMR analysis indicated that multiple genes showed pleiotropic association with MDD across the brain regions. These findings provided important leads to a better understanding of the mechanism of MDD and revealed potential therapeutic targets for the prevention and effective treatment of MDD.

scholarly journals Cortical structural differences in major depressive disorder correlate with cell type-specific transcriptional signatures

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jiao Li ◽  
Jakob Seidlitz ◽  
John Suckling ◽  
Feiyang Fan ◽  
Gong-Jun Ji ◽  
...  
Keyword(s):  
Gene Expression ◽  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Structural Changes ◽  
Brain Regions ◽  
Cell Type ◽  
Major Depressive ◽  
Structural Differences ◽  
Neuroimaging Data ◽  
Cell Type Specific

AbstractMajor depressive disorder (MDD) has been shown to be associated with structural abnormalities in a variety of spatially diverse brain regions. However, the correlation between brain structural changes in MDD and gene expression is unclear. Here, we examine the link between brain-wide gene expression and morphometric changes in individuals with MDD, using neuroimaging data from two independent cohorts and a publicly available transcriptomic dataset. Morphometric similarity network (MSN) analysis shows replicable cortical structural differences in individuals with MDD compared to control subjects. Using human brain gene expression data, we observe that the expression of MDD-associated genes spatially correlates with MSN differences. Analysis of cell type-specific signature genes suggests that microglia and neuronal specific transcriptional changes account for most of the observed correlation with MDD-specific MSN differences. Collectively, our findings link molecular and structural changes relevant for MDD.

scholarly journals Phosphodiesterase 8A to discriminate in blood samples depressed patients and suicide attempters from healthy controls based on A-to-I RNA editing modifications

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nicolas Salvetat ◽  
Fabrice Chimienti ◽  
Christopher Cayzac ◽  
Benjamin Dubuc ◽  
Francisco Checa-Robles ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Rna Editing ◽  
Whole Blood ◽  
Healthy Controls ◽  
Major Depressive ◽  
Suicide Attempters ◽  
Blood Samples ◽  
Depressed Patients ◽  
The Brain

AbstractMental health issues, including major depressive disorder, which can lead to suicidal behavior, are considered by the World Health Organization as a major threat to global health. Alterations in neurotransmitter signaling, e.g., serotonin and glutamate, or inflammatory response have been linked to both MDD and suicide. Phosphodiesterase 8A (PDE8A) gene expression is significantly decreased in the temporal cortex of major depressive disorder (MDD) patients. PDE8A specifically hydrolyzes adenosine 3′,5′-cyclic monophosphate (cAMP), which is a key second messenger involved in inflammation, cognition, and chronic antidepressant treatment. Moreover, alterations of RNA editing in PDE8A mRNA has been described in the brain of depressed suicide decedents. Here, we investigated PDE8A A-to-I RNA editing-related modifications in whole blood of depressed patients and suicide attempters compared to age-matched and sex-matched healthy controls. We report significant alterations of RNA editing of PDE8A in the blood of depressed patients and suicide attempters with major depression, for which the suicide attempt took place during the last month before sample collection. The reported RNA editing modifications in whole blood were similar to the changes observed in the brain of suicide decedents. Furthermore, analysis and combinations of different edited isoforms allowed us to discriminate between suicide attempters and control groups. Altogether, our results identify PDE8A as an immune response-related marker whose RNA editing modifications translate from brain to blood, suggesting that monitoring RNA editing in PDE8A in blood samples could help to evaluate depressive state and suicide risk.

Intrinsic gray-matter connectivity of the brain in major depressive disorder

2019 ◽  
Vol 251 ◽  
pp. 78-85 ◽  
Author(s):  
Huifeng Zhang ◽  
Meihui Qiu ◽  
Lei Ding ◽  
David Mellor ◽  
Gang Li ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Gray Matter ◽  
Major Depressive ◽  
The Brain

Altered Brain Network Degree Centrality in Major Depressive Disorder via Electro-Acupuncture Stimulation at Baihui(gv20)

2021 ◽  
Author(s):  
Shasha Li ◽  
Ya Chen ◽  
Gaoxiong Duan ◽  
Yong Pang ◽  
Huimei Liu ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Brain Function ◽  
Brain Regions ◽  
Brain Network ◽  
Degree Centrality ◽  
Major Depressive ◽  
Acupuncture Stimulation ◽  
Therapeutic Mechanisms ◽  
Abnormal Brain

Abstract Background: Although the acupuncture treatment of major depressive disorder(MDD) has been recognized by the latest clinical practice guidelines of the American Academy of Internal Medicine, complex therapeutic mechanisms need further to clarify. The aim of the study is investigate whether the aberrant resting state brain network in MDD patients could be regulated by acupuncture at GV20 using functional magnetic resonance imaging(fMRI) combined with degree centrality(DC) method. Results: Compared to healthy subjects, MDD patients exhibited significantly aberrant DC in widely brain regions, including cortical(PFC, precuneus, temporal, insula) and sub-cortical (thalamus, putamen and caudate) structures. Furthermore, results showed that acupuncture at GV20 induced down-regulation the DC of abnormal brain regions in MDD patients. Conclusions: Our findings provide imaging evidence to support that GV20-related acupuncture stimulation may modulate the abnormal brain function state in MDD patients by using fMRI technique combined with DC analysis. This study may partly interpret the neural mechanisms of acupuncture at GV20 which is used to treat patients with MDD in clinical. Trial registration: ChiCTR, ChiCTR-IOR-15006357. Registered 05 May 2015, http://www.chictr.org.cn/showproj.aspx?proj=10922.

scholarly journals Investigating the convergent mechanisms between Major Depressive Disorder and Parkinson’s disease

2020 ◽  
Author(s):  
Angela A Tran ◽  
Myra De Smet ◽  
Gary D. Grant ◽  
Tien K. Khoo ◽  
Dean L Pountney
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Cell Activation ◽  
Glutamate Excitotoxicity ◽  
Major Depressive ◽  
Glial Cell Activation ◽  
Underlying Mechanisms ◽  
The Brain

Major depressive disorder (MDD) affects more than cognition, having a temporal relationship with neuroinflammatory pathways of Parkinson’s disease (PD). Although this association is supported by epidemiological and clinical studies, the underlying mechanisms are unclear. Microglia and astrocytes play crucial roles in the pathophysiology of both MDD and PD. In PD, these cells can be activated by misfolded forms of the protein α-synuclein to release cytokines that can interact with multiple different physiological processes to produce depressive symptoms, including monoamine transport and availability, the hypothalamus-pituitary axis, and neurogenesis. In MDD, glial cell activation can be induced by peripheral inflammatory agents that cross the blood brain barrier and/or c-Fos signaling from neurons. The resulting neuroinflammation can cause neurodegeneration due to oxidative stress and glutamate excitotoxicity, contributing to PD pathology. Astrocytes are another major link due to their recognised role in the glymphatic clearance mechanism. Research suggesting that MDD causes astrocytic destruction or structural atrophy highlight the possibility that accumulation of α-synuclein in the brain is facilitated as the brain cannot adequately clear the protein aggregates. This review examines research into the overlapping pathophysiology of MDD and PD with particular focus on the roles of glial cells and neuroinflammation.

scholarly journals Blues in the Brain and Beyond: Molecular Bases of Major Depressive Disorder and Relative Pharmacological and Non-Pharmacological Treatments

Genes ◽  
2020 ◽  
Vol 11 (9) ◽  
pp. 1089 ◽  
Author(s):  
Elisabetta Maffioletti ◽  
Alessandra Minelli ◽  
Daniela Tardito ◽  
Massimo Gennarelli
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Molecular Mechanisms ◽  
Pharmacological Treatments ◽  
Major Depressive ◽  
Reciprocal Interactions ◽  
Evidence Based Treatments ◽  
Molecular Effects ◽  
Molecular Bases ◽  
The Brain

Despite the extensive research conducted in recent decades, the molecular mechanisms underlying major depressive disorder (MDD) and relative evidence-based treatments remain unclear. Various hypotheses have been successively proposed, involving different biological systems. This narrative review aims to critically illustrate the main pathogenic hypotheses of MDD, ranging from the historical ones based on the monoaminergic and neurotrophic theories, through the subsequent neurodevelopmental, glutamatergic, GABAergic, inflammatory/immune and endocrine explanations, until the most recent evidence postulating a role for fatty acids and the gut microbiota. Moreover, the molecular effects of established both pharmacological and non-pharmacological approaches for MDD are also reviewed. Overall, the existing literature indicates that the molecular mechanisms described in the context of these different hypotheses, rather than representing alternative ones to each other, are likely to contribute together, often with reciprocal interactions, to the development of MDD and to the effectiveness of treatments, and points at the need for further research efforts in this field.

scholarly journals Initial Evidence for Brain Plasticity Following a Digital Therapeutic Intervention for Depression

2019 ◽  
Vol 3 ◽  
pp. 247054701987788
Author(s):  
Megan M. Hoch ◽  
Gaelle E. Doucet ◽  
Dominik A. Moser ◽  
Won Hee Lee ◽  
Katherine A. Collins ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Resting State ◽  
Brain Plasticity ◽  
Memory Task ◽  
Brain Regions ◽  
Resting State Functional Connectivity ◽  
Major Depressive ◽  
Emotional Faces ◽  
Task Training

Background Digital therapeutics such as cognitive–emotional training have begun to show promise for the treatment of major depressive disorder. Available clinical trial data suggest that monotherapy with cognitive–emotional training using the Emotional Faces Memory Task is beneficial in reducing depressive symptoms in patients with major depressive disorder. The aim of this study was to investigate whether Emotional Faces Memory Task training for major depressive disorder is associated with changes in brain connectivity and whether changes in connectivity parameters are related to symptomatic improvement. Methods Fourteen major depressive disorder patients received Emotional Faces Memory Task training as monotherapy over a six-week period. Patients were scanned at baseline and posttreatment to identify changes in resting-state functional connectivity and effective connectivity during emotional working memory processing. Results Compared to baseline, patients showed posttreatment reduced connectivity within resting-state networks involved in self-referential and salience processing and greater integration across the functional connectome at rest. Moreover, we observed a posttreatment increase in the Emotional Faces Memory Task-induced modulation of connectivity between cortical control and limbic brain regions, which was associated with clinical improvement. Discussion These findings provide initial evidence that cognitive–emotional training may be associated with changes in short-term plasticity of brain networks implicated in major depressive disorder. Conclusion Our findings pave the way for the principled design of large clinical and neuroimaging studies.

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