@article{pmid33046833,

title = {Cocaine-related DNA methylation in caudate neurons alters 3D chromatin structure of the IRXA gene cluster},

author = {Kathryn Vaillancourt and Jennie Yang and Gary G Chen and Volodymyr Yerko and Jean-François Théroux and Zahia Aouabed and Alberto Lopez and Kimberly C Thibeault and Erin S Calipari and Benoit Labonté and Naguib Mechawar and Carl Ernst and Corina Nagy and Thierry Forné and Eric J Nestler and Deborah C Mash and Gustavo Turecki},

doi = {10.1038/s41380-020-00909-x},

issn = {1476-5578},

year  = {2021},

date = {2021-07-01},

journal = {Mol Psychiatry},

volume = {26},

number = {7},

pages = {3134--3151},

abstract = {Epigenetic mechanisms, like those involving DNA methylation, are thought to mediate the relationship between chronic cocaine dependence and molecular changes in addiction-related neurocircuitry, but have been understudied in human brain. We initially used reduced representation bisulfite sequencing (RRBS) to generate a methylome-wide profile of cocaine dependence in human post-mortem caudate tissue. We focused on the Iroquois Homeobox A (IRXA) gene cluster, where hypomethylation in exon 3 of IRX2 in neuronal nuclei was associated with cocaine dependence. We replicated this finding in an independent cohort and found similar results in the dorsal striatum from cocaine self-administering mice. Using epigenome editing and 3C assays, we demonstrated a causal relationship between methylation within the IRX2 gene body, CTCF protein binding, three-dimensional (3D) chromatin interaction, and gene expression. Together, these findings suggest that cocaine-related hypomethylation of IRX2 contributes to the development and maintenance of cocaine dependence through alterations in 3D chromatin structure in the caudate nucleus.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33972803,

title = {Extraction of nuclei from archived postmortem tissues for single-nucleus sequencing applications},

author = {Malosree Maitra and Corina Nagy and Anjali Chawla and Yu Chang Wang and Camila Nascimento and Matthew Suderman and Jean-François Théroux and Naguib Mechawar and Jiannis Ragoussis and Gustavo Turecki},

doi = {10.1038/s41596-021-00514-4},

issn = {1750-2799},

year  = {2021},

date = {2021-06-01},

journal = {Nat Protoc},

volume = {16},

number = {6},

pages = {2788--2801},

abstract = {Single-cell and single-nucleus sequencing techniques are a burgeoning field with various biological, biomedical and clinical applications. Numerous high- and low-throughput methods have been developed for sequencing the RNA and DNA content of single cells. However, for all these methods, the key requirement is high-quality input of a single-cell or single-nucleus suspension. Preparing such a suspension is the limiting step when working with fragile, archived tissues of variable quality. This hurdle can prevent such tissues from being extensively investigated with single-cell technologies. We describe a protocol for preparing single-nucleus suspensions within the span of a few hours that reliably works for multiple postmortem and archived tissue types using standard laboratory equipment. The stages of the protocol include tissue preparation and dissociation, nuclei extraction, and nuclei concentration assessment and capture. The protocol is comparable to other published protocols but does not require fluorescence-assisted nuclei sorting (FANS) or ultracentrifugation. The protocol can be carried out by a competent graduate student familiar with basic laboratory techniques and equipment. Moreover, these preparations are compatible with single-nucleus (sn)RNA-seq and assay for transposase-accessible chromatin (ATAC)-seq using the 10X Genomics Chromium system. The protocol reliably results in efficient capture of single nuclei for high-quality snRNA-seq libraries.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33556389,

title = {How stress physically re-shapes the brain: Impact on brain cell shapes, numbers and connections in psychiatric disorders},

author = {Dominic Kaul and Sibylle G Schwab and Naguib Mechawar and Natalie Matosin},

doi = {10.1016/j.neubiorev.2021.01.025},

issn = {1873-7528},

year  = {2021},

date = {2021-05-01},

journal = {Neurosci Biobehav Rev},

volume = {124},

pages = {193--215},

abstract = {Severe stress is among the most robust risk factors for the development of psychiatric disorders. Imaging studies indicate that life stress is integral to shaping the human brain, especially regions involved in processing the stress response. Although this is likely underpinned by changes to the cytoarchitecture of cellular networks in the brain, we are yet to clearly understand how these define a role for stress in human psychopathology. In this review, we consolidate evidence of macro-structural morphometric changes and the cellular mechanisms that likely underlie them. Focusing on stress-sensitive regions of the brain, we illustrate how stress throughout life may lead to persistent remodelling of the both neurons and glia in cellular networks and how these may lead to psychopathology. We support that greater translation of cellular alterations to human cohorts will support parsing the psychological sequalae of severe stress and improve our understanding of how stress shapes the human brain. This will remain a critical step for improving treatment interventions and prevention outcomes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33602921,

title = {Non-CG methylation and multiple histone profiles associate child abuse with immune and small GTPase dysregulation},

author = {Pierre-Eric Lutz and Marc-Aurèle Chay and Alain Pacis and Gary G Chen and Zahia Aouabed and Elisabetta Maffioletti and Jean-François Théroux and Jean-Christophe Grenier and Jennie Yang and Maria Aguirre and Carl Ernst and Adriana Redensek and Léon C van Kempen and Ipek Yalcin and Tony Kwan and Naguib Mechawar and Tomi Pastinen and Gustavo Turecki},

doi = {10.1038/s41467-021-21365-3},

issn = {2041-1723},

year  = {2021},

date = {2021-02-01},

journal = {Nat Commun},

volume = {12},

number = {1},

pages = {1132},

abstract = {Early-life adversity (ELA) is a major predictor of psychopathology, and is thought to increase lifetime risk by epigenetically regulating the genome. Here, focusing on the lateral amygdala, a major brain site for emotional homeostasis, we describe molecular cross-talk among multiple mechanisms of genomic regulation, including 6 histone marks and DNA methylation, and the transcriptome, in subjects with a history of ELA and controls. In the healthy brain tissue, we first uncover interactions between different histone marks and non-CG methylation in the CAC context. Additionally, we find that ELA associates with methylomic changes that are as frequent in the CAC as in the canonical CG context, while these two forms of plasticity occur in sharply distinct genomic regions, features, and chromatin states. Combining these multiple data indicates that immune-related and small GTPase signaling pathways are most consistently impaired in the amygdala of ELA individuals. Overall, this work provides insights into genomic brain regulation as a function of early-life experience.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33613346,

title = {Widespread Decrease of Cerebral Vimentin-Immunoreactive Astrocytes in Depressed Suicides},

author = {Liam Anuj O'Leary and Claudia Belliveau and Maria Antonietta Davoli and Jie Christopher Ma and Arnaud Tanti and Gustavo Turecki and Naguib Mechawar},

doi = {10.3389/fpsyt.2021.640963},

issn = {1664-0640},

year  = {2021},

date = {2021-01-01},

journal = {Front Psychiatry},

volume = {12},

pages = {640963},

abstract = {Post-mortem investigations have implicated cerebral astrocytes immunoreactive (-IR) for glial fibrillary acidic protein (GFAP) in the etiopathology of depression and suicide. However, it remains unclear whether astrocytic subpopulations IR for other astrocytic markers are similarly affected. Astrocytes IR to vimentin (VIM) display different regional densities than GFAP-IR astrocytes in the healthy brain, and so may be differently altered in depression and suicide. To investigate this, we compared the densities of GFAP-IR astrocytes and VIM-IR astrocytes in post-mortem brain samples from depressed suicides and matched non-psychiatric controls in three brain regions (dorsomedial prefrontal cortex, dorsal caudate nucleus and mediodorsal thalamus). A quantitative comparison of the fine morphology of VIM-IR astrocytes was also performed in the same regions and subjects. Finally, given the close association between astrocytes and blood vessels, we also assessed densities of CD31-IR blood vessels. Like for GFAP-IR astrocytes, VIM-IR astrocyte densities were found to be globally reduced in depressed suicides relative to controls. By contrast, CD31-IR blood vessel density and VIM-IR astrocyte morphometric features in these regions were similar between groups, except in prefrontal white matter, in which vascularization was increased and astrocytes displayed fewer primary processes. By revealing a widespread reduction of cerebral VIM-IR astrocytes in cases vs. controls, these findings further implicate astrocytic dysfunctions in depression and suicide.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35002817,

title = {Effects of Mindfulness-Based Cognitive Therapy on Peripheral Markers of Stress and Inflammation in Older-Adults With Depression and Anxiety: A Parallel Analysis of a Randomized Controlled Trial},

author = {Claudia Belliveau and Corina Nagy and Sophia Escobar and Naguib Mechawar and Gustavo Turecki and Soham Rej and Susana G Torres-Platas},

doi = {10.3389/fpsyt.2021.804269},

issn = {1664-0640},

year  = {2021},

date = {2021-01-01},

journal = {Front Psychiatry},

volume = {12},

pages = {804269},

abstract = { Depression and anxiety are prevalent in older-adults and often difficult to treat: up to 55% of patients are unresponsive to pharmacotherapy. Mindfulness-Based Cognitive Therapy (MBCT) is a promising treatment, however, its biological mechanisms remain unknown in older-adults.  We examined if, in older-adults, decreased depression and anxiety symptoms after MBCT are associated with changes in the expression levels of C-reactive protein, Interleukin-1β, Monocyte chemoattractant protein-1 and mineralocorticoid receptor compared to treatment as usual (TAU). Older-adults (age ≥60) with depression and anxiety were randomized to MBCT or treatment as usual. Gene expression levels from blood samples were measured using quantitative polymerase chain reaction ( = 37) at baseline and after 8-weeks of MBCT or TAU.  As previously published, we found a significant reduction in symptoms of depression F (1, 35) = 10.68,  = 0.002, partial η = 0.23 and anxiety F (1, 35) = 9.36,  = 0.004, partial η = 0.21 in geriatric participants following MBCT compared to TAU. However, the expression levels of measured genes were not significantly different between groups and were not associated with changes in depression and anxiety symptoms.  Our results suggest that the symptom reduction following MBCT in older-adults may not be accompanied by changes in the stress-response and inflammatory pathways. Future research should address other potential biological alterations associated to MBCT that may be responsible for the reduction of symptoms.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34512291,

title = {Effects of Early Life Stress on the Developing Basolateral Amygdala-Prefrontal Cortex Circuit: The Emerging Role of Local Inhibition and Perineuronal Nets},

author = {Angela Guadagno and Claudia Belliveau and Naguib Mechawar and Claire-Dominique Walker},

doi = {10.3389/fnhum.2021.669120},

issn = {1662-5161},

year  = {2021},

date = {2021-01-01},

journal = {Front Hum Neurosci},

volume = {15},

pages = {669120},

abstract = {The links between early life stress (ELS) and the emergence of psychopathology such as increased anxiety and depression are now well established, although the specific neurobiological and developmental mechanisms that translate ELS into poor health outcomes are still unclear. The consequences of ELS are complex because they depend on the form and severity of early stress, duration, and age of exposure as well as co-occurrence with other forms of physical or psychological trauma. The long term effects of ELS on the corticolimbic circuit underlying emotional and social behavior are particularly salient because ELS occurs during critical developmental periods in the establishment of this circuit, its local balance of inhibition:excitation and its connections with other neuronal pathways. Using examples drawn from the human and rodent literature, we review some of the consequences of ELS on the development of the corticolimbic circuit and how it might impact fear regulation in a sex- and hemispheric-dependent manner in both humans and rodents. We explore the effects of ELS on local inhibitory neurons and the formation of perineuronal nets (PNNs) that terminate critical periods of plasticity and promote the formation of stable local networks. Overall, the bulk of ELS studies report transient and/or long lasting alterations in both glutamatergic circuits and local inhibitory interneurons (INs) and their associated PNNs. Since the activity of INs plays a key role in the maturation of cortical regions and the formation of local field potentials, alterations in these INs triggered by ELS might critically participate in the development of psychiatric disorders in adulthood, including impaired fear extinction and anxiety behavior.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33344723,

title = {Severe childhood and adulthood stress associates with neocortical layer-specific reductions of mature spines in psychiatric disorders},

author = {Dominic Kaul and Caine C Smith and Julia Stevens and Anna S Fröhlich and Elisabeth B Binder and Naguib Mechawar and Sibylle G Schwab and Natalie Matosin},

doi = {10.1016/j.ynstr.2020.100270},

issn = {2352-2895},

year  = {2020},

date = {2020-11-01},

journal = {Neurobiol Stress},

volume = {13},

pages = {100270},

abstract = {Severe stress exposure causes the loss of dendritic spines on cortical pyramidal neurons and induces psychiatric-like symptoms in rodent models. These effects are strongest following early-life stress and are most persistent on apical dendrites. However, the long-term impacts and temporal effects of stress exposure on the human brain remain poorly understood. Using a novel postmortem cohort of psychiatric cases with severe stress experienced in childhood, adulthood, or no severe stress, and matched controls, we aimed to determine the impact of stress timing on pyramidal neuron structure in the human orbitofrontal cortex (OFC). We performed Golgi Cox staining and manually measured the morphology and density of over 22,000 dendritic spines on layer-specific pyramidal neuron apical dendrites. We also quantified glucocorticoid receptor mRNA and protein as a marker of stress dysregulation. Both childhood and adulthood stress were associated with large reductions in mature mushroom spine density (up to 56% loss) in both the superficial (II/III) and deeper layers (V) of the OFC. However, childhood stress caused more substantial reductions to both total and mature mushroom spines. No difference in glucocorticoid receptor mRNA and protein were seen between groups, although both negatively correlated with total spine density within the whole cohort. These findings indicate that severe stress, especially when experienced during childhood, persistently affects the fine morphological properties of neurons in the human OFC. This may impact on cell connectivity in this brain area, and at least partly explain the social and emotional symptoms that originate in the OFC in psychiatric disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31958186,

title = {Developmental trajectory of oligodendrocyte progenitor cells in the human brain revealed by single cell RNA sequencing},

author = {Kelly Perlman and Charles P Couturier and Moein Yaqubi and Arnaud Tanti and Qiao-Ling Cui and Florian Pernin and Jo Anne Stratton and Jiannis Ragoussis and Luke Healy and Kevin Petrecca and Roy Dudley and Myriam Srour and Jeffrey A Hall and Timothy E Kennedy and Naguib Mechawar and Jack P Antel},

doi = {10.1002/glia.23777},

issn = {1098-1136},

year  = {2020},

date = {2020-06-01},

journal = {Glia},

volume = {68},

number = {6},

pages = {1291--1303},

abstract = {Characterizing the developmental trajectory of oligodendrocyte progenitor cells (OPC) is of great interest given the importance of these cells in the remyelination process. However, studies of human OPC development remain limited by the availability of whole cell samples and material that encompasses a wide age range, including time of peak myelination. In this study, we apply single cell RNA sequencing to viable whole cells across the age span and link transcriptomic signatures of oligodendrocyte-lineage cells with stage-specific functional properties. Cells were isolated from surgical tissue samples of second-trimester fetal, 2-year-old pediatric, 13-year-old adolescent, and adult donors by mechanical and enzymatic digestion, followed by percoll gradient centrifugation. Gene expression was analyzed using droplet-based RNA sequencing (10X Chromium). Louvain clustering analysis identified three distinct cellular subpopulations based on 5,613 genes, comprised of an early OPC (e-OPC) group, a late OPC group (l-OPC), and a mature OL (MOL) group. Gene ontology terms enriched for e-OPCs included cell cycle and development, for l-OPCs included extracellular matrix and cell adhesion, and for MOLs included myelination and cytoskeleton. The e-OPCs were mostly confined to the premyelinating fetal group, and the l-OPCs were most highly represented in the pediatric age group, corresponding to the peak age of myelination. Cells expressing a signature characteristic of l-OPCs were identified in the adult brain in situ using RNAScope. These findings highlight the transcriptomic variability in OL-lineage cells before, during, and after peak myelination and contribute to identifying novel pathways required to achieve remyelination.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32154672,

title = {Stimulation of L-type calcium channels increases tyrosine hydroxylase and dopamine in ventral midbrain cells induced from somatic cells},

author = {Malvin Jefri and Scott Bell and Huashan Peng and Nuwan Hettige and Gilles Maussion and Vincent Soubannier and Hanrong Wu and Heika Silveira and Jean-Francois Theroux and Luc Moquin and Xin Zhang and Zahia Aouabed and Jeyashree Krishnan and Liam A O'Leary and Lilit Antonyan and Ying Zhang and Vincent McCarty and Naguib Mechawar and Alain Gratton and Andreas Schuppert and Thomas M Durcan and Edward A Fon and Carl Ernst},

doi = {10.1002/sctm.18-0180},

issn = {2157-6580},

year  = {2020},

date = {2020-06-01},

journal = {Stem Cells Transl Med},

volume = {9},

number = {6},

pages = {697--712},

abstract = {Making high-quality dopamine (DA)-producing cells for basic biological or small molecule screening studies is critical for the development of novel therapeutics for disorders of the ventral midbrain. Currently, many ventral midbrain assays have low signal-to-noise ratio due to low levels of cellular DA and the rate-limiting enzyme of DA synthesis, tyrosine hydroxylase (TH), hampering discovery efforts. Using intensively characterized ventral midbrain cells derived from human skin, which demonstrate calcium pacemaking activity and classical electrophysiological properties, we show that an L-type calcium agonist can significantly increase TH protein levels and DA content and release. Live calcium imaging suggests that it is the immediate influx of calcium occurring simultaneously in all cells that drives this effect. Genome-wide expression profiling suggests that L-type calcium channel stimulation has a significant effect on specific genes related to DA synthesis and affects expression of L-type calcium receptor subunits from the CACNA1 and CACNA2D families. Together, our findings provide an advance in the ability to increase DA and TH levels to improve the accuracy of disease modeling and small molecule screening for disorders of the ventral midbrain, including Parkinson's disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32232768,

title = {Characterization of Cerebellum-Specific Ribosomal DNA Epigenetic Modifications in Alzheimer's Disease: Should the Cerebellum Serve as a Control Tissue After All?},

author = {Tathyane C Faria and Héctor L Maldonado and Leonardo C Santos and Roger DeLabio and Spencer L M Payao and Gustavo Turecki and Naguib Mechawar and Dalileia A Santana and Carolina O Gigek and Bernardo Lemos and Marilia A C Smith and Elizabeth S Chen},

doi = {10.1007/s12035-020-01902-9},

issn = {1559-1182},

year  = {2020},

date = {2020-06-01},

journal = {Mol Neurobiol},

volume = {57},

number = {6},

pages = {2563--2571},

abstract = {Alzheimer's disease (AD) is a neurodegenerative disease, known as the most common form of dementia. In AD onset, abnormal rRNA expression has been reported to be linked in pathogenesis. Although region-specific expression patterns have previously been reported in AD, it is not until recently that the cerebellum has come under the spotlight. Specifically, it is unclear whether DNA methylation is the mechanism involved in rRNA expression regulation in AD. Hence, we sought to explore the rDNA methylation pattern of two different brain regions - auditory cortex and cerebellum - from AD and age-/sex-matched controls. Our results showed differential hypermethylation at an upstream CpG region to the rDNA promoter when comparing cerebellum controls to auditory cortex controls. This suggests a possible regulatory region from rDNA expression regulation. Moreover, when comparing between AD and control cerebellum samples, we observed hypermethylation of the rDNA promoter region as well as an increase in rDNA content. In addition, we also observed increased rRNA levels in AD compared to control cerebellum. Although still considered a pathology-free brain region, there are growing findings that continue to suggest otherwise. Indeed, cerebellum from AD has been recently described as affected by the disease, presenting a unique pattern of molecular alterations. Given that we observed that increased rDNA promoter methylation did not silence rDNA gene expression, we suggest that rDNA promoter hypermethylation is playing a protective role in rDNA genomic stability and, therefore, increasing rRNA levels in AD cerebellum.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32341540,

title = {Single-nucleus transcriptomics of the prefrontal cortex in major depressive disorder implicates oligodendrocyte precursor cells and excitatory neurons},

author = {Corina Nagy and Malosree Maitra and Arnaud Tanti and Matthew Suderman and Jean-Francois Théroux and Maria Antonietta Davoli and Kelly Perlman and Volodymyr Yerko and Yu Chang Wang and Shreejoy J Tripathy and Paul Pavlidis and Naguib Mechawar and Jiannis Ragoussis and Gustavo Turecki},

doi = {10.1038/s41593-020-0621-y},

issn = {1546-1726},

year  = {2020},

date = {2020-06-01},

journal = {Nat Neurosci},

volume = {23},

number = {6},

pages = {771--781},

abstract = {Major depressive disorder (MDD) has an enormous impact on global disease burden, affecting millions of people worldwide and ranking as a leading cause of disability for almost three decades. Past molecular studies of MDD employed bulk homogenates of postmortem brain tissue, which obscures gene expression changes within individual cell types. Here we used single-nucleus transcriptomics to examine ~80,000 nuclei from the dorsolateral prefrontal cortex of male individuals with MDD (n = 17) and of healthy controls (n = 17). We identified 26 cellular clusters, and over 60% of these showed differential gene expression between groups. We found that the greatest dysregulation occurred in deep layer excitatory neurons and immature oligodendrocyte precursor cells (OPCs), and these contributed almost half (47%) of all changes in gene expression. These results highlight the importance of dissecting cell-type-specific contributions to the disease and offer opportunities to identify new avenues of research and novel targets for treatment.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32242018,

title = {GPR56/ADGRG1 is associated with response to antidepressant treatment},

author = {Raoul Belzeaux and Victor Gorgievski and Laura M Fiori and Juan Pablo Lopez and Julien Grenier and Rixing Lin and Corina Nagy and El Chérif Ibrahim and Eduardo Gascon and Philippe Courtet and Stéphane Richard-Devantoy and Marcelo Berlim and Eduardo Chachamovich and Jean-François Théroux and Sylvie Dumas and Bruno Giros and Susan Rotzinger and Claudio N Soares and Jane A Foster and Naguib Mechawar and Gregory G Tall and Eleni T Tzavara and Sidney H Kennedy and Gustavo Turecki},

doi = {10.1038/s41467-020-15423-5},

issn = {2041-1723},

year  = {2020},

date = {2020-04-01},

journal = {Nat Commun},

volume = {11},

number = {1},

pages = {1635},

abstract = {It remains unclear why many patients with depression do not respond to antidepressant treatment. In three cohorts of individuals with depression and treated with serotonin-norepinephrine reuptake inhibitor (N = 424) we show that responders, but not non-responders, display an increase of GPR56 mRNA in the blood. In a small group of subjects we also show that GPR56 is downregulated in the PFC of individuals with depression that died by suicide. In mice, we show that chronic stress-induced Gpr56 downregulation in the blood and prefrontal cortex (PFC), which is accompanied by depression-like behavior, and can be reversed by antidepressant treatment. Gpr56 knockdown in mouse PFC is associated with depressive-like behaviors, executive dysfunction and poor response to antidepressant treatment. GPR56 peptide agonists have antidepressant-like effects and upregulated AKT/GSK3/EIF4 pathways. Our findings uncover a potential role of GPR56 in antidepressant response.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31974313,

title = {Molecular adaptations of the blood-brain barrier promote stress resilience vs. depression},

author = {Katarzyna A Dudek and Laurence Dion-Albert and Manon Lebel and Katherine LeClair and Simon Labrecque and Ellen Tuck and Carmen Ferrer Perez and Sam A Golden and Carol Tamminga and Gustavo Turecki and Naguib Mechawar and Scott J Russo and Caroline Menard},

doi = {10.1073/pnas.1914655117},

issn = {1091-6490},

year  = {2020},

date = {2020-02-01},

journal = {Proc Natl Acad Sci U S A},

volume = {117},

number = {6},

pages = {3326--3336},

abstract = {Preclinical and clinical studies suggest that inflammation and vascular dysfunction contribute to the pathogenesis of major depressive disorder (MDD). Chronic social stress alters blood-brain barrier (BBB) integrity through loss of tight junction protein claudin-5 (cldn5) in male mice, promoting passage of circulating proinflammatory cytokines and depression-like behaviors. This effect is prominent within the nucleus accumbens, a brain region associated with mood regulation; however, the mechanisms involved are unclear. Moreover, compensatory responses leading to proper behavioral strategies and active resilience are unknown. Here we identify active molecular changes within the BBB associated with stress resilience that might serve a protective role for the neurovasculature. We also confirm the relevance of such changes to human depression and antidepressant treatment. We show that permissive epigenetic regulation of  expression and low endothelium expression of repressive cldn5-related transcription factor  are associated with stress resilience. Region- and endothelial cell-specific whole transcriptomic analyses revealed molecular signatures associated with stress vulnerability vs. resilience. We identified proinflammatory TNFα/NFκB signaling and  as mediators of stress susceptibility. Pharmacological inhibition of stress-induced increase in hdac1 activity rescued  expression in the NAc and promoted resilience. Importantly, we confirmed changes in  expression in the NAc of depressed patients without antidepressant treatment in line with CLDN5 loss. Conversely, many of these deleterious -related molecular changes were reduced in postmortem NAc from antidepressant-treated subjects. These findings reinforce the importance of considering stress-induced neurovascular pathology in depression and provide therapeutic targets to treat this mood disorder and promote resilience.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32848635,

title = {Characterization of Vimentin-Immunoreactive Astrocytes in the Human Brain},

author = {Liam Anuj O'Leary and Maria Antonietta Davoli and Claudia Belliveau and Arnaud Tanti and Jie Christopher Ma and William Todd Farmer and Gustavo Turecki and Keith Kazuo Murai and Naguib Mechawar},

doi = {10.3389/fnana.2020.00031},

issn = {1662-5129},

year  = {2020},

date = {2020-01-01},

journal = {Front Neuroanat},

volume = {14},

pages = {31},

abstract = {Astrocytes are commonly identified by their expression of the intermediate filament protein glial fibrillary acidic protein (GFAP). GFAP-immunoreactive (GFAP-IR) astrocytes exhibit regional heterogeneity in density and morphology in the mouse brain as well as morphological diversity in the human cortex. However, regional variations in astrocyte distribution and morphology remain to be assessed comprehensively. This was the overarching objective of this postmortem study, which mainly exploited the immunolabeling of vimentin (VIM), an intermediate filament protein expressed by astrocytes and endothelial cells which presents the advantage of more extensively labeling cell structures. We compared the densities of vimentin-immunoreactive (VIM-IR) and GFAP-IR astrocytes in various brain regions (prefrontal and primary visual cortex, caudate nucleus, mediodorsal thalamus) from male individuals having died suddenly in the absence of neurological or psychiatric conditions. The morphometric properties of VIM-IR in these brain regions were also assessed. We found that VIM-IR astrocytes generally express the canonical astrocytic markers Aldh1L1 and GFAP but that VIM-IR astrocytes are less abundant than GFAP-IR astrocytes in all human brain regions, particularly in the thalamus, where VIM-IR cells were nearly absent. About 20% of all VIM-IR astrocytes presented a twin cell morphology, a phenomenon rarely observed for GFAP-IR astrocytes. Furthermore VIM-IR astrocytes in the striatum were often seen to extend numerous parallel processes which seemed to give rise to large VIM-IR fiber bundles projecting over long distances. Moreover, morphometric analyses revealed that VIM-IR astrocytes were more complex than their mouse counterparts in functionally homologous brain regions, as has been previously reported for GFAP-IR astrocytes. Lastly, the density of GFAP-IR astrocytes in gray and white matter were inversely correlated with vascular density, but for VIM-IR astrocytes this was only the case in gray matter, suggesting that gliovascular interactions may especially influence the regional heterogeneity of GFAP-IR astrocytes. Taken together, these findings reveal special features displayed uniquely by human VIM-IR astrocytes and illustrate that astrocytes display important region- and marker-specific differences in the healthy human brain.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31788534,

title = {The Consortium for the early identification of Alzheimer's disease-Quebec (CIMA-Q)},

author = {Sylvie Belleville and Andréa C LeBlanc and Marie-Jeanne Kergoat and Frédéric Calon and Pierrette Gaudreau and Sébastien S Hébert and Carol Hudon and Nicole Leclerc and Naguib Mechawar and Simon Duchesne and Serge Gauthier and },

doi = {10.1016/j.dadm.2019.07.003},

issn = {2352-8729},

year  = {2019},

date = {2019-12-01},

journal = {Alzheimers Dement (Amst)},

volume = {11},

pages = {787--796},

abstract = {INTRODUCTION: The Consortium for the early identification of Alzheimer's disease-Quebec (CIMA-Q) created a research infrastructure to recruit, characterize, and track disease progression in individuals at risk of dementia.nnMETHODS: CIMA-Q established standardized clinical, neuropsychological, neuroimaging, blood (plasma, serum, RNA, genomic DNA), cryopreserved peripheral blood mononuclear cells, and cerebrospinal fluid collection protocols. These data and biological materials are available to the research community.nnRESULTS: In phase 1, 115 persons with subjective cognitive decline, 88 with mild cognitive impairment, 31 with early probable Alzheimer's disease, and 56 older adults with no worries nor impairments received detailed clinical and cognitive evaluations as well as blood and peripheral blood mononuclear cells collections. Among them, 142 underwent magnetic resonance imaging, 29 a fluorodeoxyglucose positron emission tomography, and 60 a lumbar puncture.nnDISCUSSION: CIMA-Q provides procedures and resources to identify early biomarkers and novel therapeutic targets, and holds promise for detecting cognitive decline in Alzheimer's disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31374562,

title = {Evidence of decreased gap junction coupling between astrocytes and oligodendrocytes in the anterior cingulate cortex of depressed suicides},

author = {Arnaud Tanti and Pierre-Eric Lutz and John Kim and Liam O'Leary and Jean-François Théroux and Gustavo Turecki and Naguib Mechawar},

doi = {10.1038/s41386-019-0471-z},

issn = {1740-634X},

year  = {2019},

date = {2019-11-01},

journal = {Neuropsychopharmacology},

volume = {44},

number = {12},

pages = {2099--2111},

abstract = {Glial dysfunction is a major pathophysiological feature of mood disorders. While altered astrocyte (AS) and oligodendrocyte-lineage (OL) functions have been associated with depression, the crosstalk between these glial cell types has never been assessed in that context. AS are potent regulators of myelination, in part through gap junction (GJ) channels formed by the heterotypic coupling of AS-specific (Cx30 and Cx43) and OL-specific (Cx32 and Cx47) connexins. This study therefore aimed at addressing the integrity of AS/OL coupling in the anterior cingulate cortex (ACC) of depressed suicides. Using immunofluorescence and confocal imaging, we characterized the distribution of Cx30 and mapped its expression onto OL somas, myelinated axons, and brain vasculature in postmortem brain samples from depressed suicides (N = 48) and matched controls (N = 23). Differential gene expression of key components of the GJ nexus was also screened through RNA-sequencing previously generated by our group, and validated by quantitative real-time PCR. We show that Cx30 expression localized onto OL cells and myelinated fibers is decreased in deep cortical layers of the ACC in male-depressed suicides. This effect was associated with decreased expression of OL-specific connexins, as well as the downregulation of major connexin-interacting proteins essential for the scaffolding, trafficking, and function of GJs. These results provide a first evidence of impaired AS/OL GJ-mediated communication in the ACC of individuals with mood disorders. These changes in glial coupling are likely to have significant impact on brain function, and may contribute to the altered OL function previously reported in this brain region.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31042280,

title = {Assessment of Striatal Dopamine Transporter Binding in Individuals With Major Depressive Disorder: In Vivo Positron Emission Tomography and Postmortem Evidence},

author = {Diego A Pizzagalli and Sabina Berretta and Dustin Wooten and Franziska Goer and Kanoelani T Pilobello and Poornima Kumar and Laura Murray and Miranda Beltzer and Anne Boyer-Boiteau and Nathanial Alpert and Georges El Fakhri and Naguib Mechawar and Gordana Vitaliano and Gustavo Turecki and Marc Normandin},

doi = {10.1001/jamapsychiatry.2019.0801},

issn = {2168-6238},

year  = {2019},

date = {2019-08-01},

journal = {JAMA Psychiatry},

volume = {76},

number = {8},

pages = {854--861},

abstract = {IMPORTANCE: Major depressive disorder (MDD) might involve dopamine (DA) reductions. The DA transporter (DAT) regulates DA clearance and neurotransmission and is sensitive to DA levels, with preclinical studies (including those involving inescapable stressors) showing that DAT density decreases when DA signaling is reduced. Despite preclinical data, evidence of reduced DAT in MDD is inconclusive.nnOBJECTIVE: Using a highly selective DAT positron emission tomography (PET) tracer ([11C] altropane), DAT availability was probed in individuals with MDD who were not taking medication. Levels of DAT expression were also evaluated in postmortem tissues from donors with MDD who died by suicide.nnDESIGN, SETTING, AND PARTICIPANTS: This cross-sectional PET study was conducted at McLean Hospital (Belmont, Massachusetts) and Massachusetts General Hospital (Boston) and enrolled consecutive individuals with MDD who were not taking medication and demographically matched healthy controls between January 2012 and March 2014. Brain tissues were obtained from the Douglas-Bell Canada Brain Bank. For the PET component, 25 individuals with current MDD who were not taking medication and 23 healthy controls recruited from McLean Hospital were included (all provided usable data). For the postmortem component, 15 individuals with depression and 14 healthy controls were considered.nnINTERVENTION: PET scan.nnMAIN OUTCOMES AND MEASURES: Striatal and midbrain DAT binding potential was assessed. For the postmortem component, tyrosine hydroxylase and DAT levels were evaluated using Western blots.nnRESULTS: Compared with 23 healthy controls (13 women [56.5%]; mean [SD] age, 26.49 [7.26] years), 25 individuals with MDD (19 women [76.0%]; mean [SD] age, 26.52 [5.92] years) showed significantly lower in vivo DAT availability in the bilateral putamen and ventral tegmental area (Cohen d range, -0.62 to -0.71), and both reductions were exacerbated with increasing numbers of depressive episodes. Unlike healthy controls, the MDD group failed to show an age-associated reduction in striatal DAT availability, with young individuals with MDD being indistinguishable from older healthy controls. Moreover, DAT availability in the ventral tegmental area was lowest in individuals with MDD who reported feeling trapped in stressful circumstances. Lower DAT levels (and tyrosine hydroxylase) in the putamen of MDD compared with healthy controls were replicated in postmortem analyses (Cohen d range, -0.92 to -1.15).nnCONCLUSIONS AND RELEVANCE: Major depressive disorder, particularly with recurring episodes, is characterized by decreased striatal DAT expression, which might reflect a compensatory downregulation due to low DA signaling within mesolimbic pathways.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30983036,

title = {MIC-MAC: An automated pipeline for high-throughput characterization and classification of three-dimensional microglia morphologies in mouse and human postmortem brain samples},

author = {Luis Salamanca and Naguib Mechawar and Keith K Murai and Rudi Balling and David S Bouvier and Alexander Skupin},

doi = {10.1002/glia.23623},

issn = {1098-1136},

year  = {2019},

date = {2019-08-01},

journal = {Glia},

volume = {67},

number = {8},

pages = {1496--1509},

abstract = {The phenotypic changes of microglia in brain diseases are particularly diverse and their role in disease progression, beneficial, or detrimental, is still elusive. High-throughput molecular approaches such as single-cell RNA-sequencing can now resolve the high heterogeneity in microglia population for a specific physiological condition, however, the relation between the different microglial signatures and their surrounding brain microenvironment is barely understood. Thus, better tools to characterize the phenotypic variations of microglia in situ are needed, particularly for human brain postmortem samples analysis. To address this challenge, we developed MIC-MAC, a Microglia and Immune Cells Morphologies Analyser and Classifier pipeline that semiautomatically segments, extracts, and classifies all microglia and immune cells labeled in large three-dimensional (3D) confocal image stacks of mouse and human brain samples. Our imaging-based approach enables automatic 3D-morphology characterization and classification of thousands of individual microglia in situ and revealed species- and disease-specific morphological phenotypes in mouse aging, human Alzheimer's disease, and dementia with Lewy Bodie's samples. MIC-MAC is a precision diagnostic tool that allows a rapid, unbiased, and large-scale analysis of microglia morphological states in mouse models and patient brain samples.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30902874,

title = {Astrocytic Epoxyeicosatrienoic Acid Signaling in the Medial Prefrontal Cortex Modulates Depressive-like Behaviors},

author = {Wenchao Xiong and Xiong Cao and Yuanning Zeng and Xihe Qin and Minzhen Zhu and Jing Ren and Zhou Wu and Qiyuan Huang and Yuan Zhang and Mengyao Wang and Lianwan Chen and Gustavo Turecki and Naguib Mechawar and Wenjun Chen and Guoliang Yi and Xinhong Zhu},

doi = {10.1523/JNEUROSCI.3069-18.2019},

issn = {1529-2401},

year  = {2019},

date = {2019-06-01},

journal = {J Neurosci},

volume = {39},

number = {23},

pages = {4606--4623},

abstract = {Major depressive disorder is the most common mental illness. Mounting evidence indicates that astrocytes play a crucial role in the pathophysiology of depression; however, the underlying molecular mechanisms remain elusive. Compared with other neuronal cell types, astrocytes are enriched for arachidonic acid metabolism. Herein, we observed brain-region-specific alterations of epoxyeicosatrienoic acid (EET) signaling, which is an arachidonic acid metabolic pathway, in both a mouse model of depression and postmortem samples from patients with depression. The enzymatic activity of soluble epoxide hydrolase (sEH), the key enzyme in EET signaling, was selectively increased in the mPFC of susceptible mice after chronic social defeated stress and was negatively correlated with the social interaction ratio, which is an indicator of depressive-like behavior. The specific deletion of  (encode sEH) in adult astrocytes induced resilience to stress, whereas the impaired EET signaling in the mPFC evoked depressive-like behaviors in response to stress. sEH was mainly expressed on lysosomes of astrocytes. Using pharmacological and genetic approaches performed on C57BL/6J background adult male mice, we found that EET signaling modulated astrocytic ATP release  and  Moreover, astrocytic ATP release was required for the antidepressant-like effect of  deletion in adult astrocytes. In addition, sEH inhibitors produced rapid antidepressant-like effects in multiple animal models of depression, including chronic social defeated stress and chronic mild stress. Together, our results highlight that EET signaling in astrocytes in the mPFC is essential for behavioral adaptation in response to psychiatric stress. Astrocytes, the most abundant glial cells of the brain, play a vital role in the pathophysiology of depression. Astrocytes secrete adenosine ATP, which modulates depressive-like behaviors. Notably, astrocytes are enriched for arachidonic acid metabolism. In the present study, we explored the hypothesis that epoxyeicosatrienoic acid signaling, an arachidonic acid metabolic pathway, modulates astrocytic ATP release and the expression of depressive-like behaviors. Our work demonstrated that epoxyeicosatrienoic acid signaling in astrocytes in the mPFC is essential for behavioral homeostatic adaptation in response to stress, and the extent of astrocyte functioning is greater than expected based on earlier reports.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}