@article{pmid40016352,

title = {Astrocytic cannabinoid receptor 1 promotes resilience by dampening stress-induced blood-brain barrier alterations},

author = {Katarzyna A Dudek and Sam E J Paton and Luisa Bandeira Binder and Adeline Collignon and Laurence Dion-Albert and Alice Cadoret and Manon Lebel and Olivier Lavoie and Jonathan Bouchard and Fernanda Neutzling Kaufmann and Valerie Clavet-Fournier and Claudia Manca and Manuel Guzmán and Matthew Campbell and Gustavo Turecki and Naguib Mechawar and Nicolas Flamand and Flavie Lavoie-Cardinal and Cristoforo Silvestri and Vincenzo Di Marzo and Caroline Menard},

doi = {10.1038/s41593-025-01891-9},

issn = {1546-1726},

year  = {2025},

date = {2025-02-01},

journal = {Nat Neurosci},

abstract = {Blood-brain barrier (BBB) alterations contribute to stress vulnerability and the development of depressive behaviors. In contrast, neurovascular adaptations underlying stress resilience remain unclear. Here we report that high expression of astrocytic cannabinoid receptor 1 (CB1) in the nucleus accumbens (NAc) shell, particularly in the end-feet ensheathing blood vessels, is associated with resilience during chronic social stress in adult male mice. Viral-mediated overexpression of Cnr1 in astrocytes of the NAc shell results in baseline anxiolytic effects and dampens stress-induced anxiety- and depression-like behaviors in male mice. It promotes the expression of vascular-related genes and reduces astrocyte inflammatory response and morphological changes following an immune challenge with the cytokine interleukin-6, linked to stress susceptibility and mood disorders. Physical exercise and antidepressant treatment increase the expression of astrocytic Cnr1 in the perivascular region in male mice. In human tissue from male donors with major depressive disorder, we observe loss of CNR1 in the NAc astrocytes. Our findings suggest a role for the astrocytic endocannabinoid system in stress responses via modulation of the BBB.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39989284,

title = {Altered Proteomics in Brain Extracellular Vesicles from Depressed Individuals Who Died by Suicide Implicates Synaptic Processes},

author = {Pascal Ibrahim and Haruka Mitsuhashi and Lorne Taylor and Jenna Cleyle and Naguib Mechawar and Corina Nagy and Gustavo Turecki},

doi = {10.1093/ijnp/pyaf012},

issn = {1469-5111},

year  = {2025},

date = {2025-02-01},

journal = {Int J Neuropsychopharmacol},

abstract = {BACKGROUND: Major Depressive Disorder (MDD) is a common and debilitating disorder whose molecular neurobiology remains unclear. Extracellular vesicles (EVs) are small vesicles that are released by cells and are involved in intercellular communication. They carry bioactive molecules, such as proteins, that reflect the state of their cell of origin. In this study, we sought to investigate the proteomic cargo of brain EVs from depressed individuals as compared to EVs from matched neurotypical individuals. In addition, we investigated how the EV proteomic cargo compares to the proteomic profile of bulk tissue.nnMETHODS: Using mass spectrometry and label-free quantification (LFQ), we investigated the EV and bulk tissue protein profile from anterior cingulate cortex (ACC) samples from 86 individuals. We performed differential expression analysis to compare cases and controls, followed by in silico analysis to determine potential implicated functions of dysregulated proteins.nnRESULTS: EVs display distinct proteomic profiles compared to bulk tissue. Differential expression analysis showed that 70 proteins were differentially packaged in EVs in MDD, while there was no significant difference in protein levels between groups in bulk tissue. In silico analysis points to a strong role of these differential EV proteins in synaptic functions.nnCONCLUSION: To our knowledge, this is the first study to profile EV proteins in depression, providing novel information to better understand the pathophysiology of MDD. This work paves the way for discovering new therapeutic targets for MDD and prompts more investigations into EVs in MDD and other psychiatric disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39672240,

title = {Evidence of microglial involvement in the childhood abuse-associated increase in perineuronal nets in the ventromedial prefrontal cortex},

author = {Claudia Belliveau and Reza Rahimian and Gohar Fakhfouri and Clémentine Hosdey and Sophie Simard and Maria Antonietta Davoli and Dominique Mirault and Bruno Giros and Gustavo Turecki and Naguib Mechawar},

doi = {10.1016/j.bbi.2024.12.013},

issn = {1090-2139},

year  = {2025},

date = {2025-02-01},

journal = {Brain Behav Immun},

volume = {124},

pages = {321--334},

abstract = {Microglia, known for their diverse roles in the central nervous system, have recently been recognized for their involvement in degrading the extracellular matrix. Perineuronal nets (PNNs), a specialized form of this matrix, are crucial for stabilizing neuronal connections and constraining plasticity. Our group recently reported increased PNN densities in the ventromedial prefrontal cortex (vmPFC) of depressed individuals that died by suicide in adulthood after experiencing childhood abuse (DS-CA) compared to matched controls. To explore potential underlying mechanisms, we employed a comprehensive approach in similar postmortem vmPFC samples, combining a human matrix metalloproteinase and chemokine array, isolation of CD11b-positive microglia and enzyme-linked immunosorbent assays (ELISA). Our findings indicate a significant downregulation of matrix metalloproteinase (MMP)-9 and tissue inhibitors of metalloproteinases (TIMP)-2 in both whole vmPFC grey matter and isolated microglial cells from DS-CA samples. Furthermore, our experiments reveal that a history of child abuse is associated with diminished levels of microglial CX3CR1 and IL33R in both vmPFC whole lysate and CD11b isolated cells. However, levels of the CX3CR1 ligand, CX3CL1 (Fractalkine), did not differ between groups. While these data suggest potential long-lasting alterations in microglial markers in the vmPFC of individuals exposed to severe childhood adversity, direct functional assessments were not conducted. Nonetheless, these findings offer insight into how childhood abuse may contribute to PNN alterations via microglial-related mechanisms.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39954093,

title = {Microglia aggregates define distinct immune and neurodegenerative niches in Alzheimer's disease hippocampus},

author = {Sonja Fixemer and Mónica Miranda de la Maza and Gaël Paul Hammer and Félicia Jeannelle and Sophie Schreiner and Jean-Jacques Gérardy and Susana Boluda and Dominique Mirault and Naguib Mechawar and Michel Mittelbronn and David S Bouvier},

doi = {10.1007/s00401-025-02857-8},

issn = {1432-0533},

year  = {2025},

date = {2025-02-01},

journal = {Acta Neuropathol},

volume = {149},

number = {1},

pages = {19},

abstract = {In Alzheimer's disease (AD), microglia form distinct cellular aggregates that play critical roles in disease progression, including Aβ plaque-associated microglia (PaM) and the newly identified coffin-like microglia (CoM). PaM are closely associated with amyloid-β (Aβ) plaques, while CoM are enriched in the pyramidal layer of the CA2/CA1 hippocampal subfields, where they frequently engulf neurons and associate with tau-positive tangles and phosphorylated α-synuclein. To elucidate the role of these microglial subtypes, we employed high-content neuropathology, integrating Deep Spatial Profiling (DSP), multiplex chromogenic immunohistochemistry and confocal microscopy, to comprehensively map and characterise their morphological and molecular signatures, as well as their neuropathological and astrocytic microenvironments, in AD and control post-mortem samples. PaM and PaM-associated astrocytes exhibited signatures related to complement system pathways, ErbB signalling, and metabolic and neurodegenerative processes. In contrast, CoM displayed markers associated with protein degradation and immune signalling pathways, including STING, TGF-β, and NF-κB. While no direct association between CD8 + T cells and either microglial type was observed, CD163 + perivascular macrophages were frequently incorporated into PaM. These findings provide novel insights into the heterogeneity of microglial responses, in particular their distinct interactions with astrocytes and infiltrating immune cells, and shed light on specific neurodegenerative hotspots and their implications for hippocampal deterioration in AD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39954253,

title = {A multi-omics and cell type-specific characterization of the ventral striatum in human cocaine use disorder},

author = {Eric Zillich and Annasara Artioli and Andrea C Rossetti and Diana Avetyan and Hanna Belschner and Josef Frank and Frank Stein and Jennifer J Schwarz and Naguib Mechawar and Gustavo Turecki and Markus M Nöthen and Anita C Hansson and Christian C Witt and Marcella Rietschel and Philipp Koch and Rainer Spanagel and Lea Zillich and Stephanie H Witt},

doi = {10.1016/j.celrep.2025.115332},

issn = {2211-1247},

year  = {2025},

date = {2025-02-01},

journal = {Cell Rep},

volume = {44},

number = {2},

pages = {115332},

abstract = {Epigenome, transcriptome, and proteome analyses of postmortem brains have revealed initial molecular insights into cocaine use disorder (CUD). However, the inter-relationship between these omics and the contribution of individual cell types remains largely unknown. We present an in-depth analysis of molecular changes in the ventral striatum in CUD at multi-omics and single-cell resolution. Integrative multi-omics analyses of microRNA sequencing (microRNA-seq), RNA sequencing (RNA-seq), and proteomics datasets in 41 individuals and single-nuclei RNA-seq in a subset of 16 individuals revealed conserved deregulation of metabolic pathways, oxidative phosphorylation, and glutamatergic signaling. Cell type-specific analyses identified inverse metabolic pathway deregulation patterns in glial and neuronal cells, notably in astrocytes and medium-spiny neurons (MSNs). Characterizing astrocyte-neuron crosstalk revealed altered glutamatergic and cell-cell adhesion signaling in CUD. By applying a comprehensive multi-omics analytical framework, our study provides novel insights into CUD-associated molecular changes in the ventral striatum highlighting the perturbation of astrocytes, MSNs, and their crosstalk in CUD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39650737,

title = {Altered m6A RNA methylation profiles in depression implicate the dysregulation of discrete cellular functions in males and females},

author = {Haruka Mitsuhashi and Rixing Lin and Anjali Chawla and Naguib Mechawar and Corina Nagy and Gustavo Turecki},

doi = {10.1016/j.isci.2024.111316},

issn = {2589-0042},

year  = {2024},

date = {2024-12-01},

journal = {iScience},

volume = {27},

number = {12},

pages = {111316},

abstract = {Adverse environmental stress represents a significant risk factor for major depressive disorder (MDD), often resulting in disrupted synaptic connectivity which is known to be partly regulated by epigenetic mechanisms. N-methyladenosine (m6A), an epitranscriptomic modification, has emerged as a crucial regulator of activity-dependent gene regulation. In this study, we characterized m6A profiles in the ventromedial prefrontal cortex (vmPFC) of individuals with MDD. Using m6A sequencing, we identified a total of 30,279 high-confidence m6A peaks, exhibiting significant enrichment in genes related to neuronal and synaptic function. The m6A peaks between males and females with MDD that passed the significance threshold showed opposite m6A patterns, while the threshold-free m6A patterns were concordant. Distinct m6A profiles were found in MDD for each sex, with dysregulation associated with microtubule movement in males and neuronal projection in females. Our results suggest the potential roles of m6A as part of the dysregulated molecular network in MDD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39695100,

title = {Exploring PDE5A upregulation in bipolar disorder: insights from single-nucleus RNA sequencing of human basal ganglia},

author = {Zhixin Bai and Peilong Li and Xu Gao and Gaoyu Zu and Andrew Jiang and Keting Wu and Naguib Mechawar and Gustavo Turecki and Klaus Lehnert and Russell G Snell and Jin Zhou and Jia Hu and Bingbing Yan and Liang Chen and Wensheng Li and You Chen and Shuai Liu and Ying Zhu and Linya You},

doi = {10.1038/s41398-024-03202-5},

issn = {2158-3188},

year  = {2024},

date = {2024-12-01},

journal = {Transl Psychiatry},

volume = {14},

number = {1},

pages = {494},

abstract = {Basal ganglia is proposed to mediate symptoms underlying bipolar disorder (BD). To understand the cell type-specific gene expression and network changes of BD basal ganglia, we performed single-nucleus RNA sequencing of 30,752 nuclei from caudate, putamen, globus pallidus, and substantia nigra of control human postmortem brain and 24,672 nuclei from BD brain. Differential expression analysis revealed major difference lying in caudate, with BD medium spiny neurons (MSNs) expressing significantly higher PDE5A, a cGMP-specific phosphodiesterase. Gene co-expression analysis (WGCNA) showed a strong correlation of caudate MSNs and gene module green, with a PDE5A-containing hub gene network. Gene regulatory network analysis (SCENIC) indicated key regulons among different cell types and basal ganglia regions, with downstream targets of key transcriptional factors showing overlapping genes such as PDEs. Upregulation of PDE5A was further validated in 7 pairs of control and BD caudate sections. Overexpression of PDE5A in primary cultured lateral ganglion eminence-derived striatal neurons led to decreased dendrite complexity, increased apoptosis, and enhanced neuronal excitability and membrane resistance. This effect could be rescued by PDE5 specific inhibitor, tadalafil. Overexpression of PDE5A in mouse striatum by stereotaxic injection caused a decreased cGMP level, an increased gene expression profile of neuroinflammation, and BD-like behaviors. Collectively, our findings provided cell type-specific gene expression profile, and indicated a causative role of PDE5A upregulation in BD basal ganglia. This study provides a single-nucleus transcriptomic profile of human control and bipolar disorder (BD) basal ganglia. Differential expression, gene co-expression, and gene regulatory network analyses collectively indicated upregulation of PDE5A in BD caudate medium spiny neurons (MSNs), which was further validated in another cohort of BD brains. The causative role of PDE5A upregulation in BD etiology is supported by the effects of PDE5A overexpression in cultured mouse MSNs in vitro and in adult mouse striatum in vivo. The former led to reduced dendrite complexity, increased apoptosis, and neuronal hyper-excitability, which could be rescued by PDE5 specific inhibitor tadalafil. The latter caused lower cGMP levels, upregulated genes associated with neuroinflammation, and BD-like behaviors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39511452,

title = {Evidence of altered monoamine oxidase B, an astroglia marker, in early psychosis and high-risk state},

author = {Kankana Nisha Aji and Nittha Lalang and Christian Ramos-Jiménez and Reza Rahimian and Naguib Mechawar and Gustavo Turecki and Daniel Chartrand and Isabelle Boileau and Jeffrey H Meyer and Pablo M Rusjan and Romina Mizrahi},

doi = {10.1038/s41380-024-02816-x},

issn = {1476-5578},

year  = {2024},

date = {2024-11-01},

journal = {Mol Psychiatry},

abstract = {A novel radiotracer, [C]SL25.1188, targets monoamine oxidase-B (MAO-B) enzyme, found primarily in astrocytes, which metabolizes monoamines (including dopamine), particularly in subcortical regions. Altered astrocyte function in schizophrenia is supported by convergent evidence from post-mortem, genetic, transcriptomic, peripheral and preclinical findings. We aimed to test whether levels of MAO-B, an index of astrocyte function are low in the living brains of early psychosis and their high-risk states. Thirty-eight participants including antipsychotic-free/minimally exposed clinical participants with first-episode psychosis (FEP), clinical high-risk (CHR) individuals and healthy volunteers (HVs) underwent a 90-min positron emission tomography (PET) scan with [C]SL25.1188, to measure MAO-B V, an index of MAO-B concentration. Participants were excluded if tested positive on urine drug screen (except for cannabis). This study of 14 FEP (mean[SD] age, 25.7[5.7] years; 6 F), 7 CHR (mean[SD] age, 20.9[3.7] years; 4 F) and 17 HV (mean[SD] age, 31.2[13.9] years; 9 F) demonstrated significant group differences in regional MAO-B V (F = 4.56, p = 0.02, Cohen's f = 0.49), controlling for tobacco (F  = 5.37, p = 0.03) and cannabis use (F = 5.11, p = 0.03) with significantly lower MAO-B V in CHR compared to HV (Cohen's d = 0.99). We report a significant cannabis effect on MAO-B V (F = 12.57, p = 0.001, Cohen's f = 0.57), with a significant group-by-cannabis interaction (F = 3.82, p = 0.03, Cohen's f = 0.45), indicating lower MAO-B V in cannabis-using clinical groups. Lower MAO-B V levels were more robust in striatal than cortical regions, in both clinical groups (F = 2.08, p = 0.04, Cohen's f = 0.73) and in cannabis users (F = 6.42, p < 0.001, Cohen's f = 0.91). Lower MAO-B concentration supports astrocyte dysfunction in cannabis-using CHR and FEP clinical populations. Lower MAO-B is consistent with replicated striatal dopamine elevation in psychosis, as well as astrocyte dysfunction in schizophrenia.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39128570,

title = {Proteomic evidence of depression-associated astrocytic dysfunction in the human male olfactory bulb},

author = {Reza Rahimian and Kelly Perlman and Gohar Fakhfouri and Refilwe Mpai and Vincent R Richard and Christa Hercher and Lucy Penney and Maria Antonietta Davoli and Corina Nagy and René P Zahedi and Christoph H Borchers and Bruno Giros and Gustavo Turecki and Naguib Mechawar},

doi = {10.1016/j.bbi.2024.08.016},

issn = {1090-2139},

year  = {2024},

date = {2024-11-01},

journal = {Brain Behav Immun},

volume = {122},

pages = {110--121},

abstract = {The olfactory bulb (OB), a major structure of the limbic system, has been understudied in human investigations of psychopathologies such as depression. To explore more directly the molecular features of the OB in depression, a global comparative proteome analysis was carried out with human post-mortem OB samples from 11 males having suffered from depression and 12 healthy controls. We identified 188 differentially abundant proteins (with adjusted p < 0.05) between depressed cases and controls. Gene ontology and gene enrichment analyses suggested that these proteins are involved in biological processes including the complement and coagulation cascades. Cell type enrichment analysis displayed a significant reduction in several canonical astrocytic proteins in OBs from depressed patients. Furthermore, using RNA-fluorescence in-situ hybridization, we observed a decrease in the percentage of ALDH1L1 cells expressing canonical astrocytic markers including ALDOC, NFIA, GJA1 (connexin 43) and SLC1A3 (EAAT1). These results are consistent with previous reports of downregulated astrocytic marker expression in other brain regions in depressed patients. We also conducted a comparative phosphoproteomic analysis of OB samples and found a dysregulation of proteins involved in neuronal and astrocytic functions. To determine whether OB astrocytic abnormalities is specific to humans, we also performed proteomics on the OB of socially defeated male mice, a commonly used model of depression. Cell-type specific analysis revealed that in socially defeated animals, the most striking OB protein alterations were associated with oligodendrocyte-lineage cells rather than with astrocytes, highlighting an important species difference. Overall, this study further highlights cerebral astrocytic abnormalities as a consistent feature of depression in humans.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39384764,

title = {Multi-omics profiling of DNA methylation and gene expression alterations in human cocaine use disorder},

author = {Eric Zillich and Hanna Belschner and Diana Avetyan and Diego Andrade-Brito and José Jaime Martínez-Magaña and Josef Frank and Naguib Mechawar and Gustavo Turecki and Judit Cabana-Domínguez and Noèlia Fernàndez-Castillo and Bru Cormand and Janitza L Montalvo-Ortiz and Markus M Nöthen and Anita C Hansson and Marcella Rietschel and Rainer Spanagel and Stephanie H Witt and Lea Zillich},

doi = {10.1038/s41398-024-03139-9},

issn = {2158-3188},

year  = {2024},

date = {2024-10-01},

journal = {Transl Psychiatry},

volume = {14},

number = {1},

pages = {428},

abstract = {Structural and functional changes of the brain are assumed to contribute to excessive cocaine intake, craving, and relapse in cocaine use disorder (CUD). Epigenetic and transcriptional changes were hypothesized as a molecular basis for CUD-associated brain alterations. Here we performed a multi-omics study of CUD by integrating epigenome-wide methylomic (N = 42) and transcriptomic (N = 25) data from the same individuals using postmortem brain tissue of Brodmann Area 9 (BA9). Of the N = 1 057 differentially expressed genes (p < 0.05), one gene, ZFAND2A, was significantly upregulated in CUD at transcriptome-wide significance (q < 0.05). Differential alternative splicing (AS) analysis revealed N = 98 alternatively spliced transcripts enriched in axon and dendrite extension pathways. Strong convergent overlap in CUD-associated expression deregulation was found between our BA9 cohort and independent replication datasets. Epigenomic, transcriptomic, and AS changes in BA9 converged at two genes, ZBTB4 and INPP5E. In pathway analyses, synaptic signaling, neuron morphogenesis, and fatty acid metabolism emerged as the most prominently deregulated biological processes. Drug repositioning analysis revealed glucocorticoid receptor targeting drugs as most potent in reversing the CUD expression profile. Our study highlights the value of multi-omics approaches for an in-depth molecular characterization and provides insights into the relationship between CUD-associated epigenomic and transcriptomic signatures in the human prefrontal cortex.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39334854,

title = {Perineuronal Net Alterations Following Early-Life Stress: Are Microglia Pulling Some Strings?},

author = {Reza Rahimian and Claudia Belliveau and Sophie Simard and Gustavo Turecki and Naguib Mechawar},

doi = {10.3390/biom14091087},

issn = {2218-273X},

year  = {2024},

date = {2024-08-01},

journal = {Biomolecules},

volume = {14},

number = {9},

abstract = {The extracellular matrix plays a key role in synapse formation and in the modulation of synaptic function in the central nervous system. Recent investigations have revealed that microglia, the resident immune cells of the brain, are involved in extracellular matrix remodeling under both physiological and pathological conditions. Moreover, the dysregulation of both innate immune responses and the extracellular matrix has been documented in stress-related psychopathologies as well as in relation to early-life stress. However, the dynamics of microglial regulation of the ECM and how it can be impacted by early-life adversity have been understudied. This brief review provides an overview of the recent literature on this topic, drawing from both animal model and human post mortem studies. Direct and indirect mechanisms through which microglia may regulate the extracellular matrix-including perineuronal nets-are presented and discussed in light of the interactions with other cell types.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38948769,

title = {Chondroitin sulfate glycan sulfation patterns influence histochemical labeling of perineuronal nets: a comparative study of interregional distribution in human and mouse brain},

author = {Claudia Belliveau and Stéphanie Théberge and Stefanie Netto and Reza Rahimian and Gohar Fakhfouri and Clémentine Hosdey and Maria Antonietta Davoli and Aarun Hendrickson and Kathryn Hao and Bruno Giros and Gustavo Turecki and Kimberly M Alonge and Naguib Mechawar},

doi = {10.1101/2024.02.09.579711},

issn = {2692-8205},

year  = {2024},

date = {2024-06-01},

journal = {bioRxiv},

abstract = {Perineuronal nets (PNNs) are a condensed subtype of extracellular matrix that form a net-like coverings around certain neurons in the brain. PNNs are primarily composed of chondroitin sulfate (CS) proteoglycans from the lectican family that consist of CS-glycosaminoglycan (CS-GAG) side chains attached to a core protein. CS disaccharides can exist in various isoforms with different sulfation patterns. Literature suggests that CS disaccharide sulfation patterns can influence the function of PNNs as well as their labeling. This study was conducted to characterize such interregional CS disaccharide sulfation pattern differences in adult human (N = 81) and mouse (N = 19) brains. Liquid chromatography tandem mass spectrometry was used to quantify five different CS disaccharide sulfation patterns, which were then compared to immunolabeling of PNNs using  (WFL) to identify CS-GAGs and anti-aggrecan to identify CS proteoglycans. In healthy brains, significant regional and species-specific differences in CS disaccharide sulfation and single versus double-labeling pattern were identified. A secondary analysis to investigate how early-life stress (ELS) impacts these PNN features discovered that although ELS increases WFL+ PNN density, the CS-GAG sulfation code and single versus double PNN-labeling distributions remained unaffected in both species. These results underscore PNN complexity in traditional research, emphasizing the need to consider their heterogeneity in future experiments.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38995945,

title = {Chondroitin sulfate glycan sulfation patterns influence histochemical labeling of perineuronal nets: a comparative study of interregional distribution in human and mouse brain},

author = {Claudia Belliveau and Stéphanie Théberge and Stefanie Netto and Reza Rahimian and Gohar Fakhfouri and Clémentine Hosdey and Maria Antonietta Davoli and Aarun Hendrickson and Kathryn Hao and Bruno Giros and Gustavo Turecki and Kimberly M Alonge and Naguib Mechawar},

doi = {10.1093/glycob/cwae049},

issn = {1460-2423},

year  = {2024},

date = {2024-06-01},

journal = {Glycobiology},

volume = {34},

number = {8},

abstract = {Perineuronal nets (PNNs) are a condensed subtype of extracellular matrix that form a net-like coverings around certain neurons in the brain. PNNs are primarily composed of chondroitin sulfate (CS) proteoglycans from the lectican family that consist of CS-glycosaminoglycan side chains attached to a core protein. CS disaccharides can exist in various isoforms with different sulfation patterns. Literature suggests that CS disaccharide sulfation patterns can influence the function of PNNs as well as their labeling. This study was conducted to characterize such interregional CS disaccharide sulfation pattern differences in adult human (n = 81) and mouse (n = 19) brains. Liquid chromatography tandem mass spectrometry was used to quantify five different CS disaccharide sulfation patterns, which were then compared to immunolabeling of PNNs using Wisteria Floribunda Lectin (WFL) to identify CS-glycosaminoglycans and anti-aggrecan to identify CS proteoglycans. In healthy brains, significant regional and species-specific differences in CS disaccharide sulfation and single versus double-labeling pattern were identified. A secondary analysis to investigate how early-life stress impacts these PNN features discovered that although early-life stress increases WFL+ PNN density, the CS-glycosaminoglycan sulfation code and single versus double PNN-labeling distributions remained unaffected in both species. These results underscore PNN complexity in traditional research, emphasizing the need to consider their heterogeneity in future experiments.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38631765,

title = {MAPT H2 haplotype and risk of Pick's disease in the Pick's disease International Consortium: a genetic association study},

author = {Rebecca R Valentino and William J Scotton and Shanu F Roemer and Tammaryn Lashley and Michael G Heckman and Maryam Shoai and Alejandro Martinez-Carrasco and Nicole Tamvaka and Ronald L Walton and Matthew C Baker and Hannah L Macpherson and Raquel Real and Alexandra I Soto-Beasley and Kin Mok and Tamas Revesz and Elizabeth A Christopher and Michael DeTure and William W Seeley and Edward B Lee and Matthew P Frosch and Laura Molina-Porcel and Tamar Gefen and Javier Redding-Ochoa and Bernardino Ghetti and Andrew C Robinson and Christopher Kobylecki and James B Rowe and Thomas G Beach and Andrew F Teich and Julia L Keith and Istvan Bodi and Glenda M Halliday and Marla Gearing and Thomas Arzberger and Christopher M Morris and Charles L White and Naguib Mechawar and Susana Boluda and Ian R MacKenzie and Catriona McLean and Matthew D Cykowski and Shih-Hsiu J Wang and Caroline Graff and Rashed M Nagra and Gabor G Kovacs and Giorgio Giaccone and Manuela Neumann and Lee-Cyn Ang and Agostinho Carvalho and Huw R Morris and Rosa Rademakers and John A Hardy and Dennis W Dickson and Jonathan D Rohrer and Owen A Ross and },

doi = {10.1016/S1474-4422(24)00083-8},

issn = {1474-4465},

year  = {2024},

date = {2024-05-01},

journal = {Lancet Neurol},

volume = {23},

number = {5},

pages = {487--499},

abstract = {BACKGROUND: Pick's disease is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. Pick's disease is pathologically defined by the presence in the frontal and temporal lobes of Pick bodies, composed of hyperphosphorylated, three-repeat tau protein, encoded by the MAPT gene. MAPT has two distinct haplotypes, H1 and H2; the MAPT H1 haplotype is the major genetic risk factor for four-repeat tauopathies (eg, progressive supranuclear palsy and corticobasal degeneration), and the MAPT H2 haplotype is protective for these disorders. The primary aim of this study was to evaluate the association of MAPT H2 with Pick's disease risk, age at onset, and disease duration.nnMETHODS: In this genetic association study, we used data from the Pick's disease International Consortium, which we established to enable collection of data from individuals with pathologically confirmed Pick's disease worldwide. For this analysis, we collected brain samples from individuals with pathologically confirmed Pick's disease from 35 sites (brainbanks and hospitals) in North America, Europe, and Australia between Jan 1, 2020, and Jan 31, 2023. Neurologically healthy controls were recruited from the Mayo Clinic (FL, USA, or MN, USA between March 1, 1998, and Sept 1, 2019). For the primary analysis, individuals were directly genotyped for the MAPT H1-H2 haplotype-defining variant rs8070723. In a secondary analysis, we genotyped and constructed the six-variant-defined (rs1467967-rs242557-rs3785883-rs2471738-rs8070723-rs7521) MAPT H1 subhaplotypes. Associations of MAPT variants and MAPT haplotypes with Pick's disease risk, age at onset, and disease duration were examined using logistic and linear regression models; odds ratios (ORs) and β coefficients were estimated and correspond to each additional minor allele or each additional copy of the given haplotype.nnFINDINGS: We obtained brain samples from 338 people with pathologically confirmed Pick's disease (205 [61%] male and 133 [39%] female; 338 [100%] White) and 1312 neurologically healthy controls (611 [47%] male and 701 [53%] female; 1312 [100%] White). The MAPT H2 haplotype was associated with increased risk of Pick's disease compared with the H1 haplotype (OR 1·35 [95% CI 1·12 to 1·64], p=0·0021). MAPT H2 was not associated with age at onset (β -0·54 [95% CI -1·94 to 0·87], p=0·45) or disease duration (β 0·05 [-0·06 to 0·16], p=0·35). Although not significant after correcting for multiple testing, associations were observed at p less than 0·05: with risk of Pick's disease for the H1f subhaplotype (OR 0·11 [0·01 to 0·99], p=0·049); with age at onset for H1b (β 2·66 [0·63 to 4·70], p=0·011), H1i (β -3·66 [-6·83 to -0·48], p=0·025), and H1u (β -5·25 [-10·42 to -0·07], p=0·048); and with disease duration for H1x (β -0·57 [-1·07 to -0·07], p=0·026).nnINTERPRETATION: The Pick's disease International Consortium provides an opportunity to do large studies to enhance our understanding of the pathobiology of Pick's disease. This study shows that, in contrast to the decreased risk of four-repeat tauopathies, the MAPT H2 haplotype is associated with an increased risk of Pick's disease in people of European ancestry. This finding could inform development of isoform-related therapeutics for tauopathies.nnFUNDING: Wellcome Trust, Rotha Abraham Trust, Brain Research UK, the Dolby Fund, Dementia Research Institute (Medical Research Council), US National Institutes of Health, and the Mayo Clinic Foundation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38757781,

title = {Adult Hippocampal Neurogenesis in the Human Brain: Updates, Challenges, and Perspectives},

author = {Sophie Simard and Natalie Matosin and Naguib Mechawar},

doi = {10.1177/10738584241252581},

issn = {1089-4098},

year  = {2024},

date = {2024-05-01},

journal = {Neuroscientist},

pages = {10738584241252581},

abstract = {The existence of neurogenesis in the adult human hippocampus has been under considerable debate within the past three decades due to the diverging conclusions originating mostly from immunohistochemistry studies. While some of these reports conclude that hippocampal neurogenesis in humans occurs throughout physiologic aging, others indicate that this phenomenon ends by early childhood. More recently, some groups have adopted next-generation sequencing technologies to characterize with more acuity the extent of this phenomenon in humans. Here, we review the current state of research on adult hippocampal neurogenesis in the human brain with an emphasis on the challenges and limitations of using immunohistochemistry and next-generation sequencing technologies for its study.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38760318,

title = {Parvalbumin interneurons in human ventromedial prefrontal cortex: a comprehensive post-mortem study of myelination and perineuronal nets in neurotypical individuals and depressed suicides with and without a history of child abuse},

author = {Stéphanie Théberge and Claudia Belliveau and Dongyue Xie and Roy Khalaf and Kelly Perlman and Reza Rahimian and Maria Antonietta Davoli and Gustavo Turecki and Naguib Mechawar},

doi = {10.1093/cercor/bhae197},

issn = {1460-2199},

year  = {2024},

date = {2024-05-01},

journal = {Cereb Cortex},

volume = {34},

number = {5},

abstract = {Cortical parvalbumin interneurons (PV+) are major regulators of excitatory/inhibitory information processing, and their maturation is associated with the opening of developmental critical periods (CP). Recent studies reveal that cortical PV+ axons are myelinated, and that myelination along with perineuronal net (PNN) maturation around PV+ cells is associated with the closures of CP. Although PV+ interneurons are susceptible to early-life stress, their relationship between their myelination and PNN coverage remains unexplored. This study compared the fine features of PV+ interneurons in well-characterized human post-mortem ventromedial prefrontal cortex samples (n = 31) from depressed suicides with or without a history of child abuse (CA) and matched controls. In healthy controls, 81% of all sampled PV+ interneurons displayed a myelinated axon, while a subset (66%) of these cells also displayed a PNN, proposing a relationship between both attributes. Intriguingly, a 3-fold increase in the proportion of unmyelinated PV+ interneurons with a PNN was observed in CA victims, along with greater PV-immunofluorescence intensity in myelinated PV+ cells with a PNN. This study, which is the first to provide normative data on myelination and PNNs around PV+ interneurons in human neocortex, sheds further light on the cellular and molecular consequences of early-life adversity on cortical PV+ interneurons.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38589409,

title = {SNORA69 is up-regulated in the lateral habenula of individuals with major depressive disorder},

author = {Rixing Lin and Haruka Mitsuhashi and Laura M Fiori and Ryan Denniston and El Cherif Ibrahim and Catherine Belzung and Naguib Mechawar and Gustavo Turecki},

doi = {10.1038/s41598-024-58278-2},

issn = {2045-2322},

year  = {2024},

date = {2024-04-01},

journal = {Sci Rep},

volume = {14},

number = {1},

pages = {8258},

abstract = {Major depressive disorder (MDD) is a complex and potentially debilitating illness whose etiology and pathology remains unclear. Non-coding RNAs have been implicated in MDD, where they display differential expression in the brain and the periphery. In this study, we quantified small nucleolar RNA (snoRNA) expression by small RNA sequencing in the lateral habenula (LHb) of individuals with MDD (n = 15) and psychiatrically-healthy controls (n = 15). We uncovered five snoRNAs that exhibited differential expression between MDD and controls (FDR < 0.01). Specifically, SNORA69 showed increased expression in MDD and was technically validated via RT-qPCR. We further investigated the expression of Snora69 in the LHb and peripheral blood of an unpredicted chronic mild stress (UCMS) mouse model of depression. Snora69 was specifically up-regulated in mice that underwent the UCMS paradigm. SNORA69 is known to guide pseudouridylation onto 5.8S and 18S rRNAs. We quantified the relative abundance of pseudouridines on 5.8S and 18S rRNA in human post-mortem LHb samples and found increased abundance of pseudouridines in the MDD group. Overall, our findings indicate the importance of brain snoRNAs in the pathology of MDD. Future studies characterizing SNORA69's role in MDD pathology is warranted.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38457375,

title = {Profiling Small RNA From Brain Extracellular Vesicles in Individuals With Depression},

author = {Pascal Ibrahim and Ryan Denniston and Haruka Mitsuhashi and Jennie Yang and Laura M Fiori and Dariusz Żurawek and Naguib Mechawar and Corina Nagy and Gustavo Turecki},

doi = {10.1093/ijnp/pyae013},

issn = {1469-5111},

year  = {2024},

date = {2024-03-01},

journal = {Int J Neuropsychopharmacol},

volume = {27},

number = {3},

abstract = {BACKGROUND: Major depressive disorder (MDD) is a leading cause of disability with significant mortality risk. Despite progress in our understanding of the etiology of MDD, the underlying molecular changes in the brain remain poorly understood. Extracellular vesicles (EVs) are lipid-bound particles that can reflect the molecular signatures of the tissue of origin. We aimed to optimize a streamlined EV isolation protocol from postmortem brain tissue and determine whether EV RNA cargo, particularly microRNAs (miRNAs), have an MDD-specific profile.nnMETHODS: EVs were isolated from postmortem human brain tissue. Quality was assessed using western blots, transmission electron microscopy, and microfluidic resistive pulse sensing. EV RNA was extracted and sequenced on Illumina platforms. Functional follow-up was performed in silico.nnRESULTS: Quality assessment showed an enrichment of EV markers, as well as a size distribution of 30 to 200 nm in diameter, and no contamination with cellular debris. Small RNA profiling indicated the presence of several RNA biotypes, with miRNAs and transfer RNAs being the most prominent. Exploring miRNA levels between groups revealed decreased expression of miR-92a-3p and miR-129-5p, which was validated by qPCR and was specific to EVs and not seen in bulk tissue. Finally, in silico functional analyses indicate potential roles for these 2 miRNAs in neurotransmission and synaptic plasticity.nnCONCLUSION: We provide a streamlined isolation protocol that yields EVs of high quality that are suitable for molecular follow-up. Our findings warrant future investigations into brain EV miRNA dysregulation in MDD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38150991,

title = {Enhancing HIF-1α-P2X2 signaling in dorsal raphe serotonergic neurons promotes psychological resilience},

author = {Yuan Zhang and Yi-da Pan and Wen-Ying Zheng and Huan-Yu Li and Min-Zhen Zhu and Wen-Jie Ou Yang and Yu Qian and Gustavo Turecki and Naguib Mechawar and Xin-Hong Zhu},

doi = {10.1016/j.redox.2023.103005},

issn = {2213-2317},

year  = {2024},

date = {2024-02-01},

journal = {Redox Biol},

volume = {69},

pages = {103005},

abstract = {Major depressive disorder (MDD) is a devastating condition. Although progress has been made in the past seven decades, patients with MDD continue to receive an inadequate treatment, primarily due to the late onset of first-line antidepressant drugs and to their acute withdrawal symptoms. Resilience is the ability to rebound from adversity in a healthy manner and many people have psychological resilience. Revealing the mechanisms and identifying methods promoting resilience will hopefully lead to more effective prevention strategies and treatments for depression. In this study, we found that intermittent hypobaric hypoxia training (IHHT), a method for training pilots and mountaineers, enhanced psychological resilience in adult mice. IHHT produced a sustained antidepressant-like effect in mouse models of depression by inducing long-term (up to 3 months after this treatment) overexpression of hypoxia-inducible factor (HIF)-1α in the dorsal raphe nucleus (DRN) of adult mice. Moreover, DRN-infusion of cobalt chloride, which mimics hypoxia increasing HIF-1α expression, triggered a rapid and long-lasting antidepressant-like effect. Down-regulation of HIF-1α in the DRN serotonergic (DRN) neurons attenuated the effects of IHHT. HIF-1α translationally regulated the expression of P2X2, and conditionally knocking out P2rx2 (encodes P2X2 receptors) in DRN neurons, in turn, attenuated the sustained antidepressant-like effect of IHHT, but not its acute effect. In line with these results, a single sub-anesthetic dose of ketamine enhanced HIF-1α-P2X2 signaling, which is essential for its rapid and long-lasting antidepressant-like effect. Notably, we found that P2X2 protein levels were significantly lower in the DRN of patients with MDD than that of control subjects. Together, these findings elucidate the molecular mechanism underlying IHHT promoting psychological resilience and highlight enhancing HIF-1α-P2X2 signaling in DRN neurons as a potential avenue for screening novel therapeutic treatments for MDD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37931511,

title = {Substance P, NPY, CCK and their receptors in five brain regions in major depressive disorder with transcriptomic analysis of locus coeruleus neurons},

author = {Swapnali Barde and Julio Aguila and Wen Zhong and Anna Solarz and Irene Mei and Josee Prud'homme and Miklos Palkovits and Gustavo Turecki and Jan Mulder and Mathias Uhlén and Corina Nagy and Naguib Mechawar and Eva Hedlund and Tomas Hökfelt},

doi = {10.1016/j.euroneuro.2023.09.004},

issn = {1873-7862},

year  = {2024},

date = {2024-01-01},

journal = {Eur Neuropsychopharmacol},

volume = {78},

pages = {54--63},

abstract = {Major depressive disorder (MDD) is a serious disease and a burden to patients, families and society. Rodent experiments and human studies suggest that several neuropeptide systems are involved in mood regulation. The aim of this study is two-fold: (i) to monitor, with qPCR, transcript levels of the substance P/tachykinin (TAC), NPY and CCK systems in bulk samples from control and suicide subjects, targeting five postmortem brain regions including locus coeruleus (LC); and (ii) to analyse expression of neuropeptide family transcripts in LC neurons of 'normal' postmortem brains by using laser capture microdissection with Smart-Seq2 RNA sequencing. qPCR revealed distinct regional expression patterns in male and female controls with higher levels for the TAC system in the dorsal raphe nucleus and LC, versus higher transcripts levels of the NPY and CCK systems in prefrontal cortex. In suicide patients, TAC, TAC receptors and a few NPY family transcript levels were increased mainly in prefrontal cortex and LC. The second study on 'normal' noradrenergic LC neurons revealed expression of transcripts for GAL, NPY, TAC1, CCK, and TACR1 and many other peptides (e.g. Cerebellin4 and CARTPT) and receptors (e.g. Adcyap1R1 and GPR173). These data and our previous results on suicide brains indicates that the tachykinin and galanin systems may be valid targets for developing antidepressant medicines. Moreover, the perturbation of neuropeptide systems in MDD patients, and the detection of further neuropeptide and receptor transcripts in LC, shed new light on signalling in noradrenergic LC neurons and on mechanisms possibly associated with mood disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}