@article{pmid41980683,

title = {Choroid plexus inflammation in bipolar disorder},

author = {Dario Figueroa Velez and Reza Rahimian and Christine Hehnly and Jordan C Benson and Isabella Sacharczyk and Gustavo Turecki and Naguib Mechawar and Maria K Lehtinen},

doi = {10.1016/j.bbi.2026.106598},

issn = {1090-2139},

year  = {2026},

date = {2026-08-01},

journal = {Brain Behav Immun},

volume = {136},

pages = {106598},

abstract = {Inflammation has emerged as a prominent feature of bipolar disorder (BD) pathophysiology, drawing attention to brain barriers known to regulate immune-brain interactions. While perturbation of the blood-brain barrier has been reported in BD, the blood-cerebrospinal fluid (CSF) barrier formed largely by the choroid plexus (ChP) remains underexamined. To address this gap in knowledge, we used a multiplex array to measure cytokine protein abundance in postmortem ChP tissue from individuals with BD and unaffected controls, revealing elevated levels of CCL2 and SPP1, factors associated with monocyte and macrophage recruitment and activation. In contrast, expression of cytokines involved in tissue homeostasis, trophic support, and immune signaling, including OSM, IGF-1, CX3CL1, TGFB3, GDNF, LIF, BDNF, SCF, and FGFs, was reduced. Several cytokines, including CCL2 and PLGF, exhibited condition-specific divergent age trajectories. Bulk RNA sequencing of the same cohort revealed a modest set of differentially expressed genes, including transcripts associated with oxidative stress, mitochondrial function, and immune regulation that were upregulated in BD. Notably, the BD CSF biomarker NELL2 was downregulated in the ChP. Gene set enrichment analysis highlighted activation of inflammatory and cellular stress pathways, as well as reduced expression of junction-related gene programs. These findings suggest a shift in ChP function in BD characterized by increased pro-inflammatory signaling and reduced trophic and barrier-supportive activity. Together, these data identify the ChP as an active site of immune dysregulation in BD and support the broader notion of brain barrier dysfunction in mood disorder pathology.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid42427711,

title = {Multi-omics characterization of astrocyte subtypes reveals spatially coordinated astrocyte downregulation in depression},

author = {Haruka Mitsuhashi and Harish R Rao and Steffanie Amadei and Anjali Chawla and Maria Antonietta Davoli and Naguib Mechawar and Gustavo Turecki and Corina Nagy},

doi = {10.64898/2026.07.02.735636},

issn = {2692-8205},

year  = {2026},

date = {2026-07-01},

journal = {bioRxiv},

abstract = {Major depressive disorder (MDD) is a complex psychiatric disorder affecting millions of individuals worldwide. Astrocytes, which have been implicated in MDD by several studies, are the most abundant non-neuronal cells in the brain and play critical roles in synaptic regulation, blood-brain barrier maintenance, and immune modulation. While astrocytic molecular and morphological abnormalities are well-established features of MDD, these alterations have not been resolved within their spatial context. Here, we combine spatial transcriptomics with matched snRNA-seq and snATAC-seq datasets to spatially map molecularly distinct astrocyte subtypes and define their regional contributions to MDD pathology. This spatial context further enables the characterization of astrocyte interactions with neighboring cell populations, providing a more holistic assessment of how dysfunctional astrocytes influence local brain microenvironments and circuit function in MDD. We identified spatially localized astrocytic dysfunction in deep cortical layers of the MDD dlPFC, converging across transcriptomic, chromatin, and spatial modalities and centering on the PSAP-GPR37L1 signaling axis. Together, these findings identify astrocyte dysfunction as a key feature of MDD and demonstrate the value of spatially resolved molecular profiling for uncovering how altered astrocyte-neuron communication within deep cortical layers may contribute to disease pathology.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid42094851,

title = {Comprehensive analysis of cytokines in depression: independent data from patient plasma and post-mortem ventromedial prefrontal cortex},

author = {Reza Rahimian and Jonas Hagenberg and Claudia Belliveau and Rebecca Chen and Stephanie Théberge and Gohar Fakhfouri and Marina Wakid and Elisabeth Binder and Gustavo Turecki and Janine Knauer-Arloth and Naguib Mechawar},

doi = {10.1016/j.bbih.2026.101245},

issn = {2666-3546},

year  = {2026},

date = {2026-07-01},

journal = {Brain Behav Immun Health},

volume = {54},

pages = {101245},

abstract = {Preclinical and clinical evidence has implicated inflammation in the pathophysiology of depression. Abnormal cytokine levels in blood, cerebrospinal fluid, and post-mortem brain samples have been associated with depression. To our knowledge, however, a comprehensive analysis of cytokine protein levels in brain samples from patients with depression has yet to be conducted in major components of the limbic system such as the ventromedial prefrontal cortex (vmPFC). This region plays a crucial role in depression, impacting cognitive control, emotional regulation, and executive functions. In the current exploratory study, we performed a comprehensive profiling of 72 cytokines, chemokines and growth factors in well-characterized vmPFC samples from 34 depressed suicides and 14 matched sudden-death controls. A human antibody array (RayBio®, chemiluminescent detection) was used to measure all markers. In depressed suicide samples, no significant increase in any cytokine, chemokine or growth factor was detected compared to controls. In comparison, in an independent cohort we measured the levels of 43 inflammatory markers in plasma samples from 141 depressed living subjects and 36 controls using the Mesoscale Discovery V-plex assay. Our analyses indicated no significant difference in the levels of pro- or anti-inflammatory markers in the plasma of cases vs controls. We also conducted a detailed morphological analysis of Iba1-immunostained microglia in vmPFC gray matter samples from 28 depressed suicides and 13 healthy controls. The distributions of the various morphological phenotypes assessed were similar between groups, suggesting that microglia/macrophages do not display signs of morphological changes in the vmPFC of depressed suicides. Taken together, these complementary experiments do not provide evidence of depression-associated neuroinflammatory changes in the vmPFC, at least in the samples analyzed.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid42064576,

title = {Alterations of microRNAs across human and mouse limbic brain areas: molecular mechanisms and biological processes involved in major depressive disorder},

author = {Samantha Saleri and Moira Marizzoni and Patrizia Genini and Chiara Galbiati and Annamaria Cattaneo and Gustavo Turecki and Henning Grosskopf and Petra Steinacker and Markus Otto and Giulia Poggi and Christopher R Pryce and Naguib Mechawar and Nadia Cattane},

doi = {10.1016/j.ynstr.2026.100816},

issn = {2352-2895},

year  = {2026},

date = {2026-06-01},

journal = {Neurobiol Stress},

volume = {42},

pages = {100816},

abstract = {The etiology of major depressive disorder (MDD) is multifactorial with both genetic and environmental factors, such as adverse/stressful life events, contributing to risk. There is some evidence suggesting that microRNAs (miRNAs) mediate environmental-genetic interaction leading to the brain dysfunctions that underlie MDD. However, changes in miRNAs expression in human brain regions due to stress and associated with MDD are unclear. To increase the evidence in this regard, miRNA sequencing was performed on tissue samples of subgenual anterior cingulate cortex (sgACC) obtained from depressed patients and control subjects, as well on tissue samples of medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) from mice exposed to chronic social stress (CSS) and control animals. DESeq2 was applied to identify differentially expressed miRNAs (DEMs) and weighted co-expression network preservation analysis to uncover conserved molecular mechanisms between species. Finally, pathways obtained from DESeq2 and preservation analyses were overlapped to robustly identify MDD-related processes across bioinformatic approaches.Eighteen DEMs were identified in the human sgACC, 11 in the mPFC and 9 in the BLA of mice. The human sgACC DEMs were involved mainly in intracellular signaling and immune system-related pathways. The mouse mPFC and BLA DEMs were mainly involved in, respectively, intracellular signaling and nervous system functions. Preservation patterns between humans and mice indicated an over-representation of processes related to cellular signaling. Transcriptional regulation by MECP2 and Protein Kinase A signaling were the two pathways consistently altered across species, brain regions, and bioinformatic approaches. Although further studies are needed, they could represent a novel target for intervention strategies and confirm the dysregulation of intracellular signaling, immune, neuronal and synaptic functions in MDD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid42082796,

title = {Characterizing neuronal cell bodies in white matter tracts of the human brain},

author = {Drew VanderBerg and Kelly Perlman and Maria Antonietta Davoli and Gustavo Turecki and Naguib Mechawar},

doi = {10.1007/s00429-026-03112-w},

issn = {1863-2661},

year  = {2026},

date = {2026-05-01},

journal = {Brain Struct Funct},

volume = {231},

number = {5},

abstract = {Until the discovery of white matter neurons (WMN) in the 19th century, white matter (WM) was considered to be completely devoid of neuronal cell bodies. Despite evidence consistently showing neuronal soma within cortical WM and their purported implication in neuropsychiatric disorders, these neurons are understudied and have not been characterized in human long-range WM tracts. Using postmortem human brain tissue, we investigated the presence, densities and proportions of excitatory/inhibitory neurons in the uncinate fasciculus (UF) and corpus callosum (CC). We also investigated the ventromedial prefrontal cortex (vmPFC) to validate our methods by comparing our results with previously reported densities of neurons in cortical WM. To identify WMN, we employed fluorescence in situ hybridization with excitatory (SLC17A7) and inhibitory (GAD1) neuronal markers and subsequently validated these neurons at the protein level with NeuN immunohistochemistry. We found that the density of WMN in the vmPFC corresponded with previous independent estimates. The UF displayed a similar, though slightly lower density of WMN compared to the vmPFC, while the CC had a far lower density of WMN than both of these regions. Due to the higher-than-expected density of WMN in the UF, we validated the findings at a second location along the UF temporal segment and confirmed the presence of substantial numbers of WMN in this tract. This research constitutes the first ever validated observation of WMN in human long-range WM tracts, laying the foundation for future research on the phenotype and function of these neurons, and how they may be affected in brain disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid42162419,

title = {Dopamine drives persistent remodelling of the maternal brain},

author = {Jennifer C O'Chan and Giuseppina Di Salvo and Ashley M Cunningham and Sohini Dutta and Elizabeth Brindley and Benjamin H Weekley and Winnie Chen and Rasika R Iyer and Ethan Wan and Cindy Zhang and Naguib Mechawar and Gustavo Turecki and Ian Maze},

doi = {10.1038/s41586-026-10509-4},

issn = {1476-4687},

year  = {2026},

date = {2026-05-01},

journal = {Nature},

abstract = {Pregnancy and postpartum experiences represent transformative physiological states that impose lasting demands on the maternal body and brain, resulting in lifelong neural adaptations. However, the precise molecular mechanisms that drive these persistent alterations remain poorly understood. Here we used brain-wide transcriptomic profiling to define the molecular landscape of neuroplasticity induced by reproductive experience, identifying the dorsal hippocampal formation (dHF) as a key site of transcriptional remodelling. Combining single-cell RNA sequencing with a maternal-pup separation paradigm, we additionally found that chronic postpartum stress significantly disrupts dHF adaptations by altering dopamine dynamics, leading to changes in the dopamine-dependent histone post-translational modification, H3 dopaminylation, which causally mediates downstream alterations in gene expression and behaviour. In human dorsal subiculum, a brain structure within the dHF, we uncovered conserved patterns of parity-dependent alterations in H3 dopaminylation and transcription. We further established the sufficiency of dopamine modulation in regulating these adaptations via chemogenetic suppression of dopamine release into the dHF, which recapitulated key epigenomic and behavioural features of reproductive experience in virgin female mice. In sum, our findings establish dopamine as a central regulator of parity-induced neuroadaptations in humans and mice, revealing a fundamental transcriptional mechanism by which female reproductive experience remodels the brain to sustain long-term behavioural adaptations.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid42003427,

title = {A Comprehensive Characterization of the Phospholipid and Cholesterol Composition of the Uncinate Fasciculus in the Human Brain: Evidence of Age-Related Alterations},

author = {Kelly Perlman and Chuck T Chen and Mackenzie E Smith and John Kim and Gustavo Turecki and Richard P Bazinet and Naguib Mechawar},

doi = {10.1111/jnc.70428},

issn = {1471-4159},

year  = {2026},

date = {2026-04-01},

journal = {J Neurochem},

volume = {170},

number = {4},

pages = {e70428},

abstract = {The uncinate fasciculus (UF) is a long-range association fiber tract connecting the anterior temporal lobe with the orbitofrontal cortex and has been linked to a multitude of physiological and pathophysiological conditions such as aging, epilepsy, and the vulnerability to psychopathology posed by a history of childhood abuse (CA). Since the myelin sheath is highly enriched in lipids, changes in white matter (WM) microstructure observed via neuroimaging may reflect alterations in the myelin lipid profile. Given that the UF does not exist in rodents, its molecular properties are highly understudied. Therefore, we sought to quantify the phospholipid FA and cholesterol quantities of the human postmortem UF and evaluate any lipid-related or myelin-constituent gene/protein changes associated with age and history of CA. UF samples were analyzed from individuals with depression who died by suicide with (DS-CA) or without (DS) severe CA, and control individuals (CTRL), with an age span of 15 to 85 years. Phospholipids were separated by thin-layer chromatography; FAs and nonderivatized cholesterol were quantified by gas chromatography-flame ionization detection. The relative expression of myelin-constituent genes and proteins was measured by RT-qPCR and immunoblotting, respectively. We found no robust relationships between CA or depression and lipid measures or myelin-constituent gene/protein levels. In contrast, phospholipids showed pronounced age effects that differed by fraction, with an overall trend of monounsaturated FAs increasing and long-chain omega-6 polyunsaturated FAs decreasing with age. The expression of most myelin-constituent genes and proteins declined with age; PLP1 and MAG showed significant decreases. Therefore, changes in lipid composition and lipid-protein interactions likely contribute to age-related myelin deficits and may in part underlie age-associated cognitive decline.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid42027716,

title = {Ultrastructural analysis of human uncinate fasciculus with coherent anti-Stokes Raman spectroscopy},

author = {Kelly Perlman and Valérie Pineau Noël and Armand Collin and Justine Major and Murielle Mardenli and Sébastien Jerczynski and Maria Antonietta Davoli and Julien Cohen-Adad and Daniel Côté and Naguib Mechawar},

doi = {10.1117/1.BIOS.3.2.025002},

issn = {3005-4745},

year  = {2026},

date = {2026-04-01},

journal = {Biophotonics Discov},

volume = {3},

number = {2},

pages = {025002},

abstract = {SIGNIFICANCE: Characterizing the ultrastructure of myelin in the human brain is key to understanding the neurobiology of both health and disease. In postmortem human brain tissue, electron microscopy is often technically unfeasible due to poorer tissue quality.nnAIM: The uncinate fasciculus (UF) is a long-range white matter association tract that connects the anterior temporal lobe with the orbitofrontal cortex. The UF is not present in rodents yet is highly expanded in humans and nonhuman primates. As such, its molecular and ultrastructural properties are virtually unknown.nnAPPROACH: Here, we develop and validate a spectral-focusing coherent anti-Stokes Raman spectroscopy (sf-CARS) system coupled with a custom AxonDeepSeg segmentation model to characterize UF ultrastructure in the human postmortem brain (  ).nnRESULTS: We provide a proof of concept of this new methodological pipeline in the UF temporal segment and observe that the mean axon diameter detected is  and the mean myelin thickness is  . We also observe that the UF axons are thicker than those in the anterior cingulate cortex white matter.nnCONCLUSIONS: We detail and validate the full methodology, including tissue fixation and sectioning, sf-CARS acquisition settings, as well as the AxonDeepSeg deep learning model parameters, such that this pipeline can be utilized by others in the field.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41663375,

title = {Cerebellar astrocytic alterations in depression},

author = {Christa Hercher and Gina Abajian and Maria Antonietta Davoli and Gustavo Turecki and Naguib Mechawar},

doi = {10.1038/s41398-026-03866-1},

issn = {2158-3188},

year  = {2026},

date = {2026-02-01},

journal = {Transl Psychiatry},

volume = {16},

number = {1},

abstract = {Accumulating evidence suggests dysfunction of cerebellar-cerebral circuits in depression. However, the potential cellular and molecular alterations associated with depression in the cerebellum remain largely uncharacterized. While postmortem findings in the cerebral cortex indicate astrocyte dysregulation in depressed individuals who died by suicide (DS), the extent to which depression potentially alters cerebellar astrocytes is not well understood. In this study, two canonical astrocyte markers, glial fibrillary acidic protein (GFAP) and aldehyde Dehydrogenase-1 Family member L1 (ALDH1L1) were used to quantify cerebellar astrocyte subtypes, Bergmann glia (BG) in the Purkinje cell layer (PCL), velate astrocytes in the granule cell layer (GCL), and fibrous astrocytes in the white matter (WM). Purkinje cells (PCs) were also quantified due to their close association with BG. To assess potential dysregulation of astrocyte communication, we examined connexins, channel proteins essential in forming a functional network between astrocytes. Astrocytic connexins were visualized using single molecule in situ hybridization targeting connexin 30 (Cx30) and connexin 43 (Cx43), followed by immunolabeling for ALDH1L1. Our analysis revealed significant increases in ALDH1L1+ astrocyte densities in DS specific to the PCL compared to control individuals. Astrocytic connexins were significantly downregulated in DS, with Cx43 showing marked reductions in both PCL and GCL. Overall, our findings suggest that BG in the PCL and velate astrocytes in the GCL are particularly vulnerable in the depressive phenotype. Furthermore, this study supports previous findings in the cerebral cortex and extends astrocytic dysfunction to the cerebellum suggesting a widespread disruption of astrocyte-mediated communication across the brain in depression.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41501055,

title = {Disturbances of paraventricular thalamic nucleus neurons in bipolar disorder revealed by single-nucleus analysis},

author = {Masaki Nishioka and Mie Sakashita-Kubota and Kouichirou Iijima and Yukako Hasegawa and Mizuho Ishiwata and Kaito Takase and Ryuya Ichikawa and Naguib Mechawar and Gustavo Turecki and Tadafumi Kato},

doi = {10.1038/s41467-025-68094-5},

issn = {2041-1723},

year  = {2026},

date = {2026-01-01},

journal = {Nat Commun},

volume = {17},

number = {1},

pages = {1338},

abstract = {Bipolar disorder (BD) is a major global health burden, and its treatment challenges highlight the need for pathology-based therapeutic development. Emerging evidence suggests that the thalamus, particularly the paraventricular thalamic nucleus (PVT), is a key region in mood regulation. We performed single-nucleus RNA sequencing on 82 thalamic and cortical samples from 21 patients with BD and 20 controls to compare transcriptional pathology. PVT neurons showed the most striking abnormalities, including the largest number of differentially expressed genes and ~50% fewer cells in BD, whereas cortical alterations were comparatively modest. PVT neurons exhibited marked downregulation of synaptic and ion channel-related genes such as SHISA9, CACNA1C, and KCNQ3, which are linked to BD risk and serve as central nodes in downregulated networks. We also observed disrupted interactions between thalamic excitatory neurons and microglia. Overall, PVT neurons emerge as a central pathological substrate and a promising diagnostic and therapeutic target in BD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41168335,

title = {Pervasive neurovascular dysfunction in the ventromedial prefrontal cortex of female depressed suicides with a history of childhood abuse},

author = {Marina Wakid and Daniel Almeida and Ryan Denniston and Anjali Chawla and Zahia Aouabed and Maria Antonietta Davoli and Kristin Ellerbeck and Reza Rahimian and Volodymyr Yerko and Elena Leonova-Erko and Gustavo Turecki and Naguib Mechawar},

doi = {10.1038/s41380-025-03285-6},

issn = {1476-5578},

year  = {2025},

date = {2025-10-01},

journal = {Mol Psychiatry},

abstract = {Exposure to early life adversity (ELA) poses a significant global public health concern, with profound pathophysiological implications for affected individuals. Studies suggest that ELA contributes to endothelial dysfunction, bringing into question the functional integrity of the neurovascular unit in brain regions vulnerable to chronic stress. Despite the importance of the neurovasculature in maintaining normal brain physiology, human neurovascular cells remain poorly characterized, particularly with regard to their contributory role in ELA-associated pathophysiologies. In this study, we present the first comprehensive transcriptomic analysis of microvessels isolated from postmortem ventromedial prefrontal cortex samples from adult healthy controls (CTRL) and matched depressed suicides with histories of ELA. Our findings point to substantial differences between men and women, with the latter exhibiting widespread transcriptional changes at the neurovascular unit, including key vascular nodal regulators KLF2 and KLF4, alongside a broad downregulation of immune-related pathways. These results suggest that the neurovascular unit plays a larger role in the neurobiological consequences of ELA in women.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41108682,

title = {Protocol for antibody-based m6A sequencing of human postmortem brain tissues},

author = {Haruka Mitsuhashi and Naguib Mechawar and Corina Nagy and Gustavo Turecki},

doi = {10.1016/j.xpro.2025.104149},

issn = {2666-1667},

year  = {2025},

date = {2025-10-01},

journal = {STAR Protoc},

volume = {6},

number = {4},

pages = {104149},

abstract = {Here, we present an optimized N6-methyladenosine (m6A) immunoprecipitation sequencing for human postmortem brain tissue, building on previously established approaches. We describe steps for RNA extraction, RNA shearing, RNA immunoprecipitation, and library preparation. The protocol includes optimization data for each step, such as m6A profiles from total RNA versus poly(A) RNA as an input, a comparison of different commercial m6A antibodies, and immunoprecipitation with varying RNA/antibody ratios. This protocol allows reliable capture of m6A peaks from human postmortem brain tissue. For complete details on the use and execution of this protocol, please refer to Mitsuhashi et al..},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41131413,

title = {Characterization of Perineuronal Nets in the Human Cerebellum},

author = {Refilwe Mpai and Christa Hercher and Claudia Belliveau and Reza Rahimian and Jasmine Kotsiopoulos and Ally Huang and Gohar Fakhfouri and Maria Antonietta Davoli and Gustavo Turecki and Naguib Mechawar},

doi = {10.1007/s12311-025-01920-0},

issn = {1473-4230},

year  = {2025},

date = {2025-10-01},

journal = {Cerebellum},

volume = {24},

number = {6},

pages = {168},

abstract = {Perineuronal nets (PNNs) are condensed extracellular matrix structures that regulate synaptic plasticity and neuronal stability. While their distribution and function have been well characterized in rodents, PNNs remain largely understudied in the human cerebellum. Here, we provide an anatomical characterization of PNNs in the post-mortem human cerebellum and compare their distribution and cellular phenotypes with those in mouse and macaque cerebellum. Using immunofluorescence for both Wisteria floribunda lectin (WFL) and aggrecan, we observed that PNNs in humans were exclusively localized in the deep cerebellar nuclei (DCN), with no detectable labelling in cerebellar cortex. In contrast, both macaques and mice exhibited PNNs in the DCN and cortex (granule cell layer), with interspecies differences in density and marker co-localization. Combining immunolabeling with fluorescence in situ hybridization for SLC17A7, GAD1, and PVALB, we found that in human and mouse DCN, PNNs predominantly surrounded excitatory, parvalbumin-expressing neurons, whereas in macaques, PV expression was absent from PNN-enwrapped excitatory cells. These findings highlight both conserved and divergent features of cerebellar PNNs, providing novel insights into the potential functional roles of these structures in human cerebellar circuitry, with implications for understanding cerebellar plasticity and disease vulnerability.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41000899,

title = {Astrocytic glutamate regulation is shaped by adversity and glucocorticoid signalling},

author = {Dominic Kaul and Amber R Curry and Nathalie Gerstner and Anna S Fröhlich and Anthi C Krontira and Christina Kyrousi and Caine C Smith and Greg T Sutherland and Mirella Dottori and Michael J Ziller and Christos Chatzinakos and Nikolaos P Daskalakis and Silvia Cappello and Darina Czamara and Elisabeth B Binder and Cristiana Cruceanu and Janine Knauer-Arloth and Naguib Mechawar and Sibylle G Schwab and Lezanne Ooi and Natalie Matosin},

doi = {10.1101/2024.06.24.600362},

issn = {2692-8205},

year  = {2025},

date = {2025-09-01},

journal = {bioRxiv},

abstract = {Astrocytes are a brain cell type vulnerable to the effects of stress and the development of psychiatric-like phenotypes in animals, yet how this translates to humans is unclear. Here, we probed the diversity of ~145,000 total human cortical astrocytes with single nucleus and spatial transcriptomics, showing that human astrocytes comprise a molecularly and anatomically diverse cell population. In individuals with psychiatric disorders and high adversity exposure, we identified distinct alterations to glutamate-related synaptic functions, supported by histological quantification of >20,000 astrocytes. Early-life adversity exposure produced more pronounced cellular changes than adversity experienced later in life, and female cases displayed stronger transcriptomic associations than males with adversity exposure. Human pluripotent stem cell-derived astrocytes from both two- and three-dimensional models confirmed that glutamate signalling is directly impacted by glucocorticoid activation. Our findings highlight astrocytes as crucial players in how exposure to severe adversity raises risk to psychopathology and position them as strategic pharmacological targets for future intervention strategies.},

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 = {2025-05-01},

journal = {Int J Neuropsychopharmacol},

volume = {28},

number = {5},

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, we investigated the EV and bulk tissue protein profile from anterior cingulate cortex 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: Extracellular vesicles 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{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 = {2025-04-01},

journal = {Nat Neurosci},

volume = {28},

number = {4},

pages = {766--782},

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{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{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{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{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}

}