Biology subjects

Nagy, C.

Publications and source records attributed to Nagy, C..

At least 19 recordsLinked to original sources

bioRxiv2026

Neonatal Delivery of Exon Skipping Therapeutics Maximizes Brain Dystrophin Rescue in the Mdx52 Mouse Model of Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, resulting in the loss of dystrophin expression. Beyond progressive muscle degeneration, nearly half of patients exhibit cognitive and behavioral impairments, highlighting the need for effective central nervous system (CNS) therapies. In this study, we investigated whether neonatal delivery could maximize brain dystrophin rescue in mdx52 mice using exon 51 skipping strategies. We compared systemic and intracerebroventricular (ICV) delivery of an antisense oligonucleotide (ASO-51) and an AAV9-mediated U7snRNA approach (scAAV9-U7-Ex51), administered neonatally. Neonatal intravenous ASO-51 induced widespread but transient exon skipping, resulting in limited brain dystrophin restoration. ICV administration markedly increased CNS exon skipping but did not overcome the limited persistence of ASO, leading to progressive loss of exon skipping and dystrophin rescue. In contrast, neonatal ICV delivery of scAAV9-U7-Ex51 achieved robust, widespread, and sustained exon 51 skipping throughout the brain, including the hippocampus, cortex, and cerebellum, resulting in 20-50% restoration of Dp427 expression. These findings demonstrate that early CNS-directed delivery enhances brain dystrophin restoration and establish AAV-U7-mediated exon skipping as a promising strategy for addressing CNS comorbidities in DMD.

neuroscience↗

bioRxiv2026

Multi-omics characterization of astrocyte subtypes reveals spatially coordinated astrocyte downregulation in depression

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.

neuroscience↗

bioRxiv2026

Flexible belief updating drives the childhood advantage in statistical learning

Children often outperform adults in probabilistic statistical learning tasks, yet the mechanisms underlying this developmental advantage remain poorly understood. Here, we used eye-tracking measures of belief updating to examine how children and adults acquire and update predictions in a probabilistic sequence-learning task. Using the standard (oculomotor) reaction time measure, children showed stronger statistical learning than adults, replicating previous behavioral findings while revealing a more detailed profile of developmental differences in statistical learning. Critically, children updated their predictions more frequently: they were less likely to repeat previous predictions and more likely to shift their expectations in response to new input. Adults, in contrast, showed greater persistence, tending to maintain prior predictions even when those predictions were inconsistent with the underlying statistical structure. Despite these pronounced differences in updating behavior, the processing and use of prediction errors were remarkably similar across age groups. These findings indicate that developmental differences in statistical learning do not primarily arise from how prediction errors are computed, but rather from how prior beliefs and incoming information are weighted during belief updating. Childrens enhanced learning may therefore reflect reduced reliance on stable priors and greater sensitivity to current sensory evidence, supporting a more exploratory learning strategy. Adults, by contrast, appear to favor an exploitative strategy that stabilizes existing predictions but reduces flexibility in probabilistic environments. More broadly, the results suggest that developmental changes in statistical learning may reflect age-related differences in how readily learners revise their predictions in response to incoming evidence. By integrating sensitive oculomotor measures with analyses that probe the mechanisms underlying belief updating, the present study provides a more fine-grained account of how predictive learning changes across development and offers a framework for reconciling previously inconsistent developmental findings in statistical learning.

neuroscience↗

bioRxiv2026

Sex-specific hormone-sensitive regulatory architecture in adolescence as a scaffold for depression vulnerability

Adolescence is a critical developmental period during which sex differences in depression risk emerge, yet the underlying molecular mechanisms remain unclear. Here, we integrated longitudinal transcriptomic, epigenomic, and gene regulatory network analyses to characterize sex-specific regulatory dynamics of the brain across adolescence under normative conditions and elucidate how baseline molecular differences may shape later vulnerability. We observed that immediate early genes exhibited the strongest sex-biased signals, with males and females showing opposing developmental trajectories, suggesting a role in sex-specific stress-responsive programs. Across analyses, a consistent pattern emerged: males showed stronger activity-dependent neuronal signatures, whereas females showed stronger stress- and immune-related signatures. Extending these findings to a disease context using single-nucleus chromatin accessibility data, we identified hormone-responsive regulatory elements enriched in depression-associated regions, with sex- and cell type-specific links to genetic risk. Grounded in established models of sex-specific stress responses, these findings offer a developmental regulatory framework for understanding the differential presentation of, and vulnerability to, depression.

genomics↗

bioRxiv2026

A multimodal characterization of the human uncinate fasciculus

The uncinate fasciculus (UF) is a hook-shaped long-range association white matter tract that serves to bidirectionally transmit information between the anterior temporal lobe and the orbitofrontal cortex. Neuroimaging studies have suggested that changes in UF microstructure are involved in the neurobiological sequalae of childhood abuse (CA). Given that the UF is not present in rodents, it is vastly understudied with no cellular and molecular information available. To this end, we aimed to perform a multimodal characterization of the UF between individuals diagnosed with depression who died by suicide with (DS-CA) and without a history of severe CA (DS) and psychiatrically healthy individuals (CTRL). Fresh frozen UF tissue was obtained from the Douglas Bell-Canada Brain Bank, with phenotypic information collected via psychological autopsy. Immunohistochemistry with PDGFR and NogoA was used to label oligodendrocyte precursor cell (OPC) and oligodendrocyte (OL), respectively, and stereology was performed to ascertain cell density and soma volume. Single nucleus RNA sequencing (snRNAseq) was used to generate a transcriptomic survey of the cell types found in the UF. Finally, spectral focusing Coherent Anti-Stokes Raman Scattering (sf-CARS) microscopy was employed in tandem with a custom AxonDeepSeg segmentation model to measure axon diameter, myelin thickness, and g-ratio. No group differences were observed in histology or ultrastructure metrics, but nearly 50 differentially expressed genes (DEG) were identified between groups. Interestingly NECTIN3, the top DEG downregulated in OL1 and OL3 of DS-CA, is a computationally predicted target of the microRNA MIR646, the host gene of which was significantly downregulated in multiple cell types in DS-CA. Age-associated changes were pronounced and observed in all modalities, including an age-related increase in OL density, extensive changes in glial gene expression, as well as decreases in axon diameter and g-ratio. This study serves as a foundational resource on the molecular and cellular properties of the human UF. Our results suggest that observable myelin-related traces of depression or CA are limited in the UF and highlights the need for future research on the cellular and molecular properties of white matter tracts during aging.

neuroscience↗

bioRxiv2026

A glucocorticoid-responsive polygenic signature in the anterior cingulate cortex moderates the association of early-life adversity and vulnerability for depression

Stress exposure is a major risk factor for psychopathology, yet how stress mediators shape long-term psychiatric vulnerability in humans remains unclear. Glucocorticoids, central effectors of the stress response, regulate gene expression through tissue-specific transcriptional programs, suggesting that glucocorticoid-responsive networks may shape sensitivity to adversity. Using RNA-sequencing following chronic glucocorticoid exposure in a non-human primate model, we identified a gene co-expression network specific to the anterior cingulate cortex (ACC) that was highly preserved across human post-mortem brain datasets relevant to depression. We derived an expression-based polygenic score (ePGS) reflecting genetic variation in network activity and tested its interaction with adversity in the UK Biobank. The ACC-specific glucocorticoid-responsive ePGS moderated the association between adversity and depressive symptoms in adult females, with the strongest effects for early-life adversity. Network genes were enriched for neurodevelopmental processes and showed stronger co-expression during childhood, highlighting a developmentally sensitive, region-specific mechanism linking stress exposure to depression risk.

neuroscience↗

bioRxiv2025

Whole-Brain Cell-Cell Interaction Axes Explaining Tissue Vulnerability Across the Neurodegenerative Spectrum

Disrupted cell-cell communication represents a fundamental mechanism underlying neurodegeneration, yet how specific intercellular signaling patterns relate to regional brain vulnerability remains poorly understood. Here, we map whole-brain intercellular interaction networks and their spatial correspondence with tissue damage across 13 neurodegenerative conditions, including early- and late-onset Alzheimers disease, presenilin-1 mutations, clinical and pathological subtypes of frontotemporal lobar degeneration, Parkinsons disease, dementia with Lewy bodies, and amyotrophic lateral sclerosis. By integrating multiregional single-nucleus and bulk RNA-seq data with curated cell-cell interaction databases and structural MRI, we reconstruct over 1,000 whole-brain maps of ligand-receptor interactions and quantify their associations with regional atrophy patterns. Multivariate analysis identifies three dominant axes of intercellular communication that explain regional vulnerability to neurodegeneration. Notably, the first axis involves neuron-astrocyte-microglia interactions, explaining atrophy patterns shared by frontotemporal lobar degeneration and Alzheimers disease subtypes. Two complementary axes involving neurons, endothelial cells, and astrocytes explain patterns specific to mutations in PS1 and Parkinsons disease. Importantly, validation in an independent post-mortem cohort (N = 375) confirms that late-onset Alzheimers disease-associated cell-cell interactions predict observed frontal cortex atrophy. These results establish a systematic framework linking local intercellular communication networks to spatial patterns of neurodegeneration, revealing both shared and disease-specific molecular pathways that drive regional brain vulnerability and identifying cellular interaction targets for precision therapeutic interventions.

neuroscience↗

bioRxiv2025

A post-mortem investigation of the locus coeruleus- noradrenergic system in resilience to childhood abuse

Childhood abuse (CA) is one of the strongest lifetime predictors of major depressive disorder (MDD) and suicide. However, some individuals exposed to CA are resilient, avoiding the development of psychopathology. Recently, the locus coeruleus-noradrenergic (LC-NE) system has been involved in resilience following stressful events at adulthood. We investigated how a history of CA affects the integrity of the LC-NE system at the molecular and cellular level in human post-mortem brain samples of depressed suicides, and whether differential neurobiological mechanisms can be revealed in resilient individuals. Anatomical analysis revealed that CA-induced MDD and suicide is associated with decrease in LC-NE neurons density. RNA sequencing of laser captured LC-NE neurons highlighted differentially expressed genes, principally in the RES-CA group. Resilience to CA involves specific neurobiological adaptations in the LC-NE system that potentially protect against the loss of LC-NE neurons and the negative long-term outcome of CA-induced depression and suicide. Our results provide insights into potential therapeutic targets for preventing or treating CA-induced MDD.

neuroscience↗

bioRxiv2024

Specific Bacterial Taxa and Their Metabolite, DHPS, Linked to Alzheimers Disease, Parkinsons Disease, and Amyotrophic Lateral Sclerosis.

Neurodegenerative diseases (NDDs) are multifactorial disorders frequently associated with gut dysbiosis, oxidative stress, and inflammation; however, the pathophysiological mechanisms remain poorly understood. We investigated bacterial and metabolic dyshomeostasis in the gut microbiome associated with early disease stages across three NDDs, amyotrophic lateral sclerosis (ALS), Alzheimers Disease (AD), Parkinsons Disease (PD), and healthy controls (HC) and discovered a previously unrecognized link between a microbial-derived metabolite with an unknown role in human physiology, 2,3-dihydroxypropane-1-sulfonate (DHPS), and NDDs. DHPS was downregulated in AD, ALS, and PD, while Eubacterium and Desulfovibrio, capable of metabolizing this metabolite,1-4 were increased in all disease cohorts. Additionally, select taxa within the Clostridia class had strong negative correlations to DHPS suggesting a potential role in DHPS metabolism. Hydrogen sulfide is a catabolic product of DHPS,1,5 and hydrogen sulfide promotes inflammation,6-8 oxidative stress,9 mitochondrial damage,10 and gut dysbiosis,2,11 known hallmarks of NDD. These findings suggest that cryptic sulfur metabolism via DHPS is a missing link in our current understanding of NDD onset and progression. To the best of our knowledge, we are the first to provide evidence of a conserved gut-brain axis linkage of specific bacterial taxa and their metabolism of DHPS shared by three neurodegenerative diseases.

neuroscience↗

bioRxiv2023

Efficient Multiplexing of Pollinator Metabarcodes Using Oxford Nanopore MinION Sequencing: Insights for Meadow Management from Floral Environmental DNA

Many pollinating species are experiencing declines globally, making effective, fast, and portable pollinator monitoring methods more important than ever before. Pollinators can leave DNA on the flowers they visit, and metabarcoding of these environmental DNA (eDNA) traces provides an opportunity to detect the presence of flower visitors. This study introduces an efficient, cost-effective workflow for utilizing DNA barcoding to monitor biodiversity through environmental DNA (eDNA) left on flowers from pollinators, employing the portable MinION and Nanopore sequencing. The developed method employs multiplexing with dual molecular tags on universal cytochrome oxidase 1 (COI) barcode primers. We used this approach to compare the arthropod diversity present in three meadows with different vegetation at three time points during the flowering season. The utility of eDNA metabarcoding in investigating pollinator biodiversity and interactions is highlighted through our results, revealing the presence and interactions of 65 species from 30 families. We multiplexed individual eDNA samples from hundreds of flowers and found plant-pollinator dynamics that showed differences in species richness between sampling times and meadow diversity. Comparative analyses with conventional methods showed eDNA metabarcodings ability to identify diverse species and ecological interactions compared to field sampling. While some DNA likely came from eggs or microscopic insects difficult to remove from flowers, traces of eDNA from various arthropods on multiple plant species confirmed the methods applicability, promising robust ecological monitoring and research potential in the wake of global pollinator declines. This is the first reported use of MinION based nanopore sequencing to detect arthropod species from eDNA samples collected from flowers using the described affordable multiplexing method.

ecology↗

bioRxiv2023

Proteomic evidence of astrocytic dysfunction in the olfactory bulb of depressed suicides

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.

neuroscience↗

bioRxiv2023

Differential Chromatin Architecture and Risk Variants in Deep Layer Excitatory Neurons and Grey Matter Microglia Contribute to Major Depressive Disorder

Major depressive disorder (MDD) associated genetic variants reside primarily in the non-coding, regulatory genome. Here we investigate genome-wide regulatory differences and putative gene-regulatory effects of disease risk-variants by examining chromatin accessibility combined with single-cell gene-expression profiles in over 200,000 cells from the dorsolateral prefrontal cortex (DLPFC) of 84 individuals with MDD and neurotypical controls. MDD-associated accessibility alterations were prominent in deep-layer excitatory neurons characterized by transcription factor (TF) motif accessibility and binding of nuclear receptor (NR)4A2, an activity-dependent TF responsive to pathological stress. The same neurons were significantly enriched for MDD-associated genetic variation disrupting cis-regulatory sites and TF binding associated with genes involved in synaptic communication. Furthermore, a grey matter microglial cluster exhibited differentially closed chromatin in MDD affecting binding sites bound by TFs known to regulate immune homeostasis. In summary, our study points to specific cell types and regulatory mechanisms whereby genetic variation may increase predisposition to MDD.

genomics↗

bioRxiv2023

Spatial transcriptomic analysis of adult hippocampal neurogenesis in the human brain

Using spatial transcriptomics and FISH, we detected very few cells expressing neural stem cell- and proliferation-specific genes in the human dentate gyrus (DG) from childhood to middle age. However, we observed at all ages a significant number of DG cells expressing the immature neuronal marker DCX. Across ages, the majority of these cells displayed an inhibitory phenotype, while the remainder were non-committed or excitatory in nature.

neuroscience↗

bioRxiv2022

Expression of substance P, NPY and their Receptors Is Altered in Major Depression

BACKGROUNDMajor 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, including substance P(SP)/tachykinin, neuropeptide Y(NPY) and their G protein-coupled receptors are involved in mood regulation. METHODSWe assessed the transcript levels (qPCR) of SP/tachykinin and NPY systems in five regions from postmortem brains of male and female depressed subjects who committed suicide (DSS) and controls: dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), the dorsal raphe nucleus (DRN), locus coeruleus (LC) and medullary raphe nuclei (MRN). We also analysed human LC neurons isolated using LCM with Smart-seq2 RNA sequencing. RESULTSTranscripts for all nine members were detected in male and female controls with marked regional variations of the raw CT values and with the highest levels for several tachykinin and tachykinin receptor transcripts in the DRN and for NPY and NPYR transcripts in the PFC regions. Significant sex differences for controls were recorded only in the DRN (NPYR2 >in females) and LC (TAC3 and NPY >in females). Elevated expression in DSS was recorded in (i) DLPFC for SP, TAC and TAC3 in females, SP in males, and NPYR1 in both sexes; and (ii) LC for all tachykinin family transcripts in females, SP, TACR1 and TACR3 in males, NPY in both sexes, and NPYR1 in males. CONCLUSIONSThe selective perturbation of neuropeptide systems in MDD patients may assist in the search for novel treatment strategies for subjects afflicted by this grave disorder.

neuroscience↗

bioRxiv2022

Multi-omic modeling of antidepressant response implicates dynamic immune and inflammatory changes in individuals who respond to treatment

Major depressive disorder (MDD) is a leading cause of disability worldwide, and is commonly treated with antidepressant drugs (AD). Although effective, many patients fail to respond to AD treatment, and accordingly identifying factors that can predict AD response would greatly improve treatment outcomes. In this study, we developed a machine learning tool to integrate multi-omic datasets (gene expression, DNA methylation, and genotyping) to identify biomarker profiles associated with AD response in a cohort of individuals with MDD. To address this rich multi-omic dataset with high dimensional features, we developed integrative Geneset-Embedded non-negative Matrix factorization (iGEM), a non-negative matrix factorization (NMF) based model, supplemented with auxiliary information regarding genesets and gene-methylation relationships. Using our model, we identified a number of meta-phenotypes which were related to AD response. By integrating geneset information into the model, we were able to relate these meta-phenotypes to biological processes, including immune and inflammatory functions. This represents both biomarkers to predict response, as well as potential new treatment targets. Our method is applicable to other diseases with multi-omic data, and the software is open source and available on Github (https://github.com/li-lab-mcgill/iGEM).

bioinformatics↗

bioRxiv2022

Cell type specific transcriptomic differences in depression show similar patterns between males and females but implicate distinct cell types and genes

Major depressive disorder (MDD) is a common, heterogenous, and potentially serious psychiatric illness. Diverse brain cell types have been implicated in MDD etiology. Significant sexual differences exist in MDD clinical presentation and outcome, and recent evidence suggests different molecular bases for male and female MDD. We evaluated over 160,000 nuclei from 71 female and male donors, leveraging new and pre-existing single-nucleus RNA-sequencing data from the dorsolateral prefrontal cortex. Cell type specific transcriptome-wide threshold-free MDD-associated gene expression patterns were similar between the sexes, but significant differentially expressed genes (DEGs) diverged. Among 7 broad cell types and 41 clusters evaluated, microglia and parvalbumin interneurons contributed the most DEGs in females, while deep layer excitatory neurons, astrocytes, and oligodendrocyte precursors were the major contributors in males. Further, the Mic1 cluster with 38% of female DEGs and the ExN10_L46 cluster with 53% of male DEGs, stood out in the meta-analysis of both sexes.

neuroscience↗

bioRxiv2022

Coyotes in New York city carry variable dog genomic ancestry and influence their interactions with humans

Coyotes are ubiquitous on the North American landscape as a result of their recent expansion across the continent. They have been documented in the heart of some of the most urbanized cities, such as Chicago, Los Angeles, and New York City. Here, we explored the genomic composition of coyotes in the New York metropolitan area to investigate if genomic demography and admixture differs from expected for urban-dwelling canids. We identified moderate-to-high estimates of relatedness among coyotes living in Queens and adjacent neighborhoods, suggestive of a relatively small population. Although we found low background levels of domestic dog ancestry across most coyotes in our sample, we identified a male suspected to be a first-generation coyote-dog hybrid, as well as his two putative backcrossed offspring that carried approximately 25% dog ancestry. The male coyote-dog hybrid and one backcrossed offspring each carried two mutations that are known to increase human-directed hypersociability in dogs and gray wolves. An additional, unrelated coyote with little dog ancestry also carries two of these mutations. These genetic patterns suggest that gene flow from domestic dogs may become an increasingly important consideration as coyotes continue to inhabit metropolitan regions.

evolutionary biology↗

bioRxiv2021

Neuron-derived extracellular vesicles extracted from plasma show altered size and miRNA cargo as a function of antidepressant drug response

Previous work has demonstrated that microRNAs (miRNAs) change as a function of antidepressant treatment (ADT) response. However, it is unclear how representative these peripherally detected miRNA changes are to those occurring in the brain. This study aimed to use peripherally extracted neuron-derived extracellular vesicles (NDEVs) to circumvent these limitations and investigate neuronal miRNA changes associated with antidepressant response. Samples were collected at two time points (baseline and after 8 weeks of follow-up) from depressed patients who responded (N=20) and did not respond (N=20) to escitalopram treatment, as well as controls (N=20). Total extracellular vesicles (EVs) were extracted from plasma, and then further enriched for NDEVs by immunoprecipitation with L1CAM. EV size was measured using tunable resistive pulse sensing, and NDEV miRNA cargo was extracted and sequenced. Subsequently, studies in cell lines and postmortem tissue were conducted. Characterization of NDEVs revealed they were smaller than other EVs isolated from plasma (p<0.0001), had brain-specific neuronal markers, and contained miRNAs enriched for brain functions (p<0.0001) Furthermore, NDEVs from depressed patients were smaller than controls (p<0.05), and NDEV size increased with ADT response (p<0.01). Finally, changes in NDEV cargo, specifically changes in miR-21-5p, miR-30d-5p and miR-486-5p together (p<0.01), were associated with ADT response. Targets of these three miRNAs were altered in brain tissue from depressed individuals (p<0.05). Together, this study indicates that changes in peripherally isolated NDEVs can act as both a clinically accessible and informative biomarker of ADT response specifically through size and cargo.

neuroscience↗