Biology subjects

Maitra, M.

Publications and source records attributed to Maitra, M..

7 recordsLinked to original sources

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↗

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↗

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↗

bioRxiv2021

Genotype and age influence cortical-FKBP5 at multiple regulatory and single-cell-type levels in severe psychiatric disorders

Identification and characterisation of novel targets for treatment is a priority in the field of psychiatry. FKBP5 is a gene with decades of evidence suggesting its pathogenic role in a subset of psychiatric patients, with potential to be leveraged as a therapeutic target for these individuals. While it is widely reported that FKBP5/FKBP51 mRNA/protein (FKBP5/1) expression is impacted by psychiatric disease state, risk genotype and age, it is not known in which cell-types and sub-anatomical areas of the human brain this occurs. This knowledge is critical to propel FKBP5/1-targeted treatment development. Here, we performed an extensive, large-scale postmortem study (n=1024) of FKBP5/1 examining prefrontal cortex (BA9, BA11, BA24) derived from subjects that lived with schizophrenia, major depression or bipolar disorder. With an extensive battery of RNA (bulk RNA sequencing, single-nucleus RNA sequencing, microarray, qPCR, RNAscope) and protein (immunoblot, immunohistochemistry) analysis approaches, we thoroughly investigated the effects of disease-state, aging and genotype on cortical FKBP5/1 expression including in a cell-type specific manner. We identified consistently heightened FKBP5/1 levels in psychopathology and with age, but not genotype, with these effects strongest in schizophrenia. Using single-nucleus RNA sequencing (snRNAseq) and targeted histology, we established that these disease- and aging-effects on FKBP5/1 expression were most pronounced in excitatory supragranular neurons. We then found that this increase in FKBP5 levels likely impacts on synaptic plasticity, as FKBP5 gex levels strongly and inversely correlated with dendritic mushroom spine density and brain-derived neurotrophic factor (BDNF) levels in supragranular neurons. These findings pinpoint a novel cellular and molecular mechanism that has significant potential to open a new avenue of FKBP51 drug development to treat cognitive symptoms in psychiatric disorders.

neuroscience↗

bioRxiv2020

Child abuse associates with increased recruitment of perineuronal nets in the ventromedial prefrontal cortex: evidence for an implication of oligodendrocyte progenitor cells

Child abuse (CA) is a strong predictor of psychopathologies and suicide, altering normal trajectories of brain development in areas closely linked to emotional responses such as the prefrontal cortex (PFC). Yet, the cellular underpinnings of these enduring effects are unclear. Childhood and adolescence are marked by the protracted formation of perineuronal nets (PNNs), which orchestrate the closure of developmental windows of cortical plasticity by regulating the functional integration of parvalbumin interneurons (PV) into neuronal circuits. Using well-characterized post-mortem brain samples, we show that a history of CA is specifically associated with increased densities and morphological complexity of WFL-labeled PNNs in the ventromedial PFC (BA11/12), possibly suggesting increased recruitment and maturation of PNNs. Through single-nucleus sequencing and fluorescent in-situ hybridization, we found that the expression of canonical components of PNNs is enriched in oligodendrocyte progenitor cells (OPCs), and that they are upregulated in CA victims. These correlational findings suggest that early-life adversity may lead to persistent patterns of maladaptive behaviors by reducing the neuroplasticity of cortical circuits through the enhancement of developmental OPC-mediated PNN formation.

neuroscience↗

bioRxiv2020

Deep feature extraction of single-cell transcriptomes by generative adversarial network

MotivationSingle-cell RNA-sequencing (scRNA-seq) has opened the opportunities to dissect the heterogeneous cellular composition and interrogate the cell-type-specific gene expression patterns across diverse conditions. However, batch effects such as laboratory conditions and individual-variability hinder their usage in cross-condition design. ResultsWe present single-cell Generative Adversarial Network (scGAN). Our main contribution is to introduce an adversarial network to predict batch effects using the embeddings from the variational autoencoder network, which does not only need to maximize the Negative Binomial data likelihood of the raw scRNA-seq counts but also minimize the correlation between the latent embeddings and the batch effects. We demonstrate scGAN on three public scRNA-seq datasets and show that our method confers superior performance over the state-of-the-art methods in forming clusters of known cell types and identifying known psychiatric genes that are associated with major depressive disorder. AvailabilityThe code is available at https://github.com/li-lab-mcgill/singlecell-deepfeature Contactyueli@cs.mcgill.ca

bioinformatics↗

bioRxiv2018

Single-nucleus RNA sequencing shows convergent evidence from different cell types for altered synaptic plasticity in major depressive disorder.

Major depressive disorder (MDD) is a complex illness that involves the interaction of different brain systems, pathways, and cell types. Past molecular studies of MDD relied on cellular homogenates of post-mortem brain tissue, making it impossible to determine gene expression changes within individual cells. Using single-cell transcriptomics, we examined almost 80,000 nuclei from the dorsolateral prefrontal cortex of individuals with MDD and healthy controls. Our analyses identified 26 distinct cellular clusters, and over 60% of these showed transcriptional differences between groups. Specifically, 96 genes were differentially expressed, the majority of which were downregulated. Convergent evidence from our analyses, including gene expression, differential correlation, and gene ontology implicated dysregulation of synaptic plasticity in the etiopathogenesis of MDD. Our results show that this high-resolution approach can reveal previously undetectable changes in specific cell types in the context of complex phenotypes and heterogeneous tissues.

neuroscience↗