Biology subjects

Ramnauth, A. D.

Publications and source records attributed to Ramnauth, A. D..

5 recordsLinked to original sources

bioRxiv2025

spaTransfer: transfer learning for single-cell and spatialtranscriptomics data using non-negative matrix factorization

Recent advances in spatially-resolved transcriptomics have enabled profiling of gene expression in a spatial context, which has led to the generation of large-scale single-cell and spatial atlases with computationally-derived cell type or spatial domain labels. An increasingly important task with these data has become the transfer of cell type or spatial domain annotations from a given reference (or source) atlas into a new target tissue or sample. The reference and target datasets could be at different resolutions or measured on different experimental platforms. Here, we present a method to perform cross-platform transfer learning that takes as input single-cell or spatial domain labels from a reference atlas or dataset and transfers the labels to a target dataset at a similar or different resolution. Specifically, we use non-negative matrix factorization (NMF) on the reference data to identify factors associated with labels of interest and project these factors into the target dataset to label each new observation. We use a multinomial model with the factors as covariates and labels as the response to predict labels in the target dataset. In contrast to existing approaches, the advantage of our approach is interpretability, without compromising on accuracy. We demonstrate the performance of the method in two human brain tissues and show that our model identifies spatially coherent domains in the target datasets with concordance of marker gene expression. We implement spaTransfer in open-source software as an R package (github.com/cindyfang70/spaTransfer).

bioinformatics↗

bioRxiv2025

Spatio-molecular gene expression reflects dorsal anterior cingulate cortex structure and function in the human brain

In the human brain, the dorsal anterior cingulate cortex (dACC) plays key roles in various components of cognitive control, and is particularly relevant for reward processing and conflict monitoring. The dACC regulates expression of fear and pain, and its dysfunction is implicated in a number of neuropsychiatric disorders. Compared to more recently specialized neocortical areas, such as the dorsolateral prefrontal cortex (dlPFC), the dACC is evolutionarily older. The regions agranular structure, and other evolutionary specializations, such as the presence of von Economo neurons (VENs), contribute to its specialized roles in cognitive and emotional processing. Here, we generated paired spatially-resolved transcriptomics (SRT) and single-nucleus RNA-sequencing (snRNA-seq) data from adjacent tissue sections of the dACC in ten adult neurotypical donors to define molecular profiles for dACC cell types and spatial domains. Using non-negative matrix factorization (NMF), we integrated these data by identifying gene expression patterns within the snRNA-seq data, which were projected onto the SRT data to infer the spatial localization. Combining these data with publicly available resources, we revealed insights about molecular profiles, spatial topography, enrichment of disease risk, and putative connectivity of spatially-localized dACC cell types, including VENs. Utilizing published dlPFC snRNA-seq and SRT data collected in the same neurotypical brain donors used here, we deployed cross-region comparison analyses between dACC and dlPFC to understand spatio-molecular specializations and laminar organization across human brain evolution. To make this comprehensive molecular resource accessible to the scientific community, we made both raw and processed data freely available, including through interactive web applications.

neuroscience↗

bioRxiv2024

An integrated single-nucleus and spatial transcriptomics atlas reveals the molecular landscape of the human hippocampus

The hippocampus contains many unique cell types, which serve the structures specialized functions, including learning, memory and cognition. These cells have distinct spatial organization, morphology, physiology, and connectivity, highlighting the importance of transcriptome-wide profiling strategies that retain cytoarchitectural organization. Here, we generated spatially-resolved transcriptomics (SRT) and single-nucleus RNA-sequencing (snRNA-seq) data from adjacent tissue sections of the anterior human hippocampus in ten adult neurotypical donors to define molecular profiles for hippocampal cell types and spatial domains. Using non-negative matrix factorization (NMF) and label transfer, we integrated these data by defining gene expression patterns within the snRNA-seq data and inferring their expression in the SRT data. We identified NMF patterns that captured transcriptional variation across neuronal cell types and indicated that the response of excitatory and inhibitory postsynaptic specializations were prioritized in different SRT spatial domains. We used the NMF and label transfer approach to leverage existing rodent datasets, identifying patterns of activity-dependent transcription and subpopulations of dentate gyrus granule cells in our SRT dataset that may be predisposed to participate in learning and memory ensembles. Finally, we characterized the spatial organization of NMF patterns corresponding to non-cornu ammonis pyramidal neurons and identified snRNA-seq clusters mapping to distinct regions of the retrohippocampus, to three subiculum layers, and to a population of presubiculum neurons. To make this comprehensive molecular atlas accessible to the scientific community, both raw and processed data are freely available, including through interactive web applications.

neuroscience↗

bioRxiv2023

Spatially-resolved transcriptomics of human dentate gyrus across postnatal lifespan reveals heterogeneity in markers for proliferation, extracellular matrix, and neuroinflammation

The dentate gyrus of the hippocampus is important for many cognitive functions, including learning, memory, and mood. Here, we investigated age-associated changes in transcriptome-wide spatial gene expression in the human dentate gyrus across the lifespan. Genes associated with neurogenesis and the extracellular matrix were enriched in infants, while gene markers of inhibitory neurons and cell proliferation showed increases and decreases in post-infancy, respectively. While we did not find evidence for neural proliferation post-infancy, we did identify molecular signatures supporting protracted maturation of granule cells. We also identified a wide-spread hippocampal aging signature and an age-associated increase in genes related to neuroinflammation. Our findings suggest major changes to the putative neurogenic niche after infancy and identify molecular foci of brain aging in glial and neuropil enriched tissue.

neuroscience↗

bioRxiv2021

Induction of Bdnf from promoter I following electroconvulsive seizures contributes to structural plasticity in neurons of the piriform cortex

The efficacy of electroconvulsive therapy (ECT) as a treatment for psychiatric disorders, including major depressive disorder (MDD) is hypothesized to depend on induction of molecular and cellular events that trigger structural plasticity in neurons. Electroconvulsive seizures (ECS) in animal models can help to inform our understanding of how electroconvulsive therapy (ECT) impacts the brain. ECS induces structural plasticity in neuronal dendrites in many brain regions, including the piriform cortex, a highly epileptogenic region that has also been implicated in depression. ECS-induced structural plasticity is associated with differential expression of unique isoforms encoding the neurotrophin, brain-derived neurotrophic factor (BDNF), but the functional significance of these transcripts in dendritic plasticity is not clear. Here, we demonstrate that different Bdnf isoforms are expressed non-stochastically across neurons of the piriform cortex following ECS. Specifically, cells expressing Bdnf exon 1-containing transcripts show a unique spatial recruitment pattern in response to ECS. We further demonstrate that Bdnf Ex1 expression in these cells is necessary for ECS-induced dendritic spine plasticity.

neuroscience↗