Spatiotemporal analysis of gene expression in the human dentate gyrus reveals age-associated changes in cellular maturation and neuroinflammation

The lateral septum (LS) is a midline, subcortical structure, which regulates social behaviors that are frequently impaired in neurodevelopmental disorders including schizophrenia and autism spectrum disorder. Mouse studies have identified neuronal populations within the LS that express a variety of molecular markers, including vasopressin receptor, oxytocin receptor, and corticotropin releasing hormone receptor, that control specific facets of social behavior. Despite its critical role in the regulation of social behavior and notable gene expression patterns, comprehensive molecular profiling of the human LS has not been performed. Here, we conducted single nucleus RNA-sequencing (snRNA-seq) to generate the first transcriptomic profiles of the human LS using postmortem human brain tissue samples from 3 neurotypical donors. Our analysis identified 4 transcriptionally distinct neuronal cell types within the human LS that are enriched for TRPC4, the gene encoding Trp-related protein 4. Differential expression analysis revealed a distinct LS neuronal cell type that is enriched for OPRM1, the gene encoding the mu-opioid receptor. Leveraging recently collected mouse LS snRNA-seq datasets, we also conducted a cross-species analysis. Our results demonstrate that TRPC4 enrichment in the LS is highly conserved between human and mouse, while FREM2, which encodes FRAS1 related extracellular matrix protein 2, is enriched only in the human LS. Together, these results highlight transcriptional heterogeneity of the human LS, and identify robust marker genes for the human LS.

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

Thompson,

Nelson,

Tippani

et al. 2024

Preprint

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The hippocampus contains many unique cell types, which serve the structure's specialized functions, including learning, memory and cognition. These cells have distinct spatial topography, morphology, physiology, and connectivity, highlighting the need for 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 across ten adult neurotypical donors. We defined molecular profiles for hippocampal cell types and spatial domains. Using non-negative matrix factorization and transfer learning, we integrated these data to define gene expression patterns within the snRNA-seq data and infer the expression of these patterns in the SRT data. Using this approach, we leveraged existing rodent datasets that feature information on circuit connectivity and neural activity induction to make predictions about axonal projection targets and likelihood of ensemble recruitment in spatially-defined cellular populations of the human hippocampus. Finally, we integrated genome-wide association studies with transcriptomic data to identify enrichment of genetic components for neurodevelopmental, neuropsychiatric, and neurodegenerative disorders across cell types, spatial domains, and gene expression patterns of the human hippocampus. To make this comprehensive molecular atlas accessible to the scientific community, both raw and processed data are freely available, including through interactive web applications.

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Spatiotemporal analysis of gene expression in the human dentate gyrus reveals age-associated changes in cellular maturation and neuroinflammation

Cited by 5 publications

References 148 publications

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Transcriptomic characterization of human lateral septum neurons reveals conserved and divergent marker genes across species

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

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