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

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 probe their expression 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. We obtained tissue blocks of postmortem human brain containing anterior hippocampus from 10 neurotypical adult brain donors. We used the 10x Genomics Visium and 3’ Single Cell Gene Expression platforms to generate paired spatial transcriptomics and single-nucleus RNA-seq data of the human hippocampus. We performed a second spatial transcriptomics experiment using the Visium Spatial Proteogenomics (Visium-SPG) platform for two of the 10 donors.