Spatially resolved multi-omic profiling of human hippocampus reveals region-specific alterations in major depressive disorder [RNA-seq]

The human hippocampus, a center of learning and memory, has a complex architecture with high cellular and molecular heterogeneity. We present the first spatially resolved atlas of human hippocampus at the genome scale. Spatial transcriptome sequencing on 10 hippocampi identified the hippocampal sub-fields and cell types in the dentate gyrus and the cornu Ammonis regions. We deconvoluted the cellular composition in each pixel to build a gene expression landscape of each cell subtype. Psychiatrically healthy brains were compared with brains from subjects with major depressive disorder (MDD) to identify differentially modulated pathogenic genes and pathways in a region-specific manner. We observed surprisingly high variability of RNA splicing in MDD compared with control. RNA velocity analysis suggested a model for how transcriptomic instability in MDD contributes to a high inter-patient heterogeneity particularly in the pyramidal neurons. Spatially resolved chromatin accessibility profiling further identified potential epigenetic underpinnings implicated in MDD molecular neuropathology.