GSE160189
Resolving cellular and molecular diversity along the hippocampal anterior-to-posterior axis in humans
The hippocampus supports many facets of cognition, including learning, memory, and emotional processing. Anatomically, the hippocampus runs along a longitudinal axis, posterior-to-anterior in primates (corresponding to dorsal-to-ventral in rodents). The structure, function, and connectivity of the hippocampus vary along this axis.  In rodents, experiments have established the cellular, molecular, and functional heterogeneity along the hippocampal axis, resulting in comprehensive models of specialization that integrate these different types of information.  In humans however, functional heterogeneity remains an active area of investigation, and structural heterogeneity has not been described.  To better understand the cellular composition and molecular diversity along the hippocampal long axis in the human brain and define distinct molecular signatures corresponding to functional domains we performed single-nuclei RNA-sequencing on surgically resected human anterior and posterior hippocampus. Analysis of 131,325 nuclei revealed differentially expressed genes between the anterior and posterior human hippocampus at cellular resolution. We determine the program of these axis- and cell-type specific genes that are conserved in the mouse hippocampus, and we also identify patterns that are differential between the human and mouse. We further identify axis- and cell-type specific gene expression signatures that differentially intersect with human cognitive and neuropsychiatric genetic signals, identifying cell type-specific genes in the posterior hippocampus for cognitive function and in the anterior hippocampus for mood and affect. Our data illuminate a region- and cell-type-specific transcriptional landscape within the hippocampus. This data is accessible as a public resource through an interactive website (https://human-hippo-axis.cells.ucsc.edu/) and will act as a reference atlas for the human hippocampus. Overall design: We carried out single-nuclei RNA-sequencing of human resected hippocampus. Anterior and posterior hippocampus from 5 donors were processed and sequenced as separate libraries.