Human hippocampus niche and circuit neurotypical and major depression profiles

Hippocampal neuroplasticity regulates memory and emotional responses, which are altered in major depression, a leading cause of disability worldwide ¹ . Molecular underpinnings of reduced hippocampal neuroplasticity ² , fewer neurons, and smaller volume ^3,4 in MDD are unknown and may involve blunted adult hippocampal neurogenesis (AHN), a debated phenomenon in human brain ^5–8 . Dynamic changes in gene expression (GEX) are mediated, in part, by cis-regulatory elements (CREs), in response to developmental cues, environmental signals, and cellular contexts. However, the accessibility of CREs and their relation to GEX in specific hippocampus cell types in MDD is unknown. To this end, we simultaneously profiled chromatin accessibility and GEX in 349,847 human hippocampal nuclei, used machine learning ^9,10 , RNA Velocity ¹¹ and pseudotime trajectory inference ¹² to investigate the presence of progenitor cells and their progeny, and spatial transcriptomics in intact hippocampus sections to sequence cytoplasm and neuronal processes providing anatomical transcriptome mapping. We identified Type I, II and III neural progenitors and immature granule neurons. We find hyperactivated inflammation and apoptosis in immature and mature granule neurons, possibly affecting AHN and cell survival in MDD. Proteomics and transcriptomics convergent dysregulations in MDD, point to lipid metabolism, neurogenesis, synaptogenesis, cell adhesion, and plasticity. Identified molecular markers may drive biomarker and drug discovery for MDD and hippocampus resilience.