To investigate the progression of adult hippocampal neurogenesis in patients with major depressive disorder (MDD) compared to controls.
Approach:
Study Design: Postmortem hippocampal tissue analysis from 123 patients, including those with MDD and controls, using multiomic techniques.
Analytical Techniques: Single-nucleus RNA and chromatin accessibility sequencing, spatial transcriptomics, proteomics, RNA assays, immunofluorescence, and immunohistochemistry.
Key Findings:
Patients with MDD showed stalled progression from neural stem-like cells to neuroblasts.
Pseudotime analysis indicated more quiescent neural stem cells and fewer neuroblasts in MDD patients.
Stage-associated gene signatures were delayed in neural stem cells and lower in neuroblasts in MDD.
MDD patients had fewer cells expressing nestin and Ki67 in the subgranular zone.
Molecular alterations included increased expression of an interferon-related gene module in early neurogenic populations.
Interpretation:
MDD is associated with disrupted progression through the adult hippocampal neurogenic lineage rather than depletion of neural stem-like cells, alongside broader molecular alterations in hippocampal circuitry.
Limitations:
Cross-sectional postmortem design limited assessment of neurogenic changes over time.
Limited ability to distinguish MDD-related pathology from suicide-related pathology.
Modest power to examine adversity-related gene expression changes.
Conclusion:
The study provides a molecular framework for understanding disrupted neurogenic programs in MDD.
