Objective:

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.

Sources:

• Nature Medicine