Patients with major depressive disorder showed evidence of disrupted adult hippocampal neurogenesis, with analyses suggesting stalled progression from neural stem-like cells toward neuroblasts.
Investigators analyzed postmortem hippocampal tissue from 123 patients, including those with major depressive disorder (MDD) and controls without psychiatric diagnoses. The cohort included samples from the US and Europe. Single-nucleus RNA and chromatin accessibility sequencing was performed ion hippocampal tissue from controls and individuals with MDD; following quality control, the primary multiomic analysis included 19 controls and 11 patients with MDD. Researchers supplemented these analyses with spatial transcriptomics, proteomics, RNA assays, immunofluorescence, and immunohistochemistry. Patients with MDD had no psychotropic medication use within 3 months prior to death except benzodiazepines and did not have comorbid substance or alcohol use disorders.
The investigators assessed whether an adult hippocampal neurogenic lineage could be identified and whether its progression differed in MDD. They characterized neural stem cells, intermediate neural progenitors, neuroblasts, immature granule cells, and mature granule cells and examined cell type-specific gene expression and chromatin accessibility. Spatial analyses were used to determine where these populations localized within hippocampal subfields and to infer progression through the neurogenic trajectory.
Pseudotime analysis showed a shift in cell distribution among patients with MDD, characterized by more quiescent neural stem cells and fewer neuroblasts compared with controls. Stage-associated gene signatures also appeared delayed in neural stem cells and were lower in neuroblasts. The authors interpreted this pattern as impaired neurogenic progression rather than depletion of the neural stem-like cell population.
Tissue-based validation supported the trajectory findings. Patients with MDD had fewer cells expressing nestin and the proliferation marker Ki67 in the subgranular zone, as well as fewer dentate gyrus cells coexpressing DCX and TUBB3 RNA and fewer cells expressing doublecortin protein. However, the proportion of cells expressing markers of immature granule cells did not differ between groups, indicating that the observed changes were not uniform across the neurogenic lineage.
Molecular alterations accompanied the changes in neurogenic progression. Early neurogenic populations in MDD showed increased expression of an interferon-related gene module. Intermediate neural progenitors had increased expression of SOX9, a transcription factor associated with glial fate and suppression of neurogenesis, along with reduced expression of genes involved in cell growth and niche function. Neuroblasts, which were less abundant in MDD, also showed reduced expression of DCX and BDNF.
Alterations extended beyond neurogenic populations. Across mature hippocampal cells and regions, the researchers identified changes involving neurotransmission, intracellular trafficking, excitatory-inhibitory balance, neuroplasticity, cellular stress, metabolism, and neuroinflammation. Proteomic profiling of samples from 12 patients with MDD and 12 controls identified 297 differentially expressed proteins and showed convergence with pathways identified through transcriptomic analyses.
The study had several limitations. Its cross-sectional postmortem design did not allow researchers to assess neurogenic changes over time. The investigators also had limited ability to distinguish MDD-related pathology from suicide-related pathology because most patients with MDD died by suicide. Power to examine adversity-related gene expression changes was modest, and cause of death or unrecognized medical illness may have influenced the findings.
MDD was 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.
“These findings provide a molecular framework for understanding the regulation of human adult human hippocampal neurogenesis and reveal disrupted neurogenic programs, which may underlie halted [adult hippocampal neurogenesis] in MDD,” wrote lead study author Madeleine S. Peng, of the Department of Psychiatry at Columbia University and the Research Foundation for Mental Hygiene–New York State Psychiatric Institute, and colleagues.
Disclosures: Hanga Galfalvy and her family reported owning stock in Illumina. J. John Mann reported receiving royalties from Columbia University and the Research Foundation for Mental Hygiene for products unrelated to this study. The remaining authors declared no competing interests.
Source: Nature Medicine
