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Peer-reviewedCC BY-NC-NDNature Medicine

Dysregulated adult hippocampal neurogenesis in major depressive disorder

  • Madeleine Peng1,2
  • Jialin Jiang1,2
  • Lucia Polizzi1,2
  • Tiancheng Shi1,2
  • Rakshitha Ramkumar1,2
  • Victor Anosike1,2
  • Giulia Guasoni1,2
  • Alexandra M. Wamalwa1,2
  • Madeline Mariani1,2
  • Cheick A. Sissoko1,2
  • Alexandria N. Tartt1,2
  • Camille A. Fulmore1,2
12 more authors
  • Gorazd B. Rosoklija1,3,4
  • Yung-yu Huang1,2
  • Victoria Arango1,2
  • Shujuan Tao McDonald5
  • Natasha Bitoljanu3
  • J. John Mann1,6,2
  • Phi T. Nguyen1
  • Andrew J. Dwork7,1,4,2
  • Lewis M. Brown5
  • René Hen8,9,1,2
  • Hanga Galfalvy10,1
  • Maura B. Dupont11,12
12 affiliations
  1. 1Department of Psychiatry, Columbia University, New York, NY, USA
  2. 2Research Foundation for Mental Hygiene - New York State Psychiatric Institute, New York, NY, USA
  3. 3Institute of Forensic Medicine Criminalistics and Medical Deontology, Ss. Cyril and Methodius University, Skopje, North Macedonia
  4. 4Macedonian Academy of Sciences & Arts, Skopje, North Macedonia
  5. 5Quantitative Proteomics and Metabolomics Center, Department of Biological Sciences, Columbia University, New York, NY, USA
  6. 6Department of Radiology, Columbia University, New York, NY, USA
  7. 7Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
  8. 8Department of Neuroscience, Columbia University, New York, NY, USA
  9. 9Department of Pharmacology, Columbia University, New York, NY, USA
  10. 10Department of Biostatistics, Columbia University, New York, NY, USA
  11. 11Department of Psychiatry, Columbia University, New York, NY, USA. [email protected]
  12. 12Research Foundation for Mental Hygiene - New York State Psychiatric Institute, New York, NY, USA. [email protected]
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Abstract

Major depressive disorder (MDD) is associated with reduced hippocampal volume, altered connectivity and negative memory bias, suggesting disrupted hippocampal plasticity. Dysregulated adult hippocampal neurogenesis is a potential contributor, but its relevance in humans and role in MDD remain unclear. Here we investigated the molecular basis of hippocampal dysfunction in nonmedicated individuals with MDD by integrating analyses of neurogenic trajectories, cell-type- and subfield-specific gene expression, chromatin accessibility and protein expression. We identify a neurogenic lineage in the adult human hippocampal subgranular zone and provide evidence for a stalled neurogenic process in MDD, associated with transcriptional regulation, stress-related reprogramming and interferon signaling across developmental stages. Excitatory and inhibitory neurons show dysregulation of transcription factor networks affecting cell states. Cellular stress, excitatory-inhibitory imbalance, impaired synaptic plasticity, reduced metabolic capacity and immune activation, underlie impaired neurogenesis and reduced hippocampus circuit plasticity. Findings indicate genetic and epigenetic regulation of gene expression in MDD, and overlapping pathogenetic mechanisms with autoimmune, neurodevelopmental and neurodegenerative diseases. This work provides a new understanding of the pathogenesis of hippocampus-dependent cognitive symptoms in MDD and suggests potential therapeutic targets.

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Cite

BibTeXRIS
BibTeX
@article{peng2026dysregulated,
  title = {{Dysregulated adult hippocampal neurogenesis in major depressive disorder}},
  author = {Madeleine Peng and Jialin Jiang and Lucia Polizzi and Tiancheng Shi and Rakshitha Ramkumar and Victor Anosike and Giulia Guasoni and Alexandra M. Wamalwa and Madeline Mariani and Cheick A. Sissoko and Alexandria N. Tartt and Camille A. Fulmore and Gorazd B. Rosoklija and Yung-yu Huang and Victoria Arango and Shujuan Tao McDonald and Natasha Bitoljanu and J. John Mann and Phi T. Nguyen and Andrew J. Dwork and Lewis M. Brown and René Hen and Hanga Galfalvy and Maura B. Dupont},
  journal = {Nature Medicine},
  year = {2026},
  month = aug,
  doi = {10.1038/s41591-026-04571-8},
  url = {https://doi.org/10.1038/s41591-026-04571-8},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Dysregulated adult hippocampal neurogenesis in major depressive disorder
AU  - Madeleine Peng
AU  - Jialin Jiang
AU  - Lucia Polizzi
AU  - Tiancheng Shi
AU  - Rakshitha Ramkumar
AU  - Victor Anosike
AU  - Giulia Guasoni
AU  - Alexandra M. Wamalwa
AU  - Madeline Mariani
AU  - Cheick A. Sissoko
AU  - Alexandria N. Tartt
AU  - Camille A. Fulmore
AU  - Gorazd B. Rosoklija
AU  - Yung-yu Huang
AU  - Victoria Arango
AU  - Shujuan Tao McDonald
AU  - Natasha Bitoljanu
AU  - J. John Mann
AU  - Phi T. Nguyen
AU  - Andrew J. Dwork
AU  - Lewis M. Brown
AU  - René Hen
AU  - Hanga Galfalvy
AU  - Maura B. Dupont
PY  - 2026
DA  - 2026/08/21
JO  - Nature Medicine
DO  - 10.1038/s41591-026-04571-8
UR  - https://doi.org/10.1038/s41591-026-04571-8
AB  - Major depressive disorder (MDD) is associated with reduced hippocampal volume, altered connectivity and negative memory bias, suggesting disrupted hippocampal plasticity. Dysregulated adult hippocampal neurogenesis is a potential contributor, but its relevance in humans and role in MDD remain unclear. Here we investigated the molecular basis of hippocampal dysfunction in nonmedicated individuals with MDD by integrating analyses of neurogenic trajectories, cell-type- and subfield-specific gene expression, chromatin accessibility and protein expression. We identify a neurogenic lineage in the adult human hippocampal subgranular zone and provide evidence for a stalled neurogenic process in MDD, associated with transcriptional regulation, stress-related reprogramming and interferon signaling across developmental stages. Excitatory and inhibitory neurons show dysregulation of transcription factor networks affecting cell states. Cellular stress, excitatory-inhibitory imbalance, impaired synaptic plasticity, reduced metabolic capacity and immune activation, underlie impaired neurogenesis and reduced hippocampus circuit plasticity. Findings indicate genetic and epigenetic regulation of gene expression in MDD, and overlapping pathogenetic mechanisms with autoimmune, neurodevelopmental and neurodegenerative diseases. This work provides a new understanding of the pathogenesis of hippocampus-dependent cognitive symptoms in MDD and suggests potential therapeutic targets.
SN  - 1078-8956
SN  - 1546-170X
SN  - 1744-7933
ER  -