---
title: "Hippocampal gene and epigenetic alterations link impaired neurogenesis to major depressive disorder"
id: "nature-1-gene-alteration-in-human-brain-suggests-genetic-and-epigenetic-roots-of-major"
canonical_url: "https://medichelpline.com/clinical-feed/nature-1-gene-alteration-in-human-brain-suggests-genetic-and-epigenetic-roots-of-major"
content_type: "clinical_feed_article"
specialty: "Neurology"
source_name: "Nature Medicine"
source_url: "https://www.nature.com/articles/s41591-026-04682-2"
published_at: "2026-09-03T12:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Hippocampal gene and epigenetic alterations link impaired neurogenesis to major depressive disorder
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/nature-1-gene-alteration-in-human-brain-suggests-genetic-and-epigenetic-roots-of-major
- **Specialty:** [Neurology](https://medichelpline.com/clinical-feed/neurology.md)
- **Primary Source:** Nature Medicine
- **Source URL:** [Original Journal Publication](https://www.nature.com/articles/s41591-026-04682-2)
- **Published At:** 2026-09-03T12:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- A large, multimodal molecular study of the adult human **hippocampus** reports evidence for sustained **adult neurogenesis** in humans and identifies a disrupted or stalled neurogenic process in people with **major depressive disorder (MDD)**. - The study used cell- and circuit-specific molecular characterization to map alterations associated with MDD; findings implicate coordinated **genetic** and **epigenetic** changes. - Multiple biological domains were implicated, including **stress**-related pathways, **immune** signalling, **metabolic** processes and **synaptic** mechanisms, all linked to impaired hippocampal plasticity. - Results connect altered genes in the human hippocampus with psychiatric disorders and show depleted adult neurogenesis in MDD (illustrated in Fig. 1 of the briefing). - The authors propose that these cell- and circuit-level molecular signatures provide a framework for **disease subtyping** and may guide future **therapeutic development**. - The Research Briefing summarizes and contextualizes the open-access Nature Medicine article by Peng et al., Dysregulated adult hippocampal neurogenesis in major depressive disorder. - The briefing cites prior work linking adult neurogenesis to memory and stress resilience in animal models (for example, studies by Chen et al. and Anacker et al.) and situates the new human molecular data within that broader literature. - Detailed experimental methods, cohort details and specific gene lists were reported in the source article and are not reproduced in full in this briefing.
## Clinical Analysis & Structured Key Points
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[nature](https://www.nature.com/) 2. [nature medicine](https://www.nature.com/nm) 3. [research briefings](https://www.nature.com/nm/articles?type=research-briefing) 4. article * Research Briefing * Published: 03 September 2026 # Gene alteration in human brain suggests genetic and epigenetic roots of major depression [_Nature Medicine_](https://www.nature.com/nm) (2026) [Cite this article](https://www.nature.com/articles/s41591-026-04682-2#citeas) [ Save article ](https://www.nature.com/articles/s41591-026-04682-2/save-research?_csrf=gg9TZjC0zpQjB1J0GBrbiD5bbamF8fsk) [ View saved research ](https://www.nature.com/saved-research) A large, multimodal molecular characterization of the adult human hippocampus provides evidence for sustained neurogenesis and identifies a stalled neurogenic process in major depressive disorder (MDD). Cell- and circuit-specific genetic, epigenetic, stress, immune, metabolic and synaptic mechanisms are identified that underlie impaired hippocampal plasticity, providing a framework for disease subtyping and therapeutic development. This is a preview of subscription content, [access via your institution](https://wayf.springernature.com?redirect_uri=https%3A%2F%2Fwww.nature.com%2Farticles%2Fs41591-026-04682-2) ## Access options [ Access through your institution ](https://wayf.springernature.com?redirect_uri=https%3A%2F%2Fwww.nature.com%2Farticles%2Fs41591-026-04682-2) Access Nature and 54 other Nature Portfolio journals Get Nature+, our best-value online-access subscription 27,99 € / 30 days cancel any time [Learn more](https://shop.nature.com/products/plus/?region=ROW) Subscribe to this journal Receive 12 print issues and online access 251,40 € per year only 20,95 € per issue [Learn more](https://www.nature.com/nm/subscribe) Buy this article * Purchase on SpringerLink * Instant access to the full article PDF. 39,95 € Prices may be subject to local taxes which are calculated during checkout ### Additional access options: * [Log in](https://idp.nature.com/authorize/natureuser?client_id=grover&redirect_uri=https%3A%2F%2Fwww.nature.com%2Farticles%2Fs41591-026-04682-2) * [Learn about institutional subscriptions](https://www.springernature.com/gp/librarians/licensing/license-options) * [Read our FAQs](https://support.nature.com/en/support/home) * [Contact customer support](https://www.springernature.com/gp/contact) **Fig. 1: Depleted adult neurogenesis in MDD and links between altered genes and psychiatric disorders.** ![](https://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fs41591-026-04682-2/MediaObjects/41591_2026_4682_Fig1_HTML.png) ## References 1. Chen, Y.-J. et al. Follistatin mediates learning and synaptic plasticity via regulation of Asic4 expression in the hippocampus. _Proc. Natl Acad. Sci. USA_ **118** , e2109040118 (2021). **This paper shows the link between adult neurogenesis and memory in mice, involving one of the genes we found linked to adult neurogenesis in humans.** [Article](https://doi.org/10.1073%2Fpnas.2109040118) [CAS](https://www.nature.com/articles/cas-redirect/1:CAS:528:DC%2BB3MXitFGrt7fF) [PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=34544873) [PubMed Central](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488609) [ Google Scholar](http://scholar.google.com/scholar_lookup?&title=Follistatin%20mediates%20learning%20and%20synaptic%20plasticity%20via%20regulation%20of%20Asic4%20expression%20in%20the%20hippocampus&journal=Proc.%20Natl%20Acad.%20Sci.%20USA&doi=10.1073%2Fpnas.2109040118&volume=118&publication_year=2021&author=Chen%2CY-J) 2. 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Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021. _Lancet_ **403** , 2133–2161 (2024). **This paper reports on the worldwide disability burden related to depression.** [Article](https://doi.org/10.1016%2FS0140-6736%2824%2900757-8) [ Google Scholar](http://scholar.google.com/scholar_lookup?&title=Global%20incidence%2C%20prevalence%2C%20years%20lived%20with%20disability%20%28YLDs%29%2C%20disability-adjusted%20life-years%20%28DALYs%29%2C%20and%20healthy%20life%20expectancy%20%28HALE%29%20for%20371%20diseases%20and%20injuries%20in%20204%20countries%20and%20territories%20and%20811%20subnational%20locations%2C%201990-2021%3A%20a%20systematic%20analysis%20for%20the%20Global%20Burden%20of%20Disease%20Study%202021&journal=Lancet&doi=10.1016%2FS0140-6736%2824%2900757-8&volume=403&pages=2133-2161&publication_year=2024) 4. 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Psychiatry_ (2026). **This review summarizes research investigating the biological basis of suicide.** [Article](https://doi.org/10.1038%2Fs41380-026-03507-5) [PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=41820636) [PubMed Central](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC13268968) [ Google Scholar](http://scholar.google.com/scholar_lookup?&title=Pursuing%20the%20elusive%20biosignature%20for%20suicide%3A%20a%20decennial%20update&journal=Mol.%20Psychiatry&doi=10.1038%2Fs41380-026-03507-5&publication_year=2026&author=Barzilay%2CR&author=Sudol%2CK&author=Daskalakis%2CNP&author=Dupont%2CMB&author=Oquendo%2CMA) [Download references](https://citation-needed.springer.com/v2/references/10.1038/s41591-026-04682-2?format=refman&flavour=references) ## Additional information **Publisher’s note** Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. **This is a summary of:** Peng, M. S. et al. Dysregulated adult hippocampal neurogenesis in major depressive disorder. _Nat. Med_. (2026). M.B.D. used ChatGPT to help prepare their contribution to this Research Briefing ## Rights and permissions [Reprints and permissions](https://s100.copyright.com/AppDispatchServlet?title=Gene%20alteration%20in%20human%20brain%20suggests%20genetic%20and%20epigenetic%20roots%20of%20major%20depression&author=&contentID=10.1038%2Fs41591-026-04682-2&copyright=Springer%20Nature%20America%2C%20Inc.&publication=1078-8956&publicationDate=2026-09-03&publisherName=SpringerNature&orderBeanReset=true) ## About this article [![Check for updates. Verify currency and authenticity via CrossMark](https://www.nature.com/articles/s41591-026-04682-2)](https://crossmark.crossref.org/dialog/?doi=10.1038/s41591-026-04682-2) ### Cite this article Gene alteration in human brain suggests genetic and epigenetic roots of major depression. _Nat Med_ (2026). https://doi.org/10.1038/s41591-026-04682-2 [Download citation](https://citation-needed.springer.com/v2/references/10.1038/s41591-026-04682-2?format=refman&flavour=citation) * Published: 03 September 2026 * Version of record: 03 September 2026 * DOI: https://doi.org/10.1038/s41591-026-04682-2 ### Share this article Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy shareable link to clipboard Provided by the Springer Nature SharedIt content-sharing initiative ### Subjects * [Cell growth](https://www.nature.com/subjects/cell-growth) * [Clinical epigenetics](https://www.nature.com/subjects/clinical-epigenetics) [ Access through your institution ](https://wayf.springernature.com?redirect_uri=https%3A%2F%2Fwww.nature.com%2Farticles%2Fs41591-026-04682-2) [ Buy or subscribe ](https://www.nature.com/articles/s41591-026-04682-2#access-options) ## Associated content ### [Dysregulated adult hippocampal neurogenesis in major depressive disorder](https://www.nature.com/articles/s41591-026-04571-8) * Madeleine S. Peng * Jialin Jiang * Maura B. Dupont Nature Medicine Article Open Access 21 Aug 2026 * Sections * Figures * References * [References](https://www.nature.com/articles/s41591-026-04682-2#Bib1) * [Additional information](https://www.nature.com/articles/s41591-026-04682-2#additional-information) * [Rights and permissions](https://www.nature.com/articles/s41591-026-04682-2#rightslink) * [About this article](https://www.nature.com/articles/s41591-026-04682-2#article-info) Advertisement * **Fig. 1: Depleted adult neurogenesis in MDD and links between altered genes and psychiatric disorders.** 1. Chen, Y.-J. et al. Follistatin mediates learning and synaptic plasticity via regulation of Asic4 expression in the hippocampus. _Proc. Natl Acad. Sci. USA_ **118** , e2109040118 (2021). **This paper shows the link between adult neurogenesis and memory in mice, involving one of the genes we found linked to adult neurogenesis in humans.** [Article](https://doi.org/10.1073%2Fpnas.2109040118) [CAS](https://www.nature.com/articles/cas-redirect/1:CAS:528:DC%2BB3MXitFGrt7fF) [PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=34544873) [PubMed Central](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488609) [ Google Scholar](http://scholar.google.com/scholar_lookup?&title=Follistatin%20mediates%20learning%20and%20synaptic%20plasticity%20via%20regulation%20of%20Asic4%20expression%20in%20the%20hippocampus&journal=Proc.%20Natl%20Acad.%20Sci.%20USA&doi=10.1073%2Fpnas.2109040118&volume=118&publication_year=2021&author=Chen%2CY-J) 2. Anacker, C. et al. Hippocampal neurogenesis confers stress resilience by inhibiting the ventral dentate gyrus. _Nature_ **559** , 98–102 (2018). **This paper reports on the importance of adult neurogenesis for stress resilience in mice.** [Article](https://doi.org/10.1038%2Fs41586-018-0262-4) [CAS](https://www.nature.com/articles/cas-redirect/1:CAS:528:DC%2BC1cXht1eisr3E) [PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=29950730) [PubMed Central](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118212) [ Google Scholar](http://scholar.google.com/scholar_lookup?&title=Hippocampal%20neurogenesis%20confers%20stress%20resilience%20by%20inhibiting%20the%20ventral%20dentate%20gyrus&journal=Nature&doi=10.1038%2Fs41586-018-0262-4&volume=559&pages=98-102&publication_year=2018&author=Anacker%2CC) 3. GBD 2021 Diseases and Injuries Collaborators. Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021. _Lancet_ **403** , 2133–2161 (2024). **This paper reports on the worldwide disability burden related to depression.** [Article](https://doi.org/10.1016%2FS0140-6736%2824%2900757-8) [ Google Scholar](http://scholar.google.com/scholar_lookup?&title=Global%20incidence%2C%20prevalence%2C%20years%20lived%20with%20disability%20%28YLDs%29%2C%20disability-adjusted%20life-years%20%28DALYs%29%2C%20and%20healthy%20life%20expectancy%20%28HALE%29%20for%20371%20diseases%20and%20injuries%20in%20204%20countries%20and%20territories%20and%20811%20subnational%20locations%2C%201990-2021%3A%20a%20systematic%20analysis%20for%20the%20Global%20Burden%20of%20Disease%20Study%202021&journal=Lancet&doi=10.1016%2FS0140-6736%2824%2900757-8&volume=403&pages=2133-2161&publication_year=2024) 4. Boldrini, M. et al. Resilience is associated with larger dentate gyrus, while suicide decedents with major depressive disorder have fewer granule neurons. _Biol. Psychiatry_ **85** , 850–862 (2019). **This paper shows that people resilient to childhood adversity had more neural progenitor cells and granule neurons than people with depression who died by suicide.** [Article](https://doi.org/10.1016%2Fj.biopsych.2018.12.022) [PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=30819514) [PubMed Central](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830307) [ Google Scholar](http://scholar.google.com/scholar_lookup?&title=Resilience%20is%20associated%20with%20larger%20dentate%20gyrus%2C%20while%20suicide%20decedents%20with%20major%20depressive%20disorder%20have%20fewer%20granule%20neurons&journal=Biol.%20Psychiatry&doi=10.1016%2Fj.biopsych.2018.12.022&volume=85&pages=850-862&publication_year=2019&author=Boldrini%2CM) 5. Barzilay, R., Sudol, K., Daskalakis, N. P., Dupont, M. B. & Oquendo, M. A. Pursuing the elusive biosignature for suicide: a decennial update. _Mol. Psychiatry_ (2026). **This review summarizes research investigating the biological basis of suicide.** [Article](https://doi.org/10.1038%2Fs41380-026-03507-5) [PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=41820636) [PubMed Central](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC13268968) [ Google Scholar](http://scholar.google.com/scholar_lookup?&title=Pursuing%20the%20elusive%20biosignature%20for%20suicide%3A%20a%20decennial%20update&journal=Mol.%20Psychiatry&doi=10.1038%2Fs41380-026-
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