Depression was linked to stalled adult neurogenesis and widespread molecular changes in hippocampal memory circuits.
A small stream of new neurons continues to appear in the adult hippocampus even though most of the brain’s roughly 100 billion neurons are formed before birth. Research from Columbia University Vagelos College of Physicians and Surgeons suggests that this limited adult neurogenesis, the creation of new neurons, could play an important role in protecting against depression.
The researchers report for the first time that neurogenesis stalls in the brains of adults with major depressive disorder. They also identified molecular programs involved in controlling this process, providing potential targets for future treatments.
“Historically, depression was thought to be a disease of neurotransmitter deficiency, especially serotonin, but we now think that depression stems from multiple issues that affect our neurons’ ability to adapt to stress and changing environments,” says Maura Dupont, professor of psychiatry, who led the research.
“Without the ability to create new neurons, people with depression may not have the resilience to effectively adapt to the environment.”
New neurons may help separate emotions
The researchers concentrated on the hippocampus, a brain region central to episodic memory and emotional responses to the environment. It is also one of the few parts of the adult brain where new neurons are produced. Although depression involves more than the hippocampus, the region’s role in memory and emotion may influence how people interpret present experiences through the emotional weight of past ones.
“The hippocampus is important for our ability to distinguish between similar but different memories and separate the emotional connotation of past memories and current events,” Dupont says. This ability is known as pattern separation. When it becomes impaired, similar memories and the emotions attached to them can become harder to distinguish and begin to blend together.
“You may be out with a friend for lunch, but she’s tired and doesn’t talk much. With intact pattern separation, you remember this as a unique event. With impaired pattern separation, it becomes mixed with previous memories of feeling rejected, leading you to think, “They’re upset with me,” Dupont explains. “And I see this a lot in my patients, where they can only retrieve negative information from their memories.”
Research in mice has established that adult neurogenesis is necessary for pattern separation. Evidence from a recent study of people with brain tumors, whose hippocampal neurogenesis was eliminated by radiation treatment directed at that region, suggests that the same connection may exist in humans.
“It’s important to emphasize that we do not yet know the complete mechanism, particularly in humans, but the newborn neurons seem to enhance pattern separation because they are especially responsive to new experiences and can be incorporated into new memory circuits more easily, allowing new memories to be stored separately from the old ones,” Dupont says. “Turning neurogenesis back on may be a way to treat depression in some people by rewiring their hippocampus circuit.”
Depression disrupts a wider memory circuit
The changes extended beyond the production of new neurons. Neurogenesis operates within a larger hippocampal circuit that stores episodic memories along with their emotional value, and the researchers found molecular disruptions throughout that system.
Affected genes included those involved in forming new connections and communication between neurons, supplying cellular energy, and moving materials within cells. The trisynaptic circuit, a major hippocampal pathway involved in establishing new emotional memories, also showed evidence of inflammation and cellular stress in people with depression.
Half a million cells revealed the changes
To map these changes in detail, the researchers examined nearly half a million brain cells collected from people with depression and control subjects soon after each donor’s death.
Using recently developed techniques, they measured the activity of every gene in individual cells and determined whether cellular proteins had been altered. The resulting dataset allowed them to examine what each cell was doing and pinpoint where affected cells were located within the hippocampal circuit.
The analysis also identified genes with altered activity that contain genetic variants previously associated with major depression. Other disrupted genes showed epigenetic changes, which can modify gene activity without changing the underlying DNA sequence and can reflect environmental influences. “These are like dimmer switches that control how active genes are, and they are affected by life experiences such as stress, learning, aging, chemicals, etc.,” Dupont says.
Depression may have multiple molecular forms
“Overall, the wide range of effects we found could reflect different pathogenetic mechanisms, perhaps indicating that depression is not just one disease,” she adds.
Scientists still have only a limited understanding of the biological processes underlying depression, Dupont says. By defining the disorder at the level of individual cells and molecular pathways, studies like this could eventually help researchers develop treatments targeted to distinct biological forms of the condition.
“We want to reclassify depression based on its molecular features, similar to what has been done in cancer,” Dupont says. “Classifying cancers based on their cellular characteristics, not their locations, has led to new and improved treatments. We hope the same will be true for depression and other psychiatric or brain diseases.”
Reference: “Dysregulated adult hippocampal neurogenesis in major depressive disorders” by Madeleine S. Peng, Jialin Jiang, Lucia Polizzi, Tiancheng Shi, Rakshitha Ramkumar, Victor O. Anosike, Giulia Guasoni, Alexandra M. Wamalwa, Madeline B. Mariani, Cheick A. Sissoko, Alexandria N. Tartt, Camille Fulmore, Gorazd B. Rosoklija, Yung-yu Huang, Victoria Arango, Shujuan T. McDonald, Natasha Bitoljanu, J. John Mann, Phi T. Nguyen, Andrew J. Dwork, Lewis M. Brown, René Hen, Hanga Galfalvy and Maura B. Dupont, 21 August 2026, Nature Medicine.
DOI: 10.1038/s41591-026-04571-8
This work was supported by National Institutes of Health (grants AI164769, AG076949, MH133561 and AG080790), and the Bill Herrlinger Research Foundation. This study used the Confocal and Specialized Microscopy Shared Resource of the Herbert Irving Comprehensive Cancer Center at Columbia University, funded in part through the NIH/National Cancer Institute Cancer Center Support Grant P30CA013696.
Disclosure: Hanga Galfalvy and her family own stocks in Illumina, Inc., and in this study an Illumina NovaSeq 6000 was used to sequence the libraries at the JP Sulzberger Columbia Genome Center. Joseph J. Mann receives royalties from Columbia University for the Columbia Pathways App. and from the Research Foundation of Mental Hygiene for commercial use of the Columbia-Suicide Severity Rating Scale.
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