The findings provide the first evidence that neurogenesis, the process of producing new neurons, stalls in the brains of adults with major depressive disorder. Researchers also identified molecular programs involved in controlling this process, offering potential clues for developing new 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.”

How New Neurons May Shape Memory and Emotion

The researchers focused on the hippocampus, a brain region that plays a major role in episodic memory and emotional responses to the environment. It is also one of the few areas of the adult brain that continues to generate new neurons.

Although the hippocampus is not the only brain region involved in depression, its influence over both memory and emotion has made it an important area of study. Researchers believe changes there may contribute to the tendency of people with depression to interpret experiences more negatively.

“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, individual memories and the emotions attached to them may become less distinct, allowing separate experiences 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 shown that adult neurogenesis is necessary for pattern separation. A recent study involving patients with brain tumors, in whom neurogenesis was eliminated by radiation therapy directed at the hippocampus, suggests that the same relationship 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 Affects More Than New Neuron Growth

The researchers found that the changes linked to depression extended well beyond neurogenesis. New neuron formation operates within a larger hippocampal circuit that stores episodic memories along with their emotional significance, and molecular disruptions appeared throughout that system.

The affected genes included those involved in building new connections between neurons, supporting communication among brain cells, supplying cellular energy, and moving materials within cells.

The trisynaptic circuit, the hippocampus’s primary pathway for establishing new emotional memories, also displayed evidence of inflammation and cellular stress in people with depression.

To identify these changes, researchers studied nearly half a million brain cells collected from people with depression and control subjects shortly after each donor’s death.

Using an array of recently developed techniques, the team measured the activity of every gene within individual cells and examined whether cellular proteins had been altered. This enormous dataset allowed researchers to see what individual cells were doing and determine exactly where affected cells were located within the hippocampal circuit.

Genes, Environment, and the Biology of Depression

The analysis revealed altered activity in several genes whose genetic variants have previously been associated with major depression.

Other disrupted genes showed epigenetic changes that may reflect the influence of environmental factors. Epigenetic mechanisms can adjust how strongly genes are turned on or off without altering the underlying DNA sequence.

“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.

The diversity of molecular changes may also help explain why depression can look so different from one person to another.

“Overall, the wide range of effects we found could reflect different pathogenetic mechanisms, perhaps indicating that depression is not just one disease,” she adds.

Researchers still have only a limited understanding of depression’s underlying biology, according to Dupont. By defining the disorder more precisely at the cellular and molecular levels, studies like this one could eventually provide new targets for treatment.

Toward Molecular Subtypes of Depression

Dupont and her colleagues hope that depression could eventually be classified according to its molecular characteristics, much as cancer increasingly is today.

“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.”

The study, “Dysregulated adult hippocampal neurogenesis in major depressive disorders,” was published Aug. 21, 2026, in Nature Medicine.

All authors from Columbia University and/or New York State Psychiatric Institute unless noted: 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 (Ss. Cyril and Methodius University, Macedonia), Joseph J. Mann, Phi T. Nguyen, Andrew J. Dwork, Lewis M. Brown, René Hen, Hanga Galfalvy, and Maura B. Dupont.

The research was conducted in the Maura Dupont lab at Columbia University Irving Medical Center and New York State Psychiatric Institute. Sequencing was performed at the JP Sulzberger Columbia Genome Center, data clustering at Columbia’s Center for Computational Biology and Bioinformatics, and proteomics at Columbia University Department of Biology’s Quantitative Proteomics and Metabolomics Center.