Adults with major depressive disorder show disrupted production of new neurons in the hippocampus, according to a study published Aug. 21 in Nature Medicine, offering what the authors describe as the first direct evidence that neurogenesis stalls in the depressed human brain rather than simply in animal models.
Researchers led by Maura Dupont, a professor of psychiatry at Columbia University Vagelos College of Physicians and Surgeons, analyzed nearly 500,000 individual cells from postmortem hippocampal tissue donated shortly after death, comparing samples from people who had major depressive disorder with samples from people who did not. Using single-nucleus RNA sequencing, the team recorded which genes were switched on in each cell and mapped where those cells sat within the hippocampus's internal circuitry, known as the trisynaptic circuit.
Widespread molecular disruption
The hippocampus is one of the few regions of the adult human brain known to continue generating new neurons throughout life, a process thought to help the brain distinguish between similar but emotionally distinct memories, for instance telling apart two arguments with different people rather than blurring them into one generalized sense of conflict. In donors with depression, the researchers found not only fewer signs of new neuron production but also broader molecular changes across the circuit, including altered activity in genes tied to neuron-to-neuron connections, cellular energy supply, and internal transport within cells, along with signs of inflammation and cellular stress.
"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."
Maura Dupont, Columbia University
The study is observational and based on brain tissue collected after death, meaning it cannot establish that impaired neurogenesis causes depression rather than resulting from it, or from factors such as medication history, other illnesses, or the circumstances of death that often differ between donor groups. Dupont and colleagues also caution that major depressive disorder likely encompasses several biologically distinct conditions lumped under one clinical label, which could blur or exaggerate differences seen in a single postmortem cohort. Related coverage in Nature's news section notes that similar findings in mice have driven interest in this area for years, but confirming the pattern in human tissue had proven difficult.
The researchers say the molecular signatures they identified point toward specific pathways that future treatments might target to restart neurogenesis, rather than relying solely on drugs that adjust neurotransmitter levels. Dupont has said the long-term goal is to classify depression by its underlying molecular features, similar to how cancers are now categorized by genetic subtype rather than only by the organ in which they arise, which could eventually help match patients to treatments more precisely. Any such therapies remain in early, preclinical stages, and the authors say replicating the findings in larger and more diverse donor cohorts is a next priority.
