A large postmortem analysis of human brain tissue has found that adults with major depressive disorder show disrupted production of new neurons in the hippocampus, the brain region central to memory and mood — among the clearest evidence yet that a process long studied mainly in animals may also stall in the depressed human brain.
Researchers at Columbia University Irving Medical Center and the New York State Psychiatric Institute, led by Maura Dupont, professor of psychiatry at Columbia's Vagelos College of Physicians and Surgeons, examined roughly 500,000 individual brain cells from hippocampal tissue donated after death by people who had been diagnosed with major depressive disorder and by people who had not. Using single-cell techniques that record gene activity and protein changes cell by cell, the team mapped how the hippocampus's memory circuitry differed between the two groups. The findings were published Aug. 21 in Nature Medicine.
New neurons and old memories
Adult neurogenesis, the birth of new neurons after childhood, occurs in only a few brain regions, and the hippocampus is among them. Newly formed neurons are thought to help the brain perform "pattern separation," the ability to file a new experience as distinct from a similar but painful past one rather than blending the two together. The Columbia team found that in tissue from people with depression, the development of new neurons appeared to stall partway through, rather than completing the maturation process seen in tissue from people without the disorder.
The analysis also found broader disruption across the hippocampus's trisynaptic circuit, the loop of connected cell types that supports memory formation, including an altered balance of excitatory and inhibitory signaling, markers of cellular stress and inflammation, and disrupted serotonin- and glutamate-related signaling, chemical systems already linked to depression through other lines of research.
Without the ability to create new neurons, people with depression may not have the resilience to effectively adapt to the environment.
Maura Dupont, Columbia University Vagelos College of Physicians and Surgeons
Dupont and colleagues also cautioned that depression is unlikely to be a single, uniform disease at the molecular level; the tissue analysis suggested different patients' brains may arrive at similar symptoms through different underlying mechanisms, according to Nature's news coverage of the study.
Because the analysis relies on brain tissue collected after death, it can only show an association between depression and stalled neurogenesis, not prove that one causes the other. The disrupted neuron growth could be a cause of depressive symptoms, a consequence of the disorder or of medications used to treat it, or a byproduct of some other factor. Still, the researchers say identifying the specific molecular points where neuron development stalls could point toward new treatments aimed at restarting the process, adding to interest in therapies that might rewire the hippocampus's memory-emotion circuitry rather than simply targeting neurotransmitter levels.
