Depression May Impair the Brain’s Ability to Create New Neurons

People with depression may have a reduced ability to generate new neurons in the hippocampus, a brain region involved in learning, memory and emotion. That is the finding of a study¹ that provides the most comprehensive map yet of cell types in the adult human hippocampus.

For more than 20 years, researchers have suspected that impaired neurogenesis—the process through which the brain creates new neurons—could be linked to depression.² “Interestingly, this paper is the first to show at single-cell resolution exactly where in the process something is going wrong and which molecular mechanisms are involved,” says Amelia Eish, a neuroscientist at the University of Pennsylvania in Philadelphia, who was not involved in the study.

Published last week in Nature Medicine, the study does not establish that impaired neurogenesis causes depression. Researchers also emphasize that depression involves multiple brain regions, not only the hippocampus. Nevertheless, the findings could help identify new treatment targets. “We discovered several potential drug pathways that could be involved in the pathogenesis of depression,” says Maura Boldrini Dupont, a neuroscientist at Columbia University in New York City and one of the study’s authors.

The research also adds to evidence that the human brain may continue producing new neurons during adulthood. Adult neurogenesis has remained controversial for many years.³ Some studies have been unable to detect the process in adult human brains.

The new findings go further by suggesting that newly generated neurons not only exist, but may also perform distinct functions, says neuroscientist Gerd Kempermann of the German Center for Neurodegenerative Diseases in Dresden. He describes the results as “very strong and interesting.”

Study analyzes 500,000 hippocampal cells

The researchers analyzed brain tissue collected immediately after death from 30 people. Eleven donors had major depressive disorder (MDD), also known as clinical depression, while 19 had no known mental health conditions and served as a control group. The team sequenced RNA from the nuclei of approximately 500,000 cells taken from the donors’ hippocampi. Single-nucleus RNA sequencing provided a snapshot of gene activity in each cell. Because specific genes are associated with different stages of neuron development, gene activity can be used as a molecular indicator of cell maturity.

Using these data, the researchers identified likely stages, or trajectories, of adult neurogenesis. The process begins when neural stem cells—cells capable of developing into neurons—become intermediate neural progenitors. These cells then develop into neuron precursors called neuroblasts before finally becoming immature neurons.

Compared with the control group, brains from people with MDD contained a higher proportion of neural stem cells and a lower proportion of neuroblasts. The pattern suggests that the transition between stages of neuron development may be disrupted in depression. “It seemed like we were stuck on track and falling behind,” Dupont says.

‘Super-Ager’ brains generate new neurons more strongly

However, the study did not find a lower proportion of immature neurons in people with MDD than in the control group. Such a reduction might be expected if neurogenesis had stopped, says neuroscientist Evgenia Salta of the Netherlands Institute for Neuroscience in Amsterdam. “This makes it even more interesting to take a closer look at when and how neurogenic processes are affected as the disease progresses,” she says.