The brains of people with depression seem to be worse at producing new neurons than are those of people without the disorder. That’s according to a study¹ that includes the most comprehensive map of the cell types in the human adult hippocampus, a brain region involved in learning, memory and emotions.

For more than 20 years, some researchers have suspected² that a disruption in neurogenesis — the process of making new neurons — could be involved in depression. “This paper, excitingly, is the first to show at single-cell resolution exactly where in the process things appear to be awry and what molecular machinery is involved,” says Amelia Eisch, a neuroscientist at the University of Pennsylvania in Philadelphia, who was not involved with the research.

A journey into the causes and effects of depression

The study, which was published last week in Nature Medicine, doesn’t establish that impaired neurogenesis plays a part in causing depression, and researchers are careful to note that depression involves multiple brain areas, not just the hippocampus. Still, the findings could point to new therapeutic targets. “We found several potentially druggable pathways involved in the pathogenesis,” says Maura Boldrini Dupont, a neuroscientist at Columbia University in New York City and one of the authors of the paper.

The work also provides further evidence to support the idea that the human brain continues to produce new neurons into adulthood. The existence of adult neurogenesis has been the topic of a long-standing debate, because some studies³ have failed to detect it.

And it goes a step further, suggesting that these freshly generated neurons not only exist but also have a distinct function, says Gerd Kempermann, a neuroscientist at the German Center for Neurodegenerative Diseases, in Dresden. These results are “really strong and interesting,” he says.

Half a million cells

The authors analysed brain tissue collected from 30 people shortly after their deaths. Eleven of the donors had major depressive disorder (MDD), also called clinical depression; 19 didn’t have mental-health conditions and served as a control group. Researchers sequenced RNA in the nuclei of almost 500,000 cells from these individuals’ hippocampi. The single-nucleus RNA sequencing provided a snapshot of gene activity in each cell. Scientists know which genes are associated with various stages of neuronal development, so gene activity serves as a molecular marker of cell maturity.

The team then used this information to identify what is probably a trajectory of neurogenesis. This trajectory begins with neural stem cells — cells that can give rise to neurons — becoming intermediate neural progenitor cells, then developing into the precursors to neurons, known as neuroblasts, and finally into immature neurons.

Compared with the brains of people in the control groups, those of individuals with MDD had a greater proportion of neural stem cells and a lower proportion of neuroblasts, which suggests that the progression from one stage to the other has been impaired. “It looked like the trajectory was stalled, lagging behind,” says Dupont.

Brains of ‘super agers’ are strong producers of new neurons

However, the study did not detect a lower proportion of immature neurons in MDD compared with controls, which is what one would expect if neurogenesis were halted, notes Evgenia Salta, a neuroscientist at the Netherlands Institute for Neuroscience in Amsterdam. “This makes it all the more interesting to zoom in further on how and when the neurogenic process becomes affected along disease progression,” she says.