Brains of people with depression struggle to make new neurons, largest single-cell map suggests

The brains of people with depression seem to be worse at producing new neurons than those of people without the disorder, according to a study that includes the most comprehensive map yet of cell types in the adult human hippocampus — a brain region involved in learning, memory and emotions. The work was published last week in Nature Medicine and covered by Nature on 25 August.

For more than 20 years, some researchers have suspected that disrupted 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," said Amelia Eisch, a neuroscientist at the University of Pennsylvania in Philadelphia, who was not involved in the research.

The team analysed brain tissue from 30 people collected shortly after death — 11 donors with major depressive disorder and 19 controls without mental-health conditions — sequencing RNA in the nuclei of almost 500,000 hippocampal cells. Because gene activity marks stages of neuronal development, the researchers could trace a trajectory from neural stem cells through intermediate progenitors and neuroblasts to immature neurons. In brains from people with depression, they found a greater proportion of neural stem cells and a lower proportion of neuroblasts than in controls, suggesting progression along this trajectory is impaired. "It looked like the trajectory was stalled, lagging behind," said Maura Boldrini Dupont, a neuroscientist at Columbia University in New York City and one of the study's authors.

The findings do not establish that impaired neurogenesis causes depression, and researchers caution that the condition involves multiple brain regions beyond the hippocampus. Evgenia Salta, a neuroscientist at the Netherlands Institute for Neuroscience in Amsterdam, noted that the study did not detect the lower proportion of immature neurons that would be expected if neurogenesis were fully halted — "which makes it all the more interesting to zoom in further on how and when the neurogenic process becomes affected along disease progression," she said.

Still, the results could point towards new treatments. "We found several potentially druggable pathways involved in the pathogenesis," Dupont said. The work also adds weight to the long-debated idea that the human brain continues producing new neurons into adulthood — and suggests those fresh neurons may have a distinct function, according to Gerd Kempermann, a neuroscientist at the German Center for Neurodegenerative Diseases in Dresden, who described the results as "really strong and interesting."

**Sources:** Nature