Your Brain’s Immune Cells May Be Secretly Helping It Grow New Neurons

For decades, the brain’s resident immune cells were cast as villains whenever they got riled up. Inflammation in the brain meant trouble, full stop, and the delicate process of growing new neurons in adulthood seemed especially vulnerable to their wrath. But a study in mice is turning that story on its head, revealing that when you tweak the right molecular switch in these cells, they don’t destroy new neurons. They help them survive.

The cells in question are microglia, the brain’s own immune sentinels. They spend most of their time in a quiet, watchful state, pruning synapses and clearing debris. When disease or injury strikes, though, they shift into a reactive mode, pumping out inflammatory signals. It has long been assumed that this reactive state is broadly toxic to neurogenesis, the creation of fresh neurons in the adult brain. Yu Luo at the University of Cincinnati College of Medicine and her team have found something rather more nuanced.

Working with genetically engineered mice, Luo’s group knocked out a key signalling molecule called TGF-beta specifically in microglia. TGF-beta normally keeps these immune cells in their calm, homeostatic state. Remove it, and the microglia become reactive, losing their characteristic markers and ramping up inflammatory signals. The conventional wisdom would predict bad news for any nearby baby neurons. Instead, the researchers saw something unexpected: a surge of more than 66 per cent in the number of new immature neurons in the hippocampus, the brain region central to learning and memory. “The status of microglia in the hippocampus is critical in the process,” says Luo.

What’s perhaps most striking is that this wasn’t just a transient blip of immature cells that fizzled out. The team tracked newly born neurons over 12 weeks using chemical labels, and found that these cells matured into fully fledged neurons and integrated into existing brain circuits. In normal mice, roughly 30% of newborn neurons in the hippocampus survive to maturity. In the mice with reactive microglia, that figure climbed to about 50 percent. The reactive immune cells weren’t spurring extra cell division, it turns out. They were keeping more of the new neurons alive.

The molecular trail led somewhere intriguing. Single-cell RNA sequencing of hippocampal tissue revealed that newborn neurons in the knockout mice had reduced levels of PTEN, a gene that normally acts as a brake on the mTOR pathway (a cellular signalling cascade involved in growth and survival). With that brake loosened, mTOR activity ramped up in the young neurons, and that correlated with their enhanced survival. When the team administered rapamycin, a well-known mTOR inhibitor, the surplus of new neurons disappeared. The reactive microglia were still reactive, mind you, but the newborn neurons no longer got the survival boost.

Luo’s team went to considerable lengths to nail down the mechanism. They generated double-knockout mice lacking both TGF-beta signalling and IGF-1 (a growth factor long suspected of driving neurogenesis) in microglia. The extra neurons persisted. They tried eliminating TNF-alpha, an inflammatory molecule, on top of the TGF-beta knockout. Still no change. It wasn’t any single cytokine doing the heavy lifting. The effect seemed to funnel through the PTEN-mTOR axis in the neurons themselves, a sort of survival signal triggered by the altered microglia nearby.

And the consequences weren’t purely cellular. The knockout mice showed changes in behaviour too. In tests of anxiety, they spent more time exploring exposed, open areas of elevated mazes, suggesting reduced anxiety-like behaviour. They also showed some deficits in spatial learning on a Barnes maze test. Crucially, in one line of knockout mice where the microglia eventually recovered their normal state (about 12 weeks after the genetic switch), both the neurogenesis boost and the behavioural changes reversed. In another line where microglia stayed permanently reactive, the effects persisted. The behavioural shifts tracked the cellular ones, which is a tidy bit of evidence (though not absolute proof) that the new neurons were functionally integrating into hippocampal circuits.

There is a caveat worth noting. All of this work has been done in mice. “Adult neurogenesis is vital for learning, memory and mood regulation, and we hope to discover novel ways to enhance this process,” says Luo. The question of whether adult humans generate new hippocampal neurons was itself hotly debated until a 2025 study in Science settled the matter in the affirmative. So the basic machinery is there, but whether manipulating microglial TGF-beta signalling could have similar effects in people remains an open question. Luo’s team is developing microglia-integrated human brain organoids to begin testing this.

“We will be testing the future implications of adult neurogenesis in the understanding and treatment of Alzheimer’s disease,” says Joshua Peter, one of the study’s lead authors, who recently defended his PhD and has moved to managing clinical trials. TGF-beta signalling goes haywire in ageing brains and in conditions like Alzheimer’s, stroke and traumatic brain injury, all situations where coaxing the brain into producing or preserving more neurons could be genuinely useful.

The findings published in Nature Communications challenge a fairly entrenched idea in neuroscience. For years, the assumption was straightforward: neuroinflammation bad, neurogenesis good, and the two don’t mix. What Luo’s work suggests is something more complicated and, perhaps, more hopeful. The brain’s immune system isn’t simply a wrecking crew. Under the right circumstances, reactive microglia might actually be part of how the brain tries to repair itself, nudging newborn neurons past a survival bottleneck that normally claims the majority of them. If we can figure out how to harness that without the downsides, the ageing brain might have more allies than we thought.

Study link: https://www.nature.com/articles/s41467-026-68885-4