For a couple of weeks early in a mouse’s life, a small region deep in its brain gets crowded. The brain’s own immune cells multiply there until there are nearly twice as many as the grown animal will keep, and then the crowd thins. Those cells are microglia, and their fame rests on subtraction: they are known for snipping away a young brain’s spare connections, a process called synaptic pruning, and for clearing out cells no longer needed. Yet in this region the crowd arrives after most of the clearing and before the pruning begins. The timing never fitted the reputation.
A study in Nature Communications, by a UCLA team led by Lindsay De Biase and Laura DeNardo and posted earlier as a preprint, now suggests the crowd comes not to cut but to build. The region is the nucleus accumbens, part of the brain’s reward circuitry, which steers what an animal goes after and what it shies from. Trouble there has been tied to psychiatric conditions that tend to show early in life, yet little is known about how the region grows.
De Biase’s group first reported the crowding in 2020, and those same weeks are known to be a boom time for synapses, the tiny junctions where one nerve cell hands a message to the next. The team asked whether the extra microglia had come to help raise the region’s first frame of connections. To test it they used mice carrying a small deletion in their DNA that blocks a survival signal microglia need; in these animals, in the study’s words, “microglia never form at any point throughout the lifespan”.
Then the researchers listened. In thin slices of the accumbens they caught the small electrical blips that mark messages arriving at synapses, and in normal mice the blips grew steadily more frequent with age. In mice without microglia they stayed sparse, worst of all at about three weeks old. The remaining synapses were, if anything, readier to fire, as though straining to make up for absent neighbours. Under the microscope, where each synapse appears as a sending half pressed against a receiving half, the mice without microglia had fewer matched pairs. And only one kind came up short. Nerve cells receive connections that urge them to fire and connections that tell them to hold back, a little like a gas pedal and a brake. The brakes were all there. The gas-pedal synapses were missing.
The rest of the workshop looked normal. Astrocytes, the support cells known to coax synapses into forming, kept their usual shape and signals. A survey of more than 3,700 proteins found the standard parts of a synapse in standard amounts. But 229 proteins had shifted, many of them tied to how synapses are built, and among them two enzymes that microglia make in quantity: molecular scissors able to chew through the dense mesh packed between brain cells. With the bricks already on site, the team suspects, the helpers’ job may be to clear ground so new synapses can settle.
Here is the result that matters. By young adulthood the blips in mice without microglia had climbed back into the normal range. The count recovered. The mice did not. The team warns that a recovered number “does not necessarily mean that specific patterns of circuit connectivity and circuit function are comparable”.
They tested it with a lesson in caution. A tone sounds for thirty seconds, and in its last two seconds the chamber floor delivers a brief shock, except in one corner covered by a plastic platform. By the end of training both groups were stepping up in time to dodge nearly every shock; the mice without microglia in fact learned the escape faster. The next day, when the tones played with no shocks at all, they were slower to reach the platform and spent less time on it. They froze as often as normal mice, so the tone still meant danger, and every mouse reacted to shocks weaker than the test’s. What failed was not the memory of fear but the use of it to reach safety.
The same animals shunned the bare middle of an open arena and the unwalled stretches of a raised, ring-shaped track, and roamed less overall: the pattern scientists call anxiety-like behaviour, since a mouse cannot say how it feels. When the team made the accumbens glow where active and watched through a thin optical fibre, normal mice showed a rise in activity as they headed for the platform; in mice without microglia that rise was missing, and after shocks their accumbens stayed stirred up longer, like an alarm slow to fade.
Mice born without microglia lack them everywhere, always. So the team fixed the timing to the window itself. They injected a microglia-clearing drug into the accumbens of ordinary pups on the tenth day of life; by day fifteen, near the crowd’s natural peak, large patches stood empty, and by day twenty-one the cells had filled back in. As adults those mice, long after their helpers returned, still shied more from the exposed stretches and lingered more on the safe platform. A few days’ absence, in one small region, had reached forward into adulthood—though these mice, unlike the lifelong knockouts, remembered the platform lesson normally the next day. For anxiety and avoidance learning, the authors write, the results offer “strong support for a causal link” to what microglia do in the young accumbens.
The finding also sharpens a live dispute. Using the same kind of mice, a 2025 study by O’Keeffe and colleagues found synapse growth proceeding normally in the hippocampus, a memory hub, and in a patch of outer brain handling touch. The shortfall in the accumbens, the authors argue, strongly supports the view that “microglia play region-specific roles in synaptic development and refinement”. It matters, they suggest, because microglia answer to chronic stress, serious early-life infections, pollution and toxins, all listed among environmental risks for psychiatric disorders: regions like this one “may be uniquely vulnerable to perturbed circuit development” when something knocks the builders off course.
Every finding here is from mice, and each lead, the mesh-clearing scissors among them, still needs testing. But one plain thought survives the caution. A brain can count its way back to normal and still carry, in the way it meets danger, the weeks when its helpers were gone. When the work is done may weigh as much as how much of it gets done.