As expected, large numbers of excitable neurons were fired up in the hippocampus, a region of the brain involved in emotional responses.
But in the brains of the runners, calming neurons were also quickly released warding off unnecessary anxiety.
The research shows exercising mice are able to cope better with stress, and it is believed the effect is also seen in humans, reports the Journal of Neuroscience.
Professor Elizabeth Gould, of Princeton University, New York, said physical activity reorganizes the brain so anxiety is less likely to interfere with normal function.
She said: 'Understanding how the brain regulates anxious behavior gives us potential clues about helping people with anxiety disorders.
'It also tells us something about how the brain modifies itself to respond optimally to its own environment.'
The findings resolve a paradox because exercise reduces anxiety while also promoting the growth of new neurons in the hippocampus.
Because these young cells are typically more excitable than their more mature counterparts, exercise should result in more anxiety, not less.
But the researchers found exercise also strengthens the mechanisms that prevent these brain cells from firing.
Prof Gould said identifying neurons and regions important to anxiety regulation may help scientists better understand and treat human anxiety disorders.
From an evolutionary standpoint, the research also shows the brain can be extremely adaptive and tailor its own processes to an organism's lifestyle or surroundings.
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