The Yale University experts say that experiments on mice could show why regular exercise can help people suffering from depression.
Writing in the journal Nature Medicine, they say it could lead to more effective drugs.
Mental Health charities in the UK already back exercise programmes as a way of lifting depression.
"Mind has long recommended physical exercise as a way of improving mental wellbeing"
While the link between exercise and improved mood is well known, the reasons behind it are not fully understood.
The latest research focuses on an area of the brain called the hippocampus, which is already established as a target for antidepressant drugs.
The team developed a test to see which genes in this region were made more active during exercise, and highlighted one called VGF.
This gene is linked to a "growth factor" chemical involved in the development of nerve cells.
This fitted with their theory that, for depression to lift, changes in the actual structure and links between brain cells are needed, not just changes in the chemicals surrounding the cells.
The next step was to make a version of that chemical, and to test it on mice, where it showed an effect on their behaviour that roughly equated to antidepressant effects in humans.
The researchers believe that a drug based on VGF could offer "possibly even superior efficacy" to current antidepressants.
'Clinically effective'
Marcus Roberts, Head of Policy at Mind, said that, currently, the use of exercise as a treatment for mental health problems should be recommended by doctors.
"Mind has long recommended physical exercise as a way of improving mental wellbeing, and many people who experience mental distress have told us that exercise has hugely benefited their mental health.
"Our own research has shown that outdoor exercise can decrease feelings of depression and increase self-esteem by inspiring a sense of achievement - the evidence is growing that this should be treated as a clinically valid treatment."
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