Buffering the brain
It's also unclear exactly how moving your muscles can have such a significant effect on mental health. "Biochemically, there are many things that can impact mood. There are so many good, open questions about which mechanisms contribute the most to changes in depression," says de Groot.
Some researchers suspect exercise alleviates chronic depression by increasing serotonin (the neurotransmitter targeted by antidepressants) or brain-derived neurotrophic factor (which supports the growth of neurons). Another theory suggests exercise helps by normalizing sleep, which is known to have protective effects on the brain.
There are psychological explanations, too. Exercise may boost a depressed person's outlook by helping him return to meaningful activity and providing a sense of accomplishment. Then there's the fact that a person's responsiveness to stress is moderated by activity. "Exercise may be a way of biologically toughening up the brain so stress has less of a central impact," Otto says.
It's likely that multiple factors are at play. "Exercise has such broad effects that my guess is that there are going to be multiple mechanisms at multiple levels," Smits says.
So far, little work has been done to unravel those mechanisms. Michael Lehmann, PhD, a research fellow at the National Institute of Mental Health, is taking a stab at the problem by studying mice — animals that, like humans, are vulnerable to social stress.
Lehmann and his colleagues subjected some of their animals to "social defeat" by pairing small, submissive mice with larger, more aggressive mice. The alpha mice regularly tried to intimidate the submissive rodents through the clear partition that separated them. And when the partition was removed for a few minutes each day, the bully mice had to be restrained from harming the submissive mice. After two weeks of regular social defeat, the smaller mice explored less, hid in the shadows, and otherwise exhibited symptoms of depression and anxiety.
One group of mice, however, proved resilient to the stress. For three weeks before the social defeat treatment, all of the mice were subjected to two dramatically different living conditions. Some were confined to spartan cages, while others were treated to enriched environments with running wheels and tubes to explore. Unlike the mice in the bare-bones cages, bullied mice that had been housed in enriched environments showed no signs of rodent depression or anxiety after social defeat (Journal of Neuroscience, 2011). "Exercise and mental enrichment are buffering how the brain is going to respond to future stressors," Lehmann says.