Brain study reveals one type of exercise increases stress resilience

In times of serious stress, people might turn to exercise to blow off steam and shake off nervous energy. However, despite anecdotal evidence, the link between working out and relieving stress isn't well understood by scientists. Researchers haven't yet pinned down exactly how exercise modulates stress in the brain and body, despite knowing that exercise benefits mental health.

In a recent study conducted in mice, researchers became one step closer to that understanding, discovering that exercise actually strengthens the brain's resilience to stress. Exercise helps animals cope with stress by enabling an uptick in a crucial neural protein called galanin, the study suggests. This process influences stress levels, food consumption, cognition, and mood.

Leveraging this finding, researchers were able to genetically tweak even sedentary mice's levels of galanin, shifts that lowered their anxious response to stress.

The study's authors explain that this study helps pin down the biological mechanisms driving exercise's positive effects on stress. While further human experiments are needed to confirm these findings, the researchers have practical advice for people looking to get these benefits: perform regular, aerobic exercise.

"Not exercising at all and then suddenly going for a hard 10 mile run just before a stressful event isn’t as helpful as regularly jogging 3 miles several days a week over several months," researchers David Weinshenker and Rachel Tillage, tell Inverse by email.

That's because, based on these results, a history of increased exercise doesn't affect the immediate physiological response (like a release of cortisol) during a stressful event, Weinshenker and Tillage explain. Instead, exercise increases behavioral resilience after stress exposure.

"This could suggest that increased exercise doesn't impact our immediate feelings of stress, but does allow us to cope with stress in a healthier way," the co-authors say.

These findings were released Monday in the Journal of Neuroscience.

The search for the brain mechanisms — Research shows exercise protects against the deleterious effects of stress in both mice and humans. Galanin, that pivotal brain protein that modulates stress and mood, is expressed in similar areas of both animal's brains.

To examine how these factors interact and influence each other, the study team turned to mice.

"Mechanistic questions are difficult to answer in humans due to ethical and technical limitations, so we used mice for this purpose," Weinshenker and Tillage say. With these overlapping properties, the team adds that the neurobiological substrates underlying galanin's role in physical activity-related stress resilience could occur across species.

"One of the major implications from this study in that the galanin system could be a potential target for future therapies... "

The measured mice's anxious behavior 24 hours after a foot shock test — aka the stressful event. They also analyzed their levels of galanin and examined its source.

Half the mice had regular access to an exercise wheel in their cage, while others had no running wheel. Mice steadily increased their running distance over the first week, after which they ran approximately 10-16 kilometers per day. Researchers tracked the mice's activity for three weeks.

Those who exercised showed less anxious behavior after the stressful event compared to mice that didn't exercise. Exercising mice also had elevated galanin levels in the locus coeruleus, a cluster of neurons in the brainstem involved in the stress response.

The amount of time the mice spent exercising in the third week correlated with the amount of galanin in the locus coeruleus, which in turn correlated with their degree of stress resilience.

Based on these findings, the team then genetically increased galanin in the locus coeruleus in sedentary mice. This gave these inactive mice exercise's beneficial stress resilience effects, without changing their physical activity patterns.

If further human experiments confirm these findings, it could mean hijacking the galanin system could help people gain exercise's stress resilience benefits, even if they aren't able to work out.

"These findings build on what we know by isolating a specific biological mechanism — increased galanin in the locus coeruleus— by which exercise can influence how we respond to stress," Weinshenker and Tillage explain. "One of the major implications from this study in that the galanin system could be a potential target for future therapies to gain the positive effects of exercise on stress resilience for people who are not able to exercise."

Interestingly, the increased galanin didn't influence other aspects of the mice's behavior, suggesting galanin may be recruited only during periods of high stress, the team says.

More human data is needed to figure out exactly what type or how much exercise confers this stress-resilience effect. But based on the current evidence, the researchers say they can offer some general guidance:

• Aerobic exercise (like walking, running, biking, swimming) probably has a greater effect on stress resilience than non-aerobic exercise (like weight lifting).
• Exercise probably needs to be routine; completed a few times a week. Cramming in a HIIT workout or long run right before a stressful event isn't likely to be as helpful as regularly hiking or hitting the elliptical.

Abstract: The neuropeptide galanin has been implicated in stress-related neuropsychiatric disorders in humans and rodent models. While pharmacological treatments for these disorders are ineffective for many individuals, physical activity is beneficial for stress-related symptoms. Galanin is highly expressed in the noradrenergic system, particularly the locus coeruleus (LC), which is dysregulated in stress-related disorders and activated by exercise. Galanin expression is elevated in the LC by chronic exercise, and blockade of galanin transmission attenuates exercise-induced stress resilience. However, most research on this topic has been done in rats, so it is unclear whether the relationship between exercise and galanin is species-specific. Moreover, use of intracerebroventricular galanin receptor antagonists in prior studies precluded defining a causal role for LC-derived galanin specifically. Therefore, the goals of this study were twofold. First, we investigated whether physical activity (chronic wheel running) increases stress resilience and galanin expression in the LC of male and female mice. Next, we used transgenic mice that overexpress galanin in noradrenergic neurons (Gal OX) to determine how chronically elevated noradrenergic-derived galanin, alone, alters anxiogenic-like responses to stress. We found that three weeks of ad libitum access to a running wheel in their home cage increased galanin mRNA in the LC of mice, which was correlated with and conferred resilience to stress. The effects of exercise were phenocopied by galanin overexpression in noradrenergic neurons, and Gal OX mice were resistant to the anxiogenic effect of optogenetic LC activation. These findings support a role for chronically increased noradrenergic galanin in mediating resilience to stress.