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How Running Makes the Brain More Resilient to Stress

Exercise increases galanin in the locus coeruleus and boosts stress resilience.

Image credited to Tillage et al., JNeurosci 2020, labeled for reuse.
Exercise increases galanin in the locus coeruleus.
Source: Image credited to Tillage et al., JNeurosci 2020, labeled for reuse.

Galanin is a neuropeptide that was first isolated in 1983 by researchers at the Karolinska Institute in Sweden. Unlike widely-recognized "rock star" neuropeptides (e.g., dopamine, serotonin, adrenaline) that laypersons commonly associate with the neurobiology of addiction, depression, and the rush of thrill-seeking behavior, galanin has stayed under most people's radar and is not widely recognized.

Until today, the only other time I've read anything about the exercise-induced role that galanin plays in boosting stress resilience was roughly five years ago in a 2015 news release from the University of Georgia about a relatively obscure galanin-related animal study led by Phil Holmes of UGA.

For this study (Sciolino et al., 2015), the researchers used Sprague–Dawley rats to identify that galanin mediates stress resilience in response to regular exercise. "We're the only lab that's looking at that connection between galanin and exercise," Holmes said at the time. "It's good and bad—it's good that we've got our own little niche, but it's bad in that it doesn't receive enough attention."

In the early 2010s, Natale Sciolino, who was a member of Holmes' Behavioral Neuropharmacology Laboratory at the time, began using rodent models to investigate if aerobic exercise increases galanin levels in the locus coeruleus (LC) region of the brainstem, which in turn, seems to suppress the stress-induced activity of the LC (Sciolino & Holmes, 2012).

"Indeed, running promotes an adaptive response to stress and alters anxiety-like behaviors in a manner dependent on stress," Sciolino and Holmes concluded. "Thus, enhanced galanin-mediated suppression of brain norepinephrine in runners is supported by current [2012] literature as a mechanism that may contribute to the stress-protective effects of exercise."

This week, senior author Holmes along with David Weinshenker, a professor of human genetics at Emory University, and colleagues published a new study (Tillage et al., 2020) that provides fresh insights about how aerobic exercise buffers against stress by increasing levels of galanin in the LC brain region of mice. These findings were published on August 31 in The Journal of Neuroscience.

For their latest (2020) study on how exercise-induced galanin increases make the brain more resilient to stress, first author Rachel Tillage and colleagues gave one cohort of mice access to a running wheel for three weeks; another control group of mice wasn't given the option to run. Of note: If left to their own devices (i.e., ad libitum), the researchers found that most mice like to run the equivalent of a 10K (or farther) every day.

This study had two goals. First, the researchers investigated whether physical activity (chronic wheel running) boosted galanin levels in the LC and increased stress resilience in male and female mice. Second, the researchers used genetically engineered Gal OX mice "to determine how chronically elevated noradrenergic-derived galanin, alone, alters anxiogenic-like responses to stress."

In response to their first query, the researchers "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 results from a cohort of sedentary Gal OX mice showed that genetically increasing locus coeruleus galanin levels boosted stress resilience, even in mice that didn't have access to a running wheel. Galanin expression in the locus coeruleus appears to be dysregulated in stress-related disorders and activated by aerobic exercise.

In a "dose-dependent" manner, each mouse's weekly running distance correlated with the amount of galanin in their locus coeruleus, which subsequently predicted their degree of stress resilience. Notably, levels of galanin don't appear to alter other aspects of animal behavior; therefore, the authors speculate that "galanin may be recruited only during periods of high stress."

"Combined with the existing literature, the results from the present study [2020] demonstrate that noradrenergic galanin promotes stress resilience across species and that its enrichment can come from either an environmental (exercise) or genetic (transgenic overexpression) source," the authors conclude.

Another recently published galanin study (Tillage, Sciolino, Plummer, et al., 2020) using a different strain of genetically engineered mice found that noradrenergic neurons provide galanin to multiple brain areas and that noradrenergic-specific galanin opposes adaptive coping responses. "We observed reduced levels of galanin peptide in [the] pons, hippocampus, and prefrontal cortex of GalcKO–Dbh mice, indicating that noradrenergic neurons are a significant source of galanin to those brain regions," the authors conclude.

More research is needed to better understand the exact neural mechanisms that give galanin anxiolytic properties. That said, the latest galanin research adds to a growing body of evidence showing that the galanin system can be hacked via aerobic exercise and may also be a promising target for pharmacotherapies designed to treat stress-related disorders.

Image via EurekAlert, no usage restrictions.


Rachel P. Tillage, Genevieve E. Wilson, L. Cameron Liles, Philip V. Holmes, David Weinshenker. “Chronic Environmental or Genetic Elevation of Galanin in Noradrenergic Neurons Confers Stress Resilience in Mice.” The Journal of Neuroscience (First published: August 31, 2020) DOI: 10.1523/JNEUROSCI.0973-20.2020

Rachel P. Tillage, Natale R. Sciolino, Nicholas W. Plummer, Daniel Lustberg, L. Cameron Liles, Madeline Hsiang, Jeanne M. Powell, Kathleen G. Smith, Patricia Jensen & David Weinshenker. "Elimination of Galanin Synthesis in Noradrenergic Neurons Reduces Galanin in Select Brain Areas and Promotes Active Coping Behaviors." Brain Structure and Function (First published: February 17, 2020) DOI: 10.1007/s00429-020-02035-4

Natele R. Sciolino, J.M. Smith, A.M. Stranahan, K.G. Freeman, G.L. Edwards, David Weinshenker, Philip V. Holmes. "Galanin Mediates Features of Neural and Behavioral Stress Resilience Afforded by Exercise." Neuropharmacology (First published online: October 06, 2014) DOI: 10.1016/j.neuropharm.2014.09.029

Natale R. Sciolino and Philip V. Holmes. "Exercise Offers Anxiolytic Potential: A Role for Stress and Brain Noradrenergic-Galaninergic Mechanisms." Neuroscience & Behavioral Reviews (First published online: July 05, 2012) DOI: 10.1016/j.neubiorev.2012.06.005

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