Can you run from your worries? The effects of exercise on anxiety-like behavior and immune signaling in female and male mice

Exercise is a positive health behavior associated with improved mood. However, the mechanisms underlying the benefits of exercise on affective health are unclear, particularly with respect to type of exercise and sex. Chronic exercise decreases neuroinflammation, which is linked to improvements in mood and anxiety. However, exercise is also a physiological stressor that can transiently upregulate systemic inflammation, and its effects on neuroinflammation are not well understood. This study examined how acute and chronic exercise affect circulating and brain cytokine levels and anxiety-related behavior in young healthy male and female mice. In experiment 1, mice were placed on a treadmill for a 2-h bout of moderate exercise. Two hours after exercise, animals were either tested in the open field or euthanized for measurement of cytokines (IL-1β, TNF, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, IFN-γ, KC/GRO). In experiment 2, mice underwent an 8-wk moderate treadmill exercise paradigm followed by open field testing and tissue collection. Acute exercise decreased time spent in the center of the open field in males only, suggesting increased anxiety-like behavior in males. Acute exercise increased IL-6 and decreased TNF in serum, and increased amygdala principal component 1 (loading IL-12p70, IL-10, IFN-γ, and TNF) in both sexes. Chronic exercise increased open field center entries, increased IL-6 in the prefrontal cortex, decreased TNF in the dorsal hippocampus, and had minimal effects on circulating cytokines in both sexes. These results demonstrate that the effects of exercise on anxiety-related behavior and cytokine levels depend on recurrence, tissue, and brain region.NEW & NOTEWORTHY Our work highlights the contrast between anxiogenic and anxiolytic effects of acute vs. chronic exercise, respectively, in healthy mice. Acute and chronic exercise differentially affected circulating and brain cytokines, providing insight into physiological adaptations to exercise. Both sexes demonstrated similar cytokine responses to exercise. These similarities are novel with respect to exercise research and noteworthy given sex differences in anxiety with respect to acute exercise.