Voluntary exercise and increased food intake after mild chronic stress improve social avoidance behavior in mice

Highlights

• Voluntary wheel running after social defeat stress reduced social avoidance.

• Voluntary exercise did not clearly affect gene expression and monoamine levels.

• Food intake was greatest in the stress + exercise group.

• Increases in food intake influenced energy metabolism and social avoidance.

Abstract

It is well-established that exercise can influence psychological conditions, cognitive function, and energy metabolism in peripheral tissues including the skeletal muscle. However, it is not clear whether exercise can influence social interaction with others and alleviate defeat stress. This study investigated the effect of voluntary wheel running on impaired social interaction induced by chronic social defeat stress (SDS) using the resident–intruder social defeat model. Mice were divided into three groups: control, stress alone, and stress + exercise. SDS was performed by exposing C57BL/6 mice to retired ICR mice for 2.5 min. The C57BL/6 mice were continuously defeated by these resident (aggressor) mice and, following 5 days of SDS, experienced 2 days of rest with no SDS. Mice in the stress + exercise group were allowed to voluntarily run on a wheel for 2 h after every SDS exposure. Two weeks later, compared to the control group, the stress group showed a higher ratio of time spent in the corner zone of a social interaction paradigm even though SDS did not elicit depressive- and anxiety-like behaviors. We also observed that voluntary exercise, which did not affect muscle weight and gene expression, decreased social avoidance behavior of stressed mice without clear changes in brain monoamine levels. Interestingly, food intake in the stress + exercise group was the greatest among the three groups. To test the effect of the exercise-induced increase in food intake on social behavior, we set up a pair-fed group where food intake was restricted. We then compared these mice to mice in the stress alone group. We found that the ratio of time spent in the corner zone of the social interaction test was not different between ad libitum- and pair-fed groups, although pair-fed mice spent more time in the corner zone when an aggressor mouse was present than when it was absent. In addition, pair-feeding did not show exercise-induced reductions of adrenal gland weight and enhanced the loss of body fat. Our findings indicate that voluntary exercise reduces social avoidance behavior induced by SDS. Further, we determined that SDS and exercise-induced increases in food intake partially influence energy metabolism and social avoidance behavior.

Introduction

Psychological stress is often influenced by our relationships with others. For example, in human society, social defeat stress (SDS) is a critical cause of psychiatric disorders such as depression [1]. Therefore, to prevent the development of depression, it is important to establish provisions against SDS.

Several studies have established that exercise can influence not only the energy metabolism in peripheral tissues including the skeletal muscle, but also psychological conditions and cognitive function. A recent study in humans indicated that a certain amount of exercise is an important factor in overcoming the development of mood disorders such as depression and anxiety [2]. In addition, in rodents, physical training, using a treadmill or running wheel, has been reported to improve depressive-like behavior in various disorders such as diabetes, Parkinson's disease, Rett syndrome, Huntington's disease, and ethanol withdrawal [3], [4], [5], [6], [7], [8], [9]. It is thought that chronic exercise promotes neurogenesis in the hippocampus, which is damaged by stress-induced elevations of glucocorticoids, thereby improving emotional behavior [10], [11]. However, whether exercise can affect social interactions with others and protect against defeat stress has not been elucidated.

The SDS model in rodents is one of the most ubiquitously used paradigms for psychological stress [12]. This model is also called “the resident-intruder paradigm” because an “intruder” (experimental) animal is placed in the cage of a “resident” (aggressor) animal. Rodents exposed to SDS show a variety of behavioral changes, including social avoidance [12], [13], which has been shown to improve with the administration of anti-depression medication [14], [15], [16], [17]. Therefore, social avoidance induced by SDS is used as a measure of depressive-like behavior and sociality.

Generally, stress-induced elevations in glucocorticoids stimulate appetite via the central nervous system [18]. It is relatively well-established that certain types of stress can promote excess calorie intake, which is known as an allostatic behavior that can relieve psychological stress [19], [20]. It has also been shown that voluntary wheel running induces food consumption [21]. Thus, food intake may mediate behavioral changes that are induced by SDS. However, the above hypothesis has been challenged since some opposing reports have suggested that SDS reduces body weight and food intake [22], [23].

In this paper, we examined the effect of voluntary exercise on social interactions after mild SDS. Our study revealed that voluntary exercise enhances social interaction with others, and that exercise-induced increases in calorie intake after social stress are partially necessary for improving emotional behavior and maintaining body weight.