The Impact of Chronic Social Stress on Emotional Behavior in Mice and the Therapeutic Effect of Peripheral Mild-Heat Stimulation

Abstract

In today’s stressful society, mental diseases such as adjustment disorder, affective disorders including anxiety and depression, and chronic fatigue syndrome could be attributed to social stress and are considered as serious social problems. It has been long known in the acupuncture and moxibustion therapies in Japan and China that stimulation at Zhongwan and Taichong points have effects on stress-related anxiety and depression. In the present study, we therefore tested the effect of peripheral mild-heat stimulation at Zhongwan and Taichong on anxiety and brain biochemistry using a mouse model of chronic social stress. Male ddY mice (4 weeks old) were stressed by isolated rearing for 6 weeks. They received mild-heat stimulation (43℃ for 5 min) at Zhongwan and Taichong under isoflurane anesthesia after 4 weeks of the social isolation 3 times a week for 2 weeks, using the “Stress Free Apparatus” (Ryoken Co., Ltd). Control mice received only isoflurane anesthesia. Group-reared mice also underwent the same stimulus/anesthesia sessions. Two days after the last peripheral heat stimulation, anxiety was determined by the light/dark box test as the time spent in the light compartment and the number of transfer between the light and dark compartments. Before and after the last stimulation, blood was collected from an artery at the back of the eye, and serum corticosterone, immunoglobulin E (IgE) which was an index of the inflammatory immune system, and interleukin 6 (IL-6) were measured using ELISA Kit. The frontal cortex was collected after the behavioral test, and the dopamine and serotonin contents were measured also by ELISA Kit. A significant decrease of the time spent in the light compartment was observed after the isolated rearing (p < 0.01). Mild-heat stimulation significantly increased the time spent in the light compartment, indicating an anti-anxiety effect. Serum corticosterone, IgE and IL-6 were increased after stress, and the amount of serotonin in the frontal cortex was found decreased. The increased corticosterone, IgE and IL-6 were cancelled by mild-heat stimulation. These results suggest that chronic social isolation has negative biological and emotional impacts in mice and that peripheral mild-heat stimulation alleviates at least part of these stress effects.