STRESS-RELATED COMPOUND BLOCKS NEUTROPHIL MOBILIZATION AND BEHAVIORAL IMPAIRMENT INDUCED BY CHRONIC SOCIAL STRESS IN MICE

Abstract Background Excessive stress due to adverse and demanding conditions induces emotional and cognitive abnormalities and precipitates mental illnesses such as depression. Clinical and preclinical studies have linked systemic inflammation with depression. Thus, neutrophils and monocytes have been reported to increase in the circulating blood of depressive patients and mice subjected to chronic social stress as a model of depression. Altered levels of compounds have been reported in depressive patients. However, how these changes are related to stress-induced systemic inflammation and its behavioral consequences remains unexplored. Aims & Objectives In this study, using a mouse model of repeated social defeat stress (R-SDS), we aim to investigate whether one of the compounds downregulated in the blood of depressive patients (hereafter referred to as ‘Compound X’) affects stress-induced leukocyte mobilization and its behavioral consequences. Methods Male C57BL/6 mice were exposed to aggression from a male ICR mouse for two hours daily for six consecutive days. Control mice were left undisturbed for the same six days. Depression-related behaviors were then assessed for multiple behavioral tests, including the social interaction test, the elevated plus maze test, the female urine sniffing test, the sucrose splash test, the novel object recognition test, and the tail suspension test. Compound X (10 mg/kg) was administered to mice via two routes, intraperitoneally or orally, during R-SDS and subsequent behavioral testing. After the mice were sacrificed, leukocytes in the bone marrow, circulating blood, spleen, and brain were collected and analyzed by flow cytometry. Results R-SDS induced the mobilization of myeloid cells, especially neutrophils, in the blood, spleen, and brain, which was sustained for at least one week, along with depression-related behaviors. Systemic administration of Compound X blocked R-SDS-induced neutrophil mobilization to the blood, spleen, and brain and alleviated depression-related behaviors, such as social avoidance, increased passive coping behavior, and cognitive deficits. Discussion & Conclusion These results demonstrate that Compound X blocks stress- induced neutrophil mobilization into the circulation and behavioral disturbances. Thus, we propose that the reduction of this compound may promote stress-related pathology and provide a novel therapeutic target for depression.