Voluntary wheel running improves cognitive deficits and abnormal agonistic behavior induced by social isolation...

Reduced social interactions negatively impact adolescents. However, underlying mechanisms of social isolation (SI) stress and interventions remain unclear. Therefore, we investigated the effects of an exercise intervention on SI stress-induced behavioral abnormalities and the underlying mechanisms. We used male mice: Ctrl (N = 32), SI (N = 33), SI + voluntary wheel running (VWR) (N = 14), and SI + lurasidone (N = 7), and assessed emotion, anxiety, depression, social interactions, and cognitive functions using behavioral tests. In addition, we measured plasma corticosterone and performed immunohistochemical staining for ΔFosB, a marker of repeatedly activated neurons, to assess the stress response and identify brain regions associated with SI stress. Interventions lasted for 3 weeks, and behavioral assessments were initiated 2 weeks after the intervention initiation. The SI mice exhibited significant hyperactivity, reduced self-care and motivation, impaired recognition, excessive sniffing toward strangers and aggressive but avoidant social behaviors. We observed significant improvements in recognition impairments and excessive sniffing behavior after VWR. In addition, there was a trend toward reduced flight behavior. However, VWR did not induce a significant change in the number of attacks and the ΔFosB expression in the ventral tegmental area (VTA). Lurasidone administration significantly reduced sniffing and aggressive behavior and increased ΔFosB-positive cells in VTA. Our results suggest that, while VWR and lurasidone both mitigate some aspects of SI-induced behavioral deficits, they likely act independent or only partially overlapping neurobiological pathways. Thus, VWR may act through broader neuroadaptive processes, potentially involving serotonergic modulation, neurotrophic factors, or stress regulatory circuits.