Differential long-term effects of physical, social, and psychological stressors in male mice: Down-regulation of inflammatory markers and unresponsiveness of the antioxidant system (2025)

Balatskyi, V., Gospodaryov, D., Abrat, O. et al.

Abstract

The long-term molecular consequences associated with post-traumatic stress disorder (PTSD) are poorly understood. Our study examined the long-term (up to five months) metabolic consequences of acute and chronic traumatic factors, including physical (2-hour restraint), psychological (predator sound), and social (social isolation) stressors, in C57BL/6 J male mice. In the open field test, mice exposed to all stressors displayed anxiety-like behavior for up to one month. Additionally, predator sound triggered a fear response, monitored as decreased locomotion and increased defecation. Behavioral consequences were lost after eight weeks of stress exposure. Approximately five months after stress exposure, mice from all groups showed elevated corticosterone levels in blood plasma with no changes in lipid peroxide levels and antioxidant enzyme activities in the cerebral cortex. However, differences were observed in hematological parameters and mRNA levels in the cortex. Mice exposed to predator sound had higher total leukocyte count and higher levels of immature neutrophils, lower blood paraoxonase and myeloperoxidase activities, compared to controls. All stressed groups had lower mRNA levels of indirect inflammation markers CCL2 and CYP1A1 and higher mRNA levels of PPARGC1A, SHANK1, and SGK1 genes, whose products are indirectly associated with the regulation of neuronal function. Socially isolated mice additionally showed lower mRNA levels of IL-6 but higher mRNA levels of FKBP5, a regulator of glucocorticoid receptor activity in the cerebral cortex, and higher plasma IL-1β levels. Thus, our results suggest that exposure of adult male mice to both acute and chronic traumatic stressors leads to long-term metabolic consequences as suppression of inflammation and dysregulation of glucocorticoid-mediated stress response.