Impact of social isolation on stress, neuroinflammation, endocrine dysregulation, and antioxidant defense in mice exposed to rotational shiftwork/jetlag

Circadian disruption and social isolation are increasingly prevalent stressors in modern societies, each known to impair behavioral and physiological homeostasis. However, their concurrent influence remains poorly characterized. This study investigated the effects of social isolation and chronic circadian misalignment on affective behavior, neuroinflammatory signaling, endocrine function, and antioxidant defense in male AKR mice. Animals were housed either in groups or isolation under a stable 12:12 h light-dark cycle or subjected to six successive 8 h phase delays or advances every fourth day, modeling rotational shiftwork/jetlag exposure. Behavioral analyses revealed that isolated mice displayed pronounced anhedonia and anxiety-like behavior across all lighting regimens, with maximal impairment under phase advances. Molecular and biochemical assessments revealed significant elevations in pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) in the prefrontal cortex, hippocampus, and serum, accompanied by reduced melatonin levels, elevated corticosterone, and decreased antioxidant enzyme activity (SOD, CAT). These effects were observed across lighting conditions, indicating that circadian disruption and social isolation independently contribute to neuroendocrine stress, inflammation, and oxidative imbalance. Collectively, the results underscore the importance of social synchrony in maintaining circadian and physiological stability and highlight the impact of concurrent social and temporal desynchronization on health risks associated with chronic shiftwork/jetlag.