Resilience to chronic stress is characterized by circadian brain-liver coordination
Description
Background: Chronic stress has a profound impact on circadian regulation of physiology. In turn, disruption of circadian rhythms increases the risk of developing both psychiatric and metabolic disorders. To explore the role of chronic stress in modulating the links between neural and metabolic rhythms, we characterized the circadian transcriptional regulation across different brain regions and liver as well as serum metabolomics in mice exposed to chronic social defeat stress, a validated model to study depressive-like behaviors. Methods: Male C57BL/6J mice underwent chronic social defeat stress, and subsequent social interaction screening identified distinct behavioral phenotypes associated with stress resilience and susceptiblility. Stressed mice and their control litermates were sacrificed every 4 hr over the circadian cycle for comprehensive analyses of the circadian transcriptome in the hypothalamus, hippocampus, prefrontal cortex, and liver, alongside assessments of the circadian circulatory metabolome. Results: Our data demonstrates that stress adaptation is characterized by reprogramming of the brain as well as hepatic circadian transcriptome. Stress resiliency is associated with an increase in cyclic transcription in the hypothalamus, hippocampus, and liver. Furthermore, cross-tissue analyses unveiled that resilient mice have enhanced transcriptional coordination of circadian pathways between the brain and the liver. Conversely, susceptibility to social stress resulted in a loss of cross tissue coordination. Circadian serum metabolomic profiles corroborate the transcriptome data, highlighting that stress-resilient mice gain circadian rhythmicity of circulating metabolites, including bile acids and sphingomyelins. Conclusion: This study reveals that resilience to stress is characterized by enhanced metabolic rhythms and circadian brain-liver transcriptional coordination.