Resilience to Chronic Stress Is Characterized by Circadian Brain-Liver Coordination

• Published in: Biological psychiatry global open science Vol. 4; no. 6; p. 100385
• Main Authors: Savva, Christina, Vlassakev, Ivan, Bunney, Blynn G., Bunney, William E., Massier, Lucas, Seldin, Marcus, Sassone-Corsi, Paolo, Petrus, Paul, Sato, Shogo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2024; Elsevier
• Subjects: Archival Report; Chronic social stress; Circadian rhythms; Gene expression; Metabolism; Mouse model for depressive-like behaviors; Multitissue omics analysis; Circadian rhythms; Mouse model for depressive-like behaviors; Multitissue omics analysis; Chronic social stress; Gene expression; Metabolism
• ISSN: 2667-1743; 2667-1743
• DOI: 10.1016/j.bpsgos.2024.100385

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 the liver as well as serum metabolomics in mice exposed to chronic social defeat stress, a validated model for studying depressive-like behaviors. Male C57BL/6J mice underwent chronic social defeat stress, and subsequent social interaction screening identified distinct behavioral phenotypes associated with stress resilience and susceptibility. Stressed mice and their control littermates were sacrificed every 4 hours over the circadian cycle for comprehensive analyses of the circadian transcriptome in the hypothalamus, hippocampus, prefrontal cortex, and liver together with assessments of the circadian circulatory metabolome. Our data demonstrate that stress adaptation was characterized by reprogramming of the brain as well as the hepatic circadian transcriptome. Stress resiliency was associated with an increase in cyclic transcription in the hypothalamus, hippocampus, and liver. Furthermore, cross-tissue analyses revealed that resilient mice had enhanced transcriptional coordination of circadian pathways between the brain and liver. Conversely, susceptibility to social stress resulted in a loss of cross-tissue coordination. Circadian serum metabolomic profiles corroborated the transcriptome data, highlighting that stress-resilient mice gained circadian rhythmicity of circulating metabolites, including bile acids and sphingomyelins. This study reveals that resilience to stress is characterized by enhanced metabolic rhythms and circadian brain-liver transcriptional coordination. Chronic stress can have detrimental effects on both physical and mental health, often disrupting biological daily rhythms, known as circadian rhythms. To delve deeper into this phenomenon, we investigated how chronic stress affects circadian rhythms in the brain, liver, and blood metabolism of mice. Our study revealed that mice resilient to stress showed an increase in shared circadian biological processes between the liver and different brain regions together with enhanced rhythms in circulating metabolites. These findings propose an unprecedented link between stress adaptation and systemic circadian coordination and offer valuable insights into the mechanisms that underlie circadian disturbances seen in psychiatric disorders.