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Brain activity and transcriptional profiling in mice under chronic jet lag.

ABSTRACT: Shift work is known to be associated with an increased risk of neurological and psychiatric diseases, but how it contributes to the development of these diseases remains unclear. Chronic jet lag (CJL) induced by shifting light-dark cycles repeatedly is a commonly used protocol to mimic the environmental light/dark changes encountered by shift workers. Here we subjected wildtype mice to CJL and performed positron emission tomography imaging of glucose metabolism to monitor brain activities. We also conducted RNA sequencing using prefrontal cortex and nucleus accumbens tissues from these animals, which are brain regions strongly implicated in the pathology of various neurological and psychiatric conditions. Our results reveal the alterations of brain activities and systematic reprogramming of gene expression in brain tissues under CJL, building hypothesis for how CJL increases the susceptibility to neurological and psychiatric diseases.

SUBMITTER: Gao Q

PROVIDER: S-EPMC7578042 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Brain activity and transcriptional profiling in mice under chronic jet lag.

Gao Qian Q Khan Suliman S Zhang Luoying L

Scientific data 20201021 1

Shift work is known to be associated with an increased risk of neurological and psychiatric diseases, but how it contributes to the development of these diseases remains unclear. Chronic jet lag (CJL) induced by shifting light-dark cycles repeatedly is a commonly used protocol to mimic the environmental light/dark changes encountered by shift workers. Here we subjected wildtype mice to CJL and performed positron emission tomography imaging of glucose metabolism to monitor brain activities. We al ...[more]

PMID: 33087702

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Project description:BackgroundEvidence suggests that circadian rhythm disorder is associated with a variety of gastrointestinal diseases, and the circadian rhythm plays a key role in maintaining the homeostasis of intestinal flora. The underlying mechanisms are still not completely identified. This study was aimed to explore whether jet lag-caused circadian disruption influences gut microbiome and its metabolites.MethodsMice were synchronized with 12-h light/dark cycles (control group) or subjected to daily 8-h advance of the light/dark cycle for every 3 days (jet-lagged group). Four months later, fecal samples and jejunal contents were collected and analyzed by 16S rRNA gene sequencing. In addition, fecal samples were subjected to metabolome analysis with ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS).ResultsThe results of 16s rRNA sequencing showed that chronic jet lag led to decreased microbial abundance, richness, and diversity in both feces and jejunal contents. ANOSIM analysis revealed significant difference between control and jet-lagged groups. As the colonic microbiome, the abundance of Bacteroidetes phylum was significantly decreased and that of Actinobacteria phylum was increased in jet-lagged mice. Jet lag increased the ratio of Firmicutes to Bacteroidetes, an indicator for the imbalance of gut microbiota. Metabolome analysis of fecal samples showed that the levels of tryptophan and its derivatives were decreased in jet-lagged mice. In addition, fecal levels of secondary bile acids changed under jet lag conditions. Correlation analysis identified associations between tryptophan (and its derivatives) levels and colonic microbiota.ConclusionsThis study presents a comprehensive landscape of gut microbiota and its metabolites in mice subjected to chronic jet lag. The results suggest that circadian disruption may lead to changes in fecal and jejunal microbiota and fecal metabolites. Moreover, our results demonstrate a novel interplay between the gut microbiome and metabolome.

Project description:Background: Disruption of natural diurnal light cycles, such as that experienced by shift workers, is linked to enhanced cancer incidence. Several mouse models of cancer have been shown to develop more severe disease when exposed to irregular light/dark cycles, further supporting the connection between circadian disruption and increased cancer risk. Cryptochrome 2 (CRY2), a repressive component of the molecular circadian clock, facilitates the turnover of the oncoprotein c-MYC, one mechanism that may link the molecular clock to tumorigenesis. In Eμ-MYC mice, which express transgenic c-MYC in B cells and develop aggressive lymphomas and leukemia, global Cry2 deletion reduces overall survival and enhances tumor formation. Lighting conditions that mimic the disruption experienced by shift workers dampen Cry2 transcripts in peripheral tissues of C57BL/6J mice. Although it is much milder than homozygous deletion of Cry2, we hypothesized that reduced Cry2 rhythmicity could alter MYC protein accumulation and contribute to enhanced cancer risk caused by circadian disruption. We decided to test this hypothesis in the context of MYC-driven lymphoma. Methods: We housed Eμ-MYC mice in light-tight boxes set to either the control (continuous cycles of 12-hours of light followed by 12-hours of dark, LD12:12) or chronic jetlag (eight-hour light phase advances every two to three days, CJL) lighting conditions and assessed the impact of disrupted light cycles on overall survival and tumor formation in Eμ-MYC mice. Results: Environmental disruption of circadian rhythms did not alter tumor location, tumor growth, or overall survival in female or male Eμ-MYC mice on the c57BL6 genetic background. Conclusions: The dampened transcriptional rhythms of Cry2 caused by exposure to disruption of circadian light exposures is very different from the complete loss of Cry2 expression caused by genetic deletion. The lack of any phenotype caused by altered circadian gene expression patterns in contrast to the enhanced tumorigenesis caused by homozygous deletion of Cry2 suggests that the dosage of CRY2 may impact this model. Importantly, these findings indicate that the well-documented increase in cancer risk associated with circadian disruption arises from one or more mechanisms that are not recapitulated in this mouse model, and may be different in distinct tumor types.

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Brain activity and transcriptional profiling in mice under chronic jet lag.

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Brain activity and transcriptional profiling in mice under chronic jet lag.

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