Transcriptional profiling of mouse prefrontal cortex and nucleus accumbens under chronic jet lag
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE153540 | GEO | 2020/10/01
REPOSITORIES: GEO
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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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Project description:Transcriptional profiling of mouse prefrontal cortex and nucleus accumbens under chronic jet lag
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Project description:BackgroundPatients with neurological disorders often display altered circadian rhythms. The disrupted circadian rhythms through chronic jetlag or shiftwork are thought to increase the risk and severity of human disease including, cancer, psychiatric, and related brain diseases.ResultsIn this study, we investigated the impact of shiftwork or chronic jetlag (CJL) like conditions on mice's brain. Transcriptome profiling based on RNA sequencing revealed that genes associated with serious neurological disorders were differentially expressed in the nucleus accumbens (NAc) and prefrontal cortex (PFC). According to the quantitative PCR (qPCR) analysis, several key regulatory genes associated with neurological disorders were significantly altered in the NAc, PFC, hypothalamus, hippocampus, and striatum. Serotonin levels and the expression levels of serotonin transporters and receptors were significantly altered in mice treated with CJL.ConclusionOverall, these results indicate that CJL may increase the risk of neurological disorders by disrupting the key regulatory genes, biological functions, serotonin, and corticosterone. These molecular linkages can further be studied to investigate the mechanism underlying CJL or shiftwork-mediated neurological disorders in order to develop treatment strategies.
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Project description:Travel across multiple time zones results in desynchronization of environmental time cues and the sleep-wake schedule from their normal phase relationships with the endogenous circadian system. Circadian misalignment can result in poor neurobehavioral performance, decreased sleep efficiency, and inappropriately timed physiological signals including gastrointestinal activity and hormone release. Frequent and repeated transmeridian travel is associated with long-term cognitive deficits, and rodents experimentally exposed to repeated schedule shifts have increased death rates. One approach to reduce the short-term circadian, sleep-wake, and performance problems is to use mathematical models of the circadian pacemaker to design countermeasures that rapidly shift the circadian pacemaker to align with the new schedule. In this paper, the use of mathematical models to design sleep-wake and countermeasure schedules for improved performance is demonstrated. We present an approach to designing interventions that combines an algorithm for optimal placement of countermeasures with a novel mode of schedule representation. With these methods, rapid circadian resynchrony and the resulting improvement in neurobehavioral performance can be quickly achieved even after moderate to large shifts in the sleep-wake schedule. The key schedule design inputs are endogenous circadian period length, desired sleep-wake schedule, length of intervention, background light level, and countermeasure strength. The new schedule representation facilitates schedule design, simulation studies, and experiment design and significantly decreases the amount of time to design an appropriate intervention. The method presented in this paper has direct implications for designing jet lag, shift-work, and non-24-hour schedules, including scheduling for extreme environments, such as in space, undersea, or in polar regions.
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Project description:Environmental compounds have been shown to promote epigenetic transgenerational inheritance of disease. The current study was designed to determine if a hydrocarbon mixture involving jet fuel (JP-8) promotes epigenetic transgenerational inheritance of disease. Gestating F0 generation female rats were transiently exposed during the fetal gonadal development period. The direct exposure F1 generation had an increased incidence of kidney abnormalities in both females and males, prostate and pubertal abnormalities in males, and primordial follicle loss and polycystic ovarian disease in females. The first transgenerational generation is the F3 generation, and the jet fuel lineage had an increased incidence of primordial follicle loss and polycystic ovarian disease in females, and obesity in both females and males. Analysis of the jet fuel lineage F3 generation sperm epigenome identified 33 differential DNA methylation regions, termed epimutations. Observations demonstrate hydrocarbons can promote epigenetic transgenerational inheritance of disease and sperm epimutations, potential biomarkers for ancestral exposures. Methylated sperm DNA was isolated from rats ancestrally exposed to jet fuel (Jip). Three independent samples from the treatment group were obtained. Differential DNA methylation between treatment groups was determined using Nimblegen microarrays. Treated samples were paired with control samples and hybridized together on arrays (Jip1/Cip1, Jip2/Cip2, and Jip3/Cip3), resulting in three arrays for the treatment.
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Project description:Environmental compounds have been shown to promote epigenetic transgenerational inheritance of disease. The current study was designed to determine if a hydrocarbon mixture involving jet fuel (JP-8) promotes epigenetic transgenerational inheritance of disease. Gestating F0 generation female rats were transiently exposed during the fetal gonadal development period. The direct exposure F1 generation had an increased incidence of kidney abnormalities in both females and males, prostate and pubertal abnormalities in males, and primordial follicle loss and polycystic ovarian disease in females. The first transgenerational generation is the F3 generation, and the jet fuel lineage had an increased incidence of primordial follicle loss and polycystic ovarian disease in females, and obesity in both females and males. Analysis of the jet fuel lineage F3 generation sperm epigenome identified 33 differential DNA methylation regions, termed epimutations. Observations demonstrate hydrocarbons can promote epigenetic transgenerational inheritance of disease and sperm epimutations, potential biomarkers for ancestral exposures.
2014-07-22 | GSE59553 | GEO
Project description:For many years now a treatment mitigating the debilitating effects of jet lag has been sought. Rapid travel across time zones leads, in most people, to temporary symptoms, in particular poor sleep, daytime alertness and poor performance. Mis-timed circadian rhythms are considered to be the main factor underlying jet-lag symptoms, together with the sleep deprivation from long haul flights. Virtually all aspects of physiology are rhythmic, from cells to systems, and circadian rhythms are coordinated by a central pacemaker or clock in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN adapts slowly to changes in time zone, and peripheral clocks or oscillators adapt at different rates, such that the organism is in a state of desynchrony from the external environment and internally. Light exposure is the main factor controlling the circadian system and needs to be considered together with any pharmacological interventions. This review covers the relatively new chronobiotic drugs, which can hasten adaptation of the circadian system, together with drugs directly affecting alertness and sleep propensity. No current treatment can instantly shift circadian phase to a new time zone; however, adaptation can be hastened. The melatoninergic drugs are promising but larger trials in real-life situations are needed. For short stopovers it is recommended to preserve sleep and alertness without necessarily modifying the circadian system. New research suggests that modification of clock function via genetic manipulation may one day have clinical applications.
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