Choroid plexus (ChP), the brain structure primarily responsible for cerebrospinal fluid production, contains a robust circadian clock, whose role remains to be elucidated. The aim of our study was to [1] identify rhythmically controlled cellular processes in the mouse ChP and [2] assess the role and nature of signals derived from the master clock in the suprachiasmatic nuclei (SCN) that control ChP rhythms. To accomplish this goal, we used various mouse models (WT, mPer2Luc, ChP-specific Bmal1 knockout) and combined multiple experimental approaches, including surgical lesion of the SCN (SCNx), time-resolved transcriptomics, and single cell luminescence microscopy. In ChP of control (Ctrl) mice collected every 4 h over 2 circadian cycles in darkness, we found that the ChP clock regulates many processes, including the cerebrospinal fluid circadian secretome, precisely times endoplasmic reticulum stress response, and controls genes involved in neurodegenerative diseases (Alzheimer's disease, Huntington's disease, and frontotemporal dementia). In ChP of SCNx mice, the rhythmicity detected in vivo and ex vivo was severely dampened to a comparable extent as in mice with ChP-specific Bmal1 knockout, and the dampened cellular rhythms were restored by daily injections of dexamethasone in mice. Our data demonstrate that the ChP clock controls tissue-specific gene expression and is strongly dependent on the presence of a functional connection with the SCN. The results may contribute to the search for a novel link between ChP clock disruption and impaired brain health.

• Keywords
• mPer2 Luc mouse, Choroid plexus, Circadian clock, Circadian transcriptome, Glucocorticoid, Mouse, Suprachiasmatic nuclei,
• MeSH
• Circadian Clocks * physiology   MeSH
• Circadian Rhythm physiology   MeSH
• Mice, Inbred C57BL MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Suprachiasmatic Nucleus * metabolism   physiology   MeSH
• Choroid Plexus * metabolism   physiology   MeSH
• ARNTL Transcription Factors metabolism   genetics   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Bmal1 protein, mouse MeSH Browser
• ARNTL Transcription Factors MeSH

The lifestyle of human society is drifting apart from the natural environmental cycles that have influenced it since its inception. These cycles were fundamental in structuring the daily lives of people in the pre-industrial era, whether they were seasonal or daily. Factors that disrupt the regularity of human behaviour and its alignment with solar cycles, such as late night activities accompanied with food intake, greatly disturb the internal temporal organization in the body. This is believed to contribute to the rise of the so-called diseases of civilization. In this review, we discuss the connection between misalignment in daily (circadian) regulation and its impact on health, with a focus on cardiovascular and metabolic disorders. Our aim is to review selected relevant research findings from laboratory and human studies to assess the extent of evidence for causality between circadian clock disruption and pathology. Keywords: Circadian clock, Chronodisruption, Metabolism, Cardiovascular disorders, Spontaneously hypertensive rat, Human, Social jetlag, Chronotype.

• MeSH
• Chronobiology Disorders physiopathology   metabolism   complications   MeSH
• Circadian Clocks physiology   MeSH
• Circadian Rhythm * physiology   MeSH
• Cardiovascular Diseases * metabolism   etiology   epidemiology   physiopathology   MeSH
• Humans MeSH
• Metabolic Diseases * metabolism   epidemiology   physiopathology   etiology   MeSH
• Disease Models, Animal MeSH
• Risk Factors MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Normal neurodevelopment requires precise expression of the key ubiquitin ligase gene Ube3a. Comparing newly generated mouse models for Ube3a downregulation (models of Angelman syndrome) vs. Ube3a upregulation (models for autism), we find reciprocal effects of Ube3a gene dosage on phenotypes associated with circadian rhythmicity, including the amount of locomotor activity. Consistent with results from neurons in general, we find that Ube3a is imprinted in neurons of the suprachiasmatic nuclei (SCN), the pacemaking circadian brain locus, despite other claims that SCN neurons were somehow exceptional to these imprinting rules. In addition, Ube3a-deficient mice lack the typical drop in wake late in the dark period and have blunted responses to sleep deprivation. Suppression of physical activity by light in Ube3a-deficient mice is not due to anxiety as measured by behavioral tests and stress hormones; quantification of stress hormones may provide a mechanistic link to sleep alteration and memory deficits caused by Ube3a deficiency, and serve as an easily measurable biomarker for evaluating potential therapeutic treatments for Angelman syndrome. We conclude that reduced Ube3a gene dosage affects not only neurodevelopment but also sleep patterns and circadian rhythms.

• Keywords
• Angelman syndrome, UBE3A (E6AP), autism, circadian, imprinting, neurodevelopmental disorders, sleep, ubiquitin ligase,
• Publication type
• Journal Article MeSH