Abstract
Cell birth and survival in the adult hippocampus are regulated by a circadian clock. Rotating shift work and jet lag disrupt circadian rhythms and aggravate disease. Internal misalignment, a state in which abnormal phase relationships prevail between and within organs, is proposed to account for adverse effects of circadian disruption. This hypothesis has been difficult to test because phase shifts of the entraining cycle inevitably lead to transient desynchrony. Thus, it remains possible that phase shifts, regardless of internal desynchrony, account for adverse effects of circadian disruption and alter neurogenesis and cell fate.
In order to address this question, we examined cell birth and differentiation in the duper Syrian hamster (Mesocricetus auratus), a Cry1-null mutant in which re-entrainment of locomotor rhythms is greatly accelerated. Adult females were subjected to alternating 8h advances and delays at eight 16-day intervals. BrdU, a cell birth marker, was given midway through the experiment. Repeated phase shifts decreased the number of newborn non-neuronal cells in wt, but not duper hamsters. The duper mutation increased the number of BrdU-ir cells that stained for NeuN, which marks neuronal differentiation. Immunocytochemical staining for proliferating cell nuclear antigen (PCNA) indicated no overall effect of genotype or repeated shifts on cell division rates at the time of sacrifice. Cell differentiation, assessed by doublecortin (DCX), was higher in duper hamsters but was not significantly altered by repeated phase shifts. Our results support the internal misalignment hypothesis, and indicate that Cry1 regulates cell differentiation. Phase shifts may determine neuronal stem cell survival and time course of differentiation after cell birth.
Significance Statement
The birth of neurons in adult brain impacts learning and memory. Circadian disruption, such as occurs in jet lag, adversely affects neurogenesis. It is unclear whether shifts of the light:dark cycle are inherently deleterious, or whether misalignment of the phase of circadian oscillators is responsible. Repeated shifts decreased the number of non-neuronal cells born in adult dentate gyrus of wild type hamsters, but increased the percentage that developed neuronal phenotype. Duper mutants, which are deficient in the core clock gene Cryptochrome 1 and re-entrain 4 times as fast as wild types, experienced increased neurogenesis but showed no effect of phase shifts. These results implicate Cry1 in regulation of neurogenesis and indicate that circadian misalignment is critical in jet lag.
Footnotes
The authors report no conflict of interest.
Supported by NIH RO1HL138551.
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