Spontaneous Recovery of Circadian Organization in Mice Lacking a Core Component of the Molecular Clockwork. Issue 1 (February 2022)

• Record Type: Journal Article
• Authors: Riggle, Jonathan P.; Onishi, Kenneth G.; Love, Jharnae A.; Beach, Dana E.; Zucker, Irving; Prendergast, Brian J.
• Is Part Of: Journal of biological rhythms. Volume 37:Issue 1(2022)
• Page Start: 94
• Page End: 109
• Publication Date: 2022-02
• Subjects: sex difference -- clock gene -- circadian arrhythmia -- per2 -- gonadectomy; Biological rhythms -- Periodicals; Circadian rhythms -- Periodicals; 571.77
• DOI: 10.1177/07487304211060896
• Languages: English
• ISSNs: 0748-7304

Abstract

Circadian rhythms are generated by interlocked transcriptional-translational feedback loops of circadian clock genes and their protein products. Mice homozygous for a functional deletion in the Period-2 gene ( Per2 m/m mice) exhibit short free-running circadian periods and eventually lose behavioral circadian rhythmicity in constant darkness (DD). We investigated Per2 m/m mice in DD for several months and identified a categorical sex difference in the dependence on Per2 for maintenance of circadian rhythms. Nearly all female Per2 m/m mice became circadian arrhythmic in DD, whereas free-running rhythms persisted in 37% of males. Remarkably, with extended testing, Per2 m/m mice did not remain arrhythmic in DD, but after varying intervals spontaneously recovered robust, free-running circadian rhythms, with periods shorter than those expressed prior to arrhythmia. Spontaneous recovery was strikingly sex-biased, occurring in 95% of females and 33% of males. Castration in adulthood resulted in male Per2 m/m mice exhibiting female-like levels of arrhythmia in DD, but did not affect spontaneous recovery. The circadian pacemaker of many gonad-intact males, but not females, can persist in DD for long intervals without a functional PER2 protein; their circadian clocks may be in an unstable equilibrium, incapable of sustaining persistent coherent circadian organization, resulting in transient cycles of circadian organization and arrhythmia.