Perioddetermination in the food-entrainable and methamphetamine-sensitive circadian oscillator(s)

Abstract

Daily rhythmic processes are coordinated by circadian clocks, which are present in numerous central and peripheral tissues. In mammals, two circadian clocks, the food-entrainable oscillator (FEO) and methamphetamine-sensitive circadian oscillator (MASCO), are "black box" mysteries because their anatomical loci are unknown and their outputs are not expressed under normal physiological conditions. In the current study, the investigation of the timekeeping mechanisms of the FEO and MASCO in mice with disruption of all three paralogs of the canonical clock gene, Period, revealed unique and convergent findings. We found that both the MASCO and FEO in Per1 −/− /Per2 −/− /Per3 −/− mice are circadian oscillators with unusually short (∼21 h) periods. These data demonstrate that the canonical Period genes are involved in period determination in the FEO and MASCO, and computational modeling supports the hypothesis that the FEO and MASCO use the same timekeeping mechanism or are the same circadian oscillator. Finally, these studies identify Per1 −/− /Per2 −/− /Per3 −/− mice as a unique tool critical to the search for the elusive anatomical location(s) of the FEO and MASCO. food anticipatory activity | restricted feeding | suprachiasmatic nuclei | knockout | C57BL/6J

Sincronização fótica e não fótica dos ritmos circadianos em roedores subterrâneos (Ctenomys aff. knighti) e roedores modelo de laboratório (Mus musculus)

“…After the palatable meal-induced behavior rhythms (PICO outputs) were extinguished (evidenced by the presence of ultradian, but no circadian rhythms), mice were administered low-dose methamphetamine (0.005%) in their drinking water. Consistent with our previous study, all Per1/2/3 mutant mice exhibited consolidated activity (Pendergast et al, 2012). Mice initially had a ~18-h period of wheelrunning activity rhythm that persisted for several days and then switched to a stable 22-h period (Fig.…”

“…One argument in favor of this hypothesis is the maintenance of both oscillators in clockgene mutant mice (e.g. Pendergast et al 2012). …”

“…Nevertheless, the SCN has the role of a central oscillator, at the top of the hierarchy, coordinating the rhythms of peripheral oscillators and mediating photic entrainment of the circadian system (Dibner et al, 2010;Yoo et al, 2004). the expression of food anticipatory activity (FAA), the output of FEO, was confirmed in many mutant mice with deficiencies in clockgenes, some of which completely impaired the functionality of the molecular clock mechanism (Iijima et al, 2005;Pitts et al, 2003;Pendergast et al, 2009;Storch et al, 2009;Pendergast et al, 2012). This indicates that the generation of rhythmicity in the FEO relies on an alternative molecular mechanism.…”

“…-/-mice (C57BL/6J N15) for 4 to 6 generations in our breeding colony (Pendergast et al, 2012). All mice were bred and maintained in 12L:12D illuminated by fluorescent bulbs (Ecolux, 32W).…”

The Genetics of Circadian Rhythms

“…In Drosophila PER acts as the primary negative regulator, however in mouse mPER1, mPER2 and mPER3 each play independent roles in the maintenance of molecular clocks (19). An example of this is that mPER3, has a negligible role in circadian rhythms in the brain (19), but plays a role in the regulation of circadian rhythms in peripheral tissues (20). CRY paralogs show similar complexity with double knockout mutant mice for both mCRY1 and mCRY2 displaying an arrhythmic phenotype while a loss of function for one or the other resulting in either shortened or lengthened period by 1 hour, respectively (21).…”