CaMKIIα mediates feedback effects of wheel-running activity on the circadian pacemaker in mice.

CaMKIIα functional knockout mouse (K42R) showed substantial changes in the entrainment pattern of running-wheel (RW) rhythm to a short (LD6:18) but not to a long (LD18:6) photoperiod. In wild type mice (WT), entrainment to LD6:18 occurred at the light-off phase, whereas in most K42R entrainment took place at the light-on phase. These differences are well explained by lengthening of circadian period (τ) and compromising the couplings between the activity-onset and -end in K42R. Indeed, τ in K42R and WT were longer and shorter than 24 h, respectively, under the following constant darkness (DD). Without RW τ was lengthened in WT, whereas it was shortened in K42R. Similarly, activity time was lengthened in WT but shortened in K42R. Importantly, τ without RW was not different between the two genotypes, which were confirmed in naive mice. Tau and α returned to the pre-removal levels after RW re-introduction in both WT and K42R. These results indicate that the changes of behavioral rhythm in K42R are due to a lack of feedback effects of RW activity, which are mediated by CaMKIIα-dependent mechanisms. A two-oscillator model assuming involvement of CaMKIIα in the coupling between them successfully simulated the effects of RW activity in K42R.