Adaptation to Experimental Jet-Lag in R6/2 Mice despite Circadian Dysrhythmia

Abstract

The R6/2 transgenic mouse model of Huntington’s disease (HD) shows a disintegration of circadian rhythms that can be delayed by pharmacological and non-pharmacological means. Since the molecular machinery underlying the circadian clocks is intact, albeit progressively dysfunctional, we wondered if light phase shifts could modulate the deterioration in daily rhythms in R6/2 mice. Mice were subjected to four x 4 hour advances in light onset. R6/2 mice adapted to phase advances, although angles of entrainment increased with age. A second cohort was subjected to a jet-lag paradigm (6 hour delay or advance in light onset, then reversal after 2 weeks). R6/2 mice adapted to the original shift, but could not adjust accurately to the reversal. Interestingly, phase shifts ameliorated the circadian rhythm breakdown seen in R6/2 mice under normal LD conditions. Our previous finding that the circadian period (tau) of 16 week old R6/2 mice shortens to approximately 23 hours may explain how they adapt to phase advances and maintain regular circadian rhythms. We tested this using a 23 hour period light/dark cycle. R6/2 mice entrained to this cycle, but onsets of activity continued to advance, and circadian rhythms still disintegrated. Therefore, the beneficial effects of phase-shifting are not due solely to the light cycle being closer to the tau of the mice. Our data show that R6/2 mice can adapt to changes in the LD schedule, even beyond the age when their circadian rhythms would normally disintegrate. Nevertheless, they show abnormal responses to changes in light cycles. These might be caused by a shortened tau, impaired photic re-synchronization, impaired light detection and/or reduced masking by evening light. If similar abnormalities are present in HD patients, they may suffer exaggerated jet-lag. Since the underlying molecular clock mechanism remains intact, light may be a useful treatment for circadian dysfunction in HD.

Abnormal Photic Entrainment to Phase-Delaying Stimuli in the R6/2 Mouse Model of Huntington's Disease, despite Retinal Responsiveness to Light

“…As seen previously under DD, with age R6/2 mice exhibited a progressively shorter period length than was seen in WT mice (Wood et al, 2013;Ouk et al, 2017). In mice under DD at 12-13 weeks of age, there was a main effect of genotype on period length (F (1,32) ϭ 16.2; p ϭ 3E-4 w ), amplitude of rhythms (F (1,32) ϭ 14.41; p ϭ 0,0006 x ), and activity counts (F (1,32) ϭ 21.43; p ϭ 6E-5 y ), with all these parameters significantly decreased in R6/2 mice compared with WT mice (Fig.…”

“…While our Per1 light-induced expression data support previous findings that the molecular machinery of the SCN is intact, they also indicate that retinal dysfunction is unlikely to be the sole cause of dysrhythmia in R6/2 mice. In support of this suggestion, previous studies have shown that R6/2 mice respond to bright light (Cuesta et al, 2014), jet lag (Wood et al, 2013), and photoperiod length variation (Ouk et al, 2017). This raises the possi-bility that the involvement of downstream areas of the brain innervated by the SCN causes the disruption of the behavioral response to the phase-delaying light pulse.…”

“…Behaviorally, however, the situation is complex. The period length of R6/2 mice under a 12 h LD cycle is pathologically shortened (to ϳ23 h) as the disease progresses (Wood et al, 2013;Ouk et al, 2017), which is consistent with a progressive insensitivity to light. Nevertheless, symptomatic R6/2 mice remain behaviorally responsive to paradigms involving light manipulations.…”

“…The period length of R6/2 mice shortens pathologically under both DD and LL. This is also the case under a 12 h LD cycle, when the period length shortens to ϳ23 h as the disease progresses (Wood et al, 2013;Ouk et al, 2017). It is, therefore, not surprising that R6/2 mice can entrain more easily to T22 than to T26 since T22 is closer to their endogenous rhythms and required slowing down the molecular machinery of the SCN.…”

“…Nevertheless, symptomatic R6/2 mice remain behaviorally responsive to paradigms involving light manipulations. Bright-light therapy delays circadian rhythm disruption (Cuesta et al, 2014), and R6/2 mice can entrain to a 23 h day and adapt to phase advances in the jet lag paradigm (Wood et al, 2013). Furthermore, variations of photoperiod lengths are able to reverse, accelerate, or delay the circadian disruption (Ouk et al, 2017).…”