Prolonged day length exposure improves circadian deficits and survival in a transgenic mouse model of Huntington's disease

Abstract

Prolonged day length exposure improves circadian deficits and survival in a transgenic mouse model of Huntington's disease, Neurobiology of Sleep and Circadian Rhythms, http://dx. AbstractThe circadian disruption seen in patients of Huntington's disease (HD) is recapitulated in the R6/2 mouse model. As the disease progresses, the activity of R6/2 mice increases dramatically during the rest (light) period and decreases during the active (dark) period, eventually leading to a complete disintegration of rest-activity rhythms by the age of ~16 weeks. The suprachiasmatic nucleus controls circadian rhythms by entraining the rest-activity rhythms to the environmental light-dark cycle. Since R6/2 mice can shift their rest-activity rhythms in response to a jet-lag paradigm and also respond positively to bright light therapy (1000 lux), we investigated whether or not a prolonged day length exposure could reduce their daytime activity and improve their behavioural circadian rhythms. We found that a long-day photoperiod (16 h light/8 h dark cycle; 100 lux) significantly improved the survival of R6/2 mice by 2.4 weeks, compared to mice kept under standard conditions (12 h light/12 h dark cycle). Furthermore, a long-day photoperiod improved the nocturnality of R6/2 mice. Mice kept under long-day photoperiod also maintained acrophase in activity rhythms (a parameter of rhythmicity strength) in phase with that of WT mice, even if they were symptomatic. By contrast, a short-day photoperiod (8 h light/16 h dark cycle) was deleterious to R6/2 mice and further reduced the survival by ~1 week. Together, our 2 results support the idea that light therapy may be beneficial for improving circadian dysfunction in HD patients. AbbreviationsANOVA -analysis of variance; DD -constant darkness; EEG -electroencephalography; HDHuntington's disease; HPA axis -hypothalamic-pituitary-adrenal axis; LD -light-dark; L-DOPA -levodopa; REM sleep -rapid eye movement sleep; SCN -suprachiasmatic nucleus; WT -wild type

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.…”

“…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).…”