Dysfunctions in circadian behavior and physiology in mouse models of Huntington's disease

Abstract

Many patients with Huntington's disease (HD) exhibit disturbances in their daily cycle of sleep and wake as part of their symptoms. These patients have difficulty sleeping at night and staying awake during the day, which has a profound impact on the quality of life of the patients and their care-givers. In the present study, we examined diurnal and circadian rhythms of four models of HD including the BACHD, CAG 140 knock-in and R6/2 CAG 140 and R6/2 CAG 250 lines of mice. The BACHD and both R6/2 lines showed profound circadian phenotypes as measured by wheel-running activity. Focusing on the BACHD line for further analysis, the amplitude of the rhythms in the BACHD mice declined progressively with age. In addition, the circadian regulation of heart rate and body temperature in freely behaving BACHD mice were also disrupted. Furthermore, the distribution of sleep as well as the autonomic regulation of heart rate was disrupted in this HD model. To better understand the mechanistic underpinnings of the circadian disruption, we used electrophysiological tools to record from neurons within the central clock in the suprachiasmatic nucleus (SCN). The BACHD mice exhibit reduced rhythms in spontaneous electrical activity in SCN neurons. Interestingly, the expression of the clock gene PERIOD2 was not altered in the SCN of the BACHD line. Together, this data is consistent with the hypothesis that the HD mutations interfere with the expression of robust circadian rhythms in behavior and physiology. The data raise the possibility that the electrical activity within the central clock itself may be altered in this disease.

Circadian rhythm disruption in a mouse model of Rett syndrome circadian disruption in RTT

“…Methods used were similar to those described previously (Kudo et al, 2011;Loh et al, 2013). Male Mecp2 −/y mutant mice and WT littermates were housed in cages containing running wheels (Mini Mitter Co., Bend, OR) from 6 to 7 weeks of age and their wheelrunning activity recorded as revolutions (rev) per 3 min intervals.…”

“…Methods used were similar to those described previously (Kudo et al, 2011. Male Mecp2 −/y mutant mice and WT littermates (6-7 weeks old) entrained on a 12:12 LD or DL cycle were anesthetized in an isoflurane chamber at ZT 2.5 and ZT 12.5 for ZT 4-6 and ZT 14-16 recordings respectively.…”

Sleep deficits but no metabolic deficits in premanifest Huntington's disease

“…Although pathogenic pathways are beginning to be unraveled offering targets for treatment,8 the precise pathophysiological mechanisms of HD are poorly understood 9. Previously we have shown that sleep disturbances are present in early manifest disease,10 and several studies on transgenic animal models of HD have shown that sleep progressively worsens as the disease develops11, 12, 13, 14 dependently on age and gene dosage 15. However, we do not know whether sleep problems are present during the premanifest stage in individuals carrying the HD gene mutation.…”

Inhibition of specific histone deacetylases suppresses pathogenesis in a Drosophila model of Huntington’s disease

“…15). HD patients display sleep disturbances, including insomnia and altered circadian rhythms [Taylor et al, 1997;Morton et al, 2005], and this aspect of the disease is mirrored in animal models [Morton et al, 2005;Rudenko et al, 2009;Gonzales and Yin, 2010;Kudo et al, 2011;Oakeshott et al, 2011]. In two recently published studies, SIRT1 was shown to counteract the activity of the clock machinery and regulate several circadian genes [Asher et al, 2008;Nakahata et al, 2008].…”

“…Sleep disturbances are a prominent feature of Huntington's disease that can interfere with quality of life, as patients often have difficulty sleeping at night and staying awake during the day; these phenotypes have been replicated in several models of HD [Morton et al, 2005;Videnovic et al, 2009;Gonzales and Yin, 2010;Kudo et al, 2011]. We hypothesized that, if our Httex1p Q93 model also exhibits abnormal sleep behavior and if the reported biochemical interaction of Sir2 with clock genes is indicative of a regulatory relationship between Sir2 and the circadian machinery in vivo, reducing Sir2 levels might improve the altered activity rhythms of mutant Htt expressing flies.…”