Disintegration of the Sleep-Wake Cycle and Circadian Timing in Huntington's Disease

Abstract

Sleepdisturbancesinneurologicaldisordershaveadevastatingimpactonpatientandcareralike.However,theirpathologicaloriginisunknown.Here we show that patients with Huntington's disease (HD) have disrupted night-day activity patterns. This disruption was mirrored in a transgenic model of HD (R6/2 mice) in which daytime activity increased and nocturnal activity fell, eventually leading to the complete disintegration of circadian behavior. The behavioral disturbance was accompanied by marked disruption of expression of the circadian clock genes mPer2 and mBmal1 in the suprachiasmatic nuclei (SCN), the principal circadian pacemaker in the brain. The circadian peak of expression of mPer2 was prematurely truncated, and the mRNA levels of mBmal1 were attenuated and failed to exhibit a significant circadian oscillation. Circadian cycles of gene expression in the motor cortex and striatum, markers of behavioral activation in wild-type mice, were also suppressed in the R6/2 mice, providing a neural correlate of the disturbed activity cycles. Increased daytime activity was also associated with reduced SCN expression of prokineticin 2, a transcriptional target of mBmal1 encoding a neuropeptide that normally suppresses daytime activity in nocturnal mammals. Together, these molecular abnormalities could explain the pathophysiological changes in circadian behavior. We propose that circadian sleep disturbances are an important pathological feature of HD, that they arise from pathology within the SCN molecular oscillation, and that their treatment will bring appreciable benefits to HD patients.

The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

“…As stated above (Section 1), there is a disintegration of the normal sleep-wake cycle and circadian rhythms in R6/2 mice (Morton et al, 2005b), and this deregulation can contribute, at least in part, to the cognitive deficits observed in these transgenic mice. Thus, in a recent study R6/2 mice were treated with the sedative drug chloral hydrate or alprazolam (a short-acting benzodiazepine) to test whether circadian and cognitive disturbances could be reversed by imposing a daily cycle of sleep .…”

“…On the other hand, "dark cell degeneration" has also been described in a small number of neurons in 12- (Stack et al, 2005) and 14-week-old mice (i.e., at a very late stage in the development of the disease) (Iannicola et al, 2000;Turmaine et al, 2000;Yu et al, 2003). Moreover, a progressive loss of orexin neurons was found in the lateral hypothalamus of R6/2 mice, which was correlated with the occurrence of narcoleptic-like episodes and seemed to be related with a disintegration of the sleep-wake cycle and of the circadian rhythm in these mice (Morton et al, 2005b). Furthermore, a loss of retinal ganglion neurons was reported in these transgenic animals (Helmlinger et al, 2002).…”

Assessment of circadian function in fibroblasts of patients with bipolar disorder

“…Consistence with our hypothesis, attenuated expression of mBmal1 in SCN was reported to accompany disrupted rest-activity patterns in mouse models. 88 Furthermore, the CLOCK mutant mice, which have reduced pacemaker amplitude, 89 showed mania-like behavior. 90 It has been reported that reduced amplitude of circadian oscillators can increase the efficacy of perturbing agents such as light and other stimuli in causing phase shifts in various organisms.…”

The human lateral tuberal nucleus: Immunohistochemical characterization and analogy to the rodent PV1-nucleus

“…In individuals with either Parkinson's or Alzheimer's disease, the number of cells does not change, but their characteristics do: they undergo cytoskeletal alterations and manifest cytoplasmatic inclusions such as Levy bodies (Hofman, 1997;Braak and Braak, 1998;Kremer, 1992;Kremer et al, 1990;Kremer and Bots, 1993). The fact that patients with neurodegenerative disease often suffer from cachexia and sleep disorders during the later stages of their disease (Kremer, 1992;Braak and Braak, 1992;Morton et al, 2005), supports the contention that the human LTN may be involved in the regulation of food intake and of the sleep-wake cycle.…”