The Q175 Mouse Model of Huntington’s Disease Shows Gene Dosage- and Age-Related Decline in Circadian Rhythms of Activity and Sleep Dawn H. Loh, Takashi Kudo, Danny Truong, Yingfei Wu, Christopher S. Colwell* Laboratory of Circadian and Sleep Medicine, Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California, United States of America Abstract Sleep and circadian disruptions are commonly reported by patients with neurodegenerative diseases, suggesting these may be an endophenotype of the disorders. Several mouse models of Huntington’s disease (HD) that recapitulate the disease progression and motor dysfunction of HD also exhibit sleep and circadian rhythm disruption. Of these, the strongest effects are observed in the transgenic models with multiple copies of mutant huntingtin gene. For developing treatments of the human disease, knock-in (KI) models offer advantages of genetic precision of the insertion and control of mutation copy number. Therefore, we assayed locomotor activity and immobility-defined sleep in a new model of HD with an expansion of the KI repeats (Q175). We found evidence for gene dose- and age-dependent circadian disruption in the behavior of the Q175 line. We did not see evidence for loss of cells or disruption of the molecular oscillator in the master pacemaker, the suprachiasmatic nucleus (SCN). The combination of the precise genetic targeting in the Q175 model and the observed sleep and circadian disruptions make it tractable to study the interaction of the underlying pathology of HD and the mechanisms by which the disruptions occur. Citation: Loh DH, Kudo T, Truong D, Wu Y, Colwell CS (2013) The Q175 Mouse Model of Huntington’s Disease Shows Gene Dosage- and Age-Related Decline in Circadian Rhythms of Activity and Sleep. PLoS ONE 8(7): e69993. doi:10.1371/journal.pone.0069993 Editor: Eric M. Mintz, Kent State University, United States of America Received April 2, 2013; Accepted June 18, 2013; Published July 30, 2013 Copyright: ß 2013 Loh et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study was supported by the CHDI Foundation (http://chdifoundation.org/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: ccolwell@mednet.ucla.edu Introduction Huntington’s disease (HD) is characterized by motor dysfunc- tion and cognitive decline, and is caused by an autosomal dominant expansion of CAG repeats in the Huntingtin (HTT) gene [1]. HD patients present primarily with involuntary movements (chorea) and loss of motor control. It is invariably fatal, age of onset varies with the severity of the mutation, and there are no significant treatment options to date [2,3]. In addition to the motor dysfunction, HD patients often present with non-motor symptoms that include cognitive dysfunction [4,5], affective disorders [6–8] and sleep and circadian rhythm disruptions [9– 12], which can all precede the onset of chorea. As sleep and circadian disruptions can themselves lead to similar non-motor symptoms like mood disorders and cognitive dysfunction (e.g. [13– 16]), it is vital to parse out the relative contribution of sleep and circadian rhythm disruptions. To study the underlying mechanisms of sleep-wake disturbances associated with HD, we first need to identify suitable animal models that recapitulate as many symptom sets of HD as possible. While there are numerous mouse models of HD, no single model has yet been determined to be the ideal mirror of human HD [17]. Two examples of transgenic insertion HD mouse models are the exon 1-fragment model (R6/2 [18]) and the stable 90Q-repeat with full-length human HTT gene model (BACHD [19]). Circadian deficits begin in the R6/2 line at 10 weeks, starting with imprecise activity onset and progressing to a complete loss of rhythms in activity [10,20]. The BACHD model exhibits a decline in the power of circadian rhythms of activity at 3 months [20,21]. Of the current complement of HD mouse models, the knock-in of 140 CAG repeats into exon 1 of the mouse Htt gene (CAG140 KI [22,23]) has considerable benefits as the genetically precise insertion of the mutation into the Htt locus rules out position and copy number effects that may affect the other transgenic models. The age-related decline in circadian rhythms in the CAG 140 KI line was not distinguishable from the age-related decline also observed in WT mice at 12 months of age, suggesting that the effects of the targeted CAG repeats are subtle in the heterozygote mutants [20]. A spontaneous expansion mutant that arose in this line of mice, with over 175 CAG repeats (Q175), has motor and cognitive deficits that have earlier onsets than the CAG140 line [24], and thus may also exhibit sleep and circadian rhythm disruption that can be detected before WT rhythms also decline. We examined the spontaneous expansion Q175 model for sleep and circadian rhythm disruptions over the course of 12 months of age. We also examined the decline in motor function and the impact of the mutation on circadian gene expression in the SCN. Methods Animals The experimental protocols used in this study were approved by the UCLA Animal Research Committee (ARC 2009-022), and all PLOS ONE | www.plosone.org 1 July 2013 | Volume 8 | Issue 7 | e69993