PT  - JOURNAL ARTICLE
AU  - Huei-Bin Wang
AU  - Dawn H. Loh
AU  - Daniel S. Whittaker
AU  - Tamara Cutler
AU  - David Howland
AU  - Christopher S. Colwell
TI  - Time restricted feeding improves circadian dysfunction as well as motor symptoms in the Q175 mouse model of Huntington’s disease.
AID  - 10.1523/ENEURO.0431-17.2017
DP  - 2018 Jan 02
TA  - eneuro
PG  - ENEURO.0431-17.2017
4099  - http://www.eneuro.org/content/early/2018/01/02/ENEURO.0431-17.2017.short
4100  - http://www.eneuro.org/content/early/2018/01/02/ENEURO.0431-17.2017.full
AB  - Huntington’s disease (HD) patients suffer from a progressive neurodegeneration that results in cognitive, psychiatric, cardiovascular and motor dysfunction. Disturbances in sleep/wake cycles are common among HD patients with reports of delayed sleep onset, frequent bedtime awakenings, and fatigue during the day. The heterozygous Q175 mouse model of HD has been shown to phenocopy many HD core symptoms including circadian dysfunctions. Because circadian dysfunction manifests early in the disease in both patients and mouse models, we sought to determine if early intervention that improve circadian rhythmicity can benefit HD and delay disease progression. We determined the effects of time-restricted feeding (TRF) on the Q175 mouse model. At 6 months of age, the animals were divided into two groups: ad lib and TRF. The TRF-treated Q175 mice were exposed to a 6-hr feeding/18-hr fasting regimen that was designed to be aligned with the middle of the time when mice are normally active. After 3 months of treatment (when mice reached the early disease stage), the TRF-treated Q175 mice showed improvements in their locomotor activity rhythm and sleep awakening time. Furthermore, we found improved heart rate variability (HRV), suggesting that their autonomic nervous system dysfunction was improved. Importantly, treated Q175 mice exhibited improved motor performance compared to untreated Q175 controls, and the motor improvements were correlated with improved circadian output. Finally, we found that the expression of several HD-relevant markers were restored to WT levels in the striatum of the treated mice using NanoString gene expression assays.Significance Statement HD is a genetically caused disease with no known cure. Lifestyle changes that not only improve the quality of life but also delay disease progression for HD patients are greatly needed. In this study, we found that time restricted feeding (TRF) improves activity/rest rhythms in the Q175 mouse model of HD. This treatment also improved motor performance and heart rate variability in the HD mice. Finally, TRF altered the expression of HD relevant markers in the striatum. Our study demonstrates the therapeutic potential of circadian-based treatment strategies in a pre-clinical model of HD.