Circadian-based Treatment Strategy Effective in the BACHD Mouse Model of Huntington’s Disease

Daniel S. Whittaker, Dawn H. Loh, Huei Bin Wang, Yu Tahara, Dika Kuljis, Tamara Cutler, Cristina A. Ghiani, Shigenobu Shibata, Gene D. Block, Christopher S. Colwell

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Huntington’s disease (HD) patients suffer from 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 excessive fatigue. The BACHD mouse model exhibits many HD core symptoms including circadian dysfunction. Because circadian dysfunction manifests early in the disease in both patients and mouse models, we sought to determine if early interventions that improve circadian rhythmicity could benefit HD symptoms and delay disease progression. We evaluated the effects of time-restricted feeding (TRF) on the BACHD mouse model. At 3 months of age, the animals were divided into 2 groups: ad lib and TRF. The TRF-treated BACHD mice were exposed to a 6-h feeding/18-h fasting regimen that was designed to be aligned with the middle (ZT 15-21) of the period when mice are normally active (ZT 12-24). Following 3 months of treatment (when mice reached the early disease stage), the TRF-treated BACHD mice showed improvements in their locomotor activity and sleep behavioral rhythms. Furthermore, we found improved heart rate variability, suggesting that their autonomic nervous system dysfunction was improved. On a molecular level, TRF altered the phase but not the amplitude of the PER2::LUC rhythms measured in vivo and in vitro. Importantly, treated BACHD mice exhibited improved motor performance compared with untreated BACHD controls, and the motor improvements were correlated with improved circadian output. It is worth emphasizing that 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. Our study demonstrates the therapeutic potential of circadian-based treatment strategies in a preclinical model of HD.

Original languageEnglish
JournalJournal of Biological Rhythms
DOIs
Publication statusAccepted/In press - 2018 Jan 1

Fingerprint

Huntington Disease
Sleep
Therapeutics
Disease Progression
Autonomic Nervous System
Periodicity
Locomotion
Fatigue
Psychiatry
Life Style
Fasting
Heart Rate
Quality of Life

Keywords

  • BACHD
  • circadian rhythms
  • feed/fast cycle
  • Huntington’s disease
  • time-restricted feeding

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Whittaker, D. S., Loh, D. H., Wang, H. B., Tahara, Y., Kuljis, D., Cutler, T., ... Colwell, C. S. (Accepted/In press). Circadian-based Treatment Strategy Effective in the BACHD Mouse Model of Huntington’s Disease. Journal of Biological Rhythms. https://doi.org/10.1177/0748730418790401

Circadian-based Treatment Strategy Effective in the BACHD Mouse Model of Huntington’s Disease. / Whittaker, Daniel S.; Loh, Dawn H.; Wang, Huei Bin; Tahara, Yu; Kuljis, Dika; Cutler, Tamara; Ghiani, Cristina A.; Shibata, Shigenobu; Block, Gene D.; Colwell, Christopher S.

In: Journal of Biological Rhythms, 01.01.2018.

Research output: Contribution to journalArticle

Whittaker, Daniel S. ; Loh, Dawn H. ; Wang, Huei Bin ; Tahara, Yu ; Kuljis, Dika ; Cutler, Tamara ; Ghiani, Cristina A. ; Shibata, Shigenobu ; Block, Gene D. ; Colwell, Christopher S. / Circadian-based Treatment Strategy Effective in the BACHD Mouse Model of Huntington’s Disease. In: Journal of Biological Rhythms. 2018.
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