Blue light therapy improves circadian dysfunction as well as motor symptoms in two mouse models of Huntington's disease

Huei-Bin Wang; Daniel S Whittaker; Danny Truong; Aly K Mulji; Cristina A Ghiani; Dawn H Loh; Christopher S Colwell

doi:10.1016/j.nbscr.2016.12.002

Blue light therapy improves circadian dysfunction as well as motor symptoms in two mouse models of Huntington's disease

Neurobiol Sleep Circadian Rhythms. 2017 Jan 20:2:39-52. doi: 10.1016/j.nbscr.2016.12.002. eCollection 2017 Jan.

Authors

Huei-Bin Wang¹, Daniel S Whittaker¹, Danny Truong¹, Aly K Mulji^{1

2}, Cristina A Ghiani^{1

3}, Dawn H Loh¹, Christopher S Colwell¹

Affiliations

¹ Department of Psychiatry and Biobehavioral Sciences, University of California - Los Angeles, 710 Westwood Plaza, Los Angeles, CA 90024-1759, USA.
² Integrative Biology and Physiology, University of California - Los Angeles, 710 Westwood Plaza, Los Angeles, CA 90024-1759, USA.
³ Department of Pathology, Laboratory of Circadian and Sleep Medicine, University of California - Los Angeles, 710 Westwood Plaza, Los Angeles, CA 90024-1759, USA.

Abstract

Patients with Huntington's disease (HD) exhibit movement disorders, psychiatric disturbance and cognitive impairments as the disease progresses. Abnormal sleep/wake cycles are common among HD patients with reports of delayed sleep onset, fatigue during the day, and a delayed pattern of melatonin secretion all of which suggest circadian dysfunction. Mouse models of HD confirm disrupted circadian rhythms with pathophysiology found in the central circadian clock (suprachiasmatic nucleus). Importantly, circadian dysfunction manifests early in disease, even before the classic motor symptoms, in both patients and mouse models. Therefore, we hypothesize that the circadian dysfunction may interact with the disease pathology and exacerbate the HD symptoms. If correct, early intervention may benefit patients and delay disease progression. One test of this hypothesis is to determine whether light therapy designed to strengthen this intrinsic timing system can delay the disease progression in mouse models. Therefore, we determined the impact of blue wavelength-enriched light on two HD models: the BACHD and Q175 mice. Both models received 6 h of blue-light at the beginning of their daily light cycle for 3 months. After treatment, both genotypes showed improvements in their locomotor activity rhythm without significant change to their sleep behavior. Critically, treated mice of both lines exhibited improved motor performance compared to untreated controls. Focusing on the Q175 genotype, we sought to determine whether the treatment altered signaling pathways in brain regions known to be impacted by HD using NanoString gene expression assays. We found that the expression of several HD relevant markers was altered in the striatum and cortex of the treated mice. Our study demonstrates that strengthening the circadian system can delay the progression of HD in pre-clinical models. This work suggests that lighting conditions should be considered when managing treatment of HD and other neurodegenerative disorders.

Keywords: BACHD; BACHD, bacterial artificial chromosome mouse model of HD; Blue light therapy; Circadian rhythms; HD, Huntington's disease; HTT, Huntingtin protein; Htt, huntingtin gene; Huntington's disease; KI, knock in; Photic therapy; Q175; SCN, suprachiasmatic nucleus; UCLA, University of California, Los Angeles; ZT, Zeitgeber time; ipRGCs, intrinsically photoreceptive retinal ganglion cells.