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

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.

Time-Restricted Feeding Improves Circadian Dysfunction as well as Motor Symptoms in the Q175 Mouse Model of Huntington’s Disease

“…The locomotor activity recorded as previously described (Wang et al, 2017). Mice were entrained to a 12/12 h LD cycle for a minimum of two weeks before data collection.…”

“…We used the 10 d of activity data collected just before the motor performance tests during the final two weeks of the TRF schedule. The data were analyzed to determine the period and rhythmic strength as previously described (Loh et al, 2013; Wang et al, 2017). The periodogram analysis uses a χ 2 test with a threshold of 0.001 significance, from which the amplitude of the periodicities is determined at the circadian harmonic to obtain the rhythm power.…”

“…Immobility-defined sleep was determined as described previously (Loh et al, 2013; Wang et al, 2017). Mice were housed in see-through plastic cages containing bedding (without the addition of nesting material) and the food hopper.…”

“…The challenging beam test is a modified version of the beam traversal test first described by Goldberg and colleagues (Goldberg et al, 2003), and was used to characterize the motor deficits of Q175 mutant mice in previous studies (Loh et al, 2013, Wang et al, 2017). The beam narrows in four intervals from 33 mm > 24 mm > 18 mm > 6 mm, with each segment spanning 253 mm in length.…”

“…Tissue collection and data analysis were performed as described previously (Wang et al, 2017). Four weeks after the final behavioral tests were performed, the Q175 mutants were anesthetized with isoflurane before dissection of the striatum at ZT 15.…”