Abnormal Photic Entrainment to Phase-Delaying Stimuli in the R6/2 Mouse Model of Huntington's Disease, despite Retinal Responsiveness to Light

Abstract

The circadian clock located in the suprachiasmatic nucleus (SCN) in mammals entrains to ambient light via the retinal photoreceptors. This allows behavioral rhythms to change in synchrony with seasonal and daily changes in light period. Circadian rhythmicity is progressively disrupted in Huntington's disease (HD) and in HD mouse models such as the transgenic R6/2 line. Although retinal afferent inputs to the SCN are disrupted in R6/2 mice at late stages, they can respond to changes in light/dark cycles, as seen in jet lag and 23 h/d paradigms. To investigate photic entrainment and SCN function in R6/2 mice at different stages of disease, we first assessed the effect on locomotor activity of exposure to a 15 min light pulse given at different times of the day. We then placed the mice under five non-standard light conditions. These were light cycle regimes (T-cycles) of T21 (10.5 h light/dark), T22 (11 h light/dark), T26 (13 h light/dark), constant light, or constant dark. We found a progressive impairment in photic synchronization in R6/2 mice when the stimuli required the SCN to lengthen rhythms (phase-delaying light pulse, T26, or constant light), but normal synchronization to stimuli that required the SCN to shorten rhythms (phase-advancing light pulse and T22). Despite the behavioral abnormalities, we found that Per1 and c-fos gene expression remained photo-inducible in SCN of R6/2 mice. Both the endogenous drift of the R6/2 mouse SCN to shorter periods and its inability to adapt to phase-delaying changes will contribute to the HD circadian dysfunction.

Rapid Jetlag Resetting of Behavioral, Physiological, and Molecular Rhythms in Proestrous Female Mice

“…One could speculate that the light pulse at ZT18 caused by the LD shift could have induced the accelerated phase shift in adult and aging females. This time point, however, lies within a "delay region" and therefore it causes phase delay under acute light exposure (Ouk et al, 2019;Pendergast et al, 2010). Furthermore, given that males exhibit greater phase shift to light pulses at the end of the dark phase compared with females (Brockman et al, 2011), we can reject the notion that the accelerated phase shift in PE and aging females is the result of a light pulse at ZT18.…”

Chronic circadian phase advance in male mice induces depressive-like responses and suppresses neuroimmune activation

“…Here, we hypothesized that modeling “chronic jetlag” in mice would alter mood and related neuroimmune pathways. We implemented a model of 6-hr phase advance of the light phase every 3 days; this produces a 22-hr-like (T22-like) cycle ( Casiraghi et al., 2012 ) that in mice is at the lower limit of the entrainment range ( Ouk et al., 2019 ; Walbeek and Gorman, 2017 ). Overall, our results show that mice undergoing chronic advance shifts have a more depressive-like phenotype.…”

A Phenomenological Mouse Circadian Pacemaker Model

“…Figure 4 demonstrates another validation of the model. With the C57BL/6J mouse model parameters ( Table 1 ), comparison of the generated model curves to the experimental data presented in Ouk et al (2019) results in a poor match, particularly near the region of phase delay near CT 15. This is expected since the mice used in Ouk et al (2019) are not wild-type C57BL/6J mice, but rather mice on a CBA × C57BL/6J background.…”

“…With the C57BL/6J mouse model parameters ( Table 1 ), comparison of the generated model curves to the experimental data presented in Ouk et al (2019) results in a poor match, particularly near the region of phase delay near CT 15. This is expected since the mice used in Ouk et al (2019) are not wild-type C57BL/6J mice, but rather mice on a CBA × C57BL/6J background. There are several experimental discrepancies in circadian photosensitivity results between the CBA and C57BL/6 mouse, which are discussed by Yoshimura et al (1994) .…”

“…As a further validation of the model parameters, and to demonstrate the sensitivity of the parameters to specific strains of mice, we also compared our model with the data for a non-C57BL/6J mouse. Ouk et al (2019) used mice from a CBA × C57BL/6J background. The mice were entrained to an LD12:12 cycle for 7 to 10 days, followed by 10 to 14 days in DD.…”