Disruption of Peripheral Circadian Timekeeping in a Mouse Model of Huntington's Disease and Its Restoration by Temporally Scheduled Feeding

Abstract

Behavioral circadian rhythms disintegrate progressively in the R6/2 mouse model of Huntington's disease (HD), recapitulating the sleep-wake disturbance seen in HD patients. Here we show that disturbances in circadian pacemaking are not restricted to the brain, but also encompass peripheral metabolic pathways in R6/2 mice. Notably, circadian rhythms of clock-driven genes that are key metabolic outputs in the liver are abolished in vivo. This deficiency is accompanied by arrhythmic expression of the clock genes Cry1 and Dbp, and a phase-advanced Per2 cycle. Compromised circadian metabolic cycles are not, however, a consequence of deficient pacemaking intrinsic to the liver, because when cultured in vitro, R6/2 liver slices exhibit self-sustained circadian bioluminescence rhythms. We therefore propose that compromised metabolic cycles arise from an internal desynchronization secondary to altered feeding patterns and impaired circadian signaling from the central pacemaker of the suprachiasmatic nucleus (SCN). Importantly, the SCN-independent food-entrainable oscillator remains intact in R6/2 mice and, when invoked, can restore daily behavioral cycles and reverse some of the metabolic abnormalities seen in the liver. Disturbances of metabolism have long been thought to be an important feature of HD. Uncoupling liver metabolism from circadian drives will reduce metabolic efficiency and cause imbalances in metabolites known to be deleterious to brain function. Thus, even subtle imbalances in liver function may exacerbate symptoms of HD, where neurological function is already compromised.

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

“…In the HD-N171-82Q mouse model, CR improves motor performance and survival while reducing cell death (Duan et al, 2003). Prior work in the R6/2 HD model has shown that TRF can restore HD-driven disruption in circadian gene expression in the liver (Maywood et al, 2010) and improve locomotor activity as well as exploratory behavior in the open field without increasing life span (Skillings et al, 2014). Together, these data suggest that feeding schedules could play a role in the treatment of HD and could lead to the development of new treatment options for neurodegenerative disorders.…”

Neuroendocrine and neurotrophic signaling in Huntington’s disease: Implications for pathogenic mechanisms and treatment strategies

“…For example, in the R6/2 mouse model of HD the rhythmic transcription of core clock genes in the SCN and other brain regions is disrupted in vivo, but then rescued when assessed in in vitro explants, suggesting that circadian deficits are due to alterations of the intrinsic circuitry of the SCN (20,90). This is supported by a reduced circadian rhythm in spontaneous electrical activity in SCN neurons in BACHD transgenic mice (89).…”

“…Support for this notion comes from transgenic animal models of HD, such as in the R6/2, R6/1 and BACHD mice, which have shown that circadian disruption precedes the presentation of disease features (20,89,90). Furthermore, humans with manifest HD also display circadian rhythm abnormalities, with disturbances in rest-activity profiles and abnormal day-night ratios, as well as alterations in sleep-wake timing and melatonin and cortisol profiles (20,88,91).…”

Disruption of gene expression rhythms in mice lacking secretory vesicle proteins IA-2 and IA-2β

“…Normally, SCN-regulated physiological rhythms lead to entrainment of peripheral oscillators, coordinating the cells within a tissue and resulting in rhythmic gene expression throughout the body (50,53). Even when the SCN is dysfunctional, manipulations, including glucocorticoid treatment, temporally restricted food intake, and forced exercise can entrain rhythmic gene expression rhythms in peripheral tissues (4,39,45,47,50).…”