Circadian dysfunction in the Q175 model of Huntington's disease: Network analysis

Abstract

Disturbances in sleep/wake cycle are a common complaint of individuals with Huntington's disease (HD) and are displayed by HD mouse models. The underlying mechanisms, including the possible role of the circadian timing system, have been the topic of a number of recent studies. The (z)Q175 mouse is a knock‐in model in which the human exon 1 sequence of the huntingtin gene is inserted into the mouse DNA with approximately 190 CAG repeats. Among the numerous models available, the heterozygous Q175 offers strong construct validity with a single copy of the mutation, genetic precision of the insertion and control of mutation copy number. In this review, we will summarize the evidence that this model exhibits disrupted diurnal and circadian rhythms in locomotor activity. We found overwhelming evidence for autonomic dysfunction including blunted daily rhythms in heart rate and core body temperature (CBT), reduced heart rate variability, and almost a complete failure of the sympathetic arm of the autonomic nervous system to function during the baroreceptor reflex. Mechanistically, the Q175 mouse model exhibits deficits in the neural output of the central circadian clock, the suprachiasmatic nucleus along with an enhancement of at least one type of potassium current in these neurons. Finally, we report a novel network analysis examining the phase coherence between activity, CBT, and cardiovascular measures. Such analyses found that even young Q175 mutants (heterozygous or homozygous) show coherence degradation, and suggests that loss of phase coherence is a variable that should be considered as a possible biomarker for HD.

The Molecular Clock and Neurodegenerative Disease: A Stressful Time

“…There were selective deficits in circadian activity such as lower waking activities and more fragmented sleep patterns. ASO mice had normal Per2 expression and lower daytime firing rates in the SCN neurons, which have also been observed in HD models (Smarr et al, 2019). Importantly, ASO mice showed no negative effects in their light adaptation responses, indicating that photic entrainment remained intact.…”

“…The rhythmicity of peripheral oscillators is also affected by HD. Q175 mice have blunted cardiac and body temperature rhythms, impaired autonomic nervous system function, and a completely ablated sympathetic nervous system ( Smarr et al, 2019 ). A newly emerging chronotherapy is time restricted feeding (TRF), in which eating is restricted to a 6- to 8-h time window ( Manoogian and Panda, 2017 ).…”

Maternal stress during pregnancy alters fetal cortico-cerebellar connectivity in utero and increases child sleep problems after birth

“…This may have caused the finding of a significant ratio between circadian and ultradian power, in the absence of an association for either one alone. Importantly, it has recently been found that ultradian rhythms by circadian rhythms are indicative of health [51][52][53] , indicating that the ratio between circadian and ultradian power is of particular interest. Consistent with this observation, we found that higher maternal prenatal stress correlated with a lower ratio between circadian and ultradian power.…”

Hsp40 overexpression in pacemaker neurons delays circadian dysfunction in a Drosophila model of Huntington's disease

“…In R6/2 HD mice, free-running activity rhythms are disrupted, and the SCN molecular oscillations are impaired in vivo , while persisting in organotypic slices, suggesting that the inputs to and outputs from the central clock are affected rather than the molecular clock ( Morton et al, 2005 ; Pallier et al, 2007 ). Dysfunctional intrinsically photosensitive retinal ganglion cells, reduction of VIP immunostaining in the SCN, and disrupted rhythms in SCN electrophysiology, cortisol, melatonin, body temperature, heart rate and metabolic outputs ( Smarr et al, 2019 ; Fifel and Videnovic, 2020 ; Colwell, 2021 ) provide evidence for circadian disturbances in HD mice at levels of clock input and output, thus also affecting molecular clockwork in vivo , resulting in overt behavioural and peripheral rhythm disturbances. Although the HD flies used in this study had a subset of their clock neurons targeted, they exhibited a definite circadian disturbance in the overt behavioural rhythms, molecular oscillations, and circadian output neuropeptide Pdf, recapitulating the central clock and circadian output impairments seen in vivo in HD mice.…”