Neurocardiovascular deficits in the Q175 mouse model of Huntington's disease

Abstract

Cardiovascular dysautonomia as well as the deterioration of circadian rhythms are among the earliest detectable pathophysiological changes in individuals with Huntington's disease (HD). Preclinical research requires mouse models that recapitulate disease symptoms and the Q175 knock‐in model offers a number of advantages but potential autonomic dysfunction has not been explored. In this study, we sought to test the dual hypotheses that cardiovascular dysautonomia can be detected early in disease progression in the Q175 model and that this dysfunction varies with the daily cycle. Using radiotelemetry implants, we observed a significant reduction in the diurnal and circadian activity rhythms in the Q175 mutants at the youngest ages. By middle age, the autonomically driven rhythms in core body temperature were highly compromised, and the Q175 mutants exhibited striking episodes of hypothermia that increased in frequency with mutant huntingtin gene dosage. In addition, Q175 mutants showed higher resting heart rate (HR) during sleep and greatly reduced correlation between activity and HR. HR variability was reduced in the mutants in both time and frequency domains, providing more evidence of autonomic dysfunction. Measurement of the baroreceptor reflex revealed that the Q175 mutant could not appropriately increase HR in response to a pharmacologically induced decrease in blood pressure. Echocardiograms showed reduced ventricular mass and ejection fraction in mutant hearts. Finally, cardiac histopathology revealed localized points of fibrosis resembling those caused by myocardial infarction. Thus, the Q175 mouse model of HD exhibits cardiovascular dysautonomia similar to that seen in HD patients with prominent sympathetic dysfunction during the resting phase of the activity rhythm.

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

“…It has been shown that dysfunction in the circadian regulation of autonomic outputs can be detected early in disease progression in the Q175 mice (Cutler et al, 2017). In the present study, we measured the impact of TRF on activity, CBT, HR, and HRV measured simultaneously in freely moving Q175 mice (Fig.…”

“…It reflects the dynamic balance of sympathetic and parasympathetic control of heart function, and displays a robust circadian rhythm. A prior study demonstrated that the Q175 mice exhibit a loss of circadian control in HRV day/night differences, as well as an overall decrease in HRV over a 24-h period when compared to WT controls (Cutler et al, 2017). It is worthwhile to note that a similar decrease in HRV has also been reported in HD patients beginning during the presymptomatic stage of disease progression (Andrich et al, 2002; Aziz et al, 2010b).…”

“…For the telemetry measurements, methods employed were similar to those previously described (Schroeder et al, 2016; Cutler et al, 2017). Two groups (ad lib and TRF) of Het Q175 mice ( n = 7/group) were surgically implanted with a wireless radio-frequency transmitter (ETA-F20, Data Sciences International).…”

“…Data collection and analysis were performed as described previously (Cutler et al, 2017). Data were extracted in 20-s intervals then filtered to remove extreme noise.…”

Overview of Huntington's Disease Models: Neuropathological, Molecular, and Behavioral Differences

“…The expanded CAG encodes a long poly‐glutamine (poly‐Q) sequence insertion in which mutant HTT aggregates form inclusion bodies that disrupt multiple cellular functions. Although deficits in skeletal muscle energy metabolism (Lodi et al., ), insulin sensitivity (Lalic et al., ), cardiovascular (Cutler et al., ), endocrine function (Aziz et al., ; Moffitt, McPhail, Woodman, Hobbs, & Bates, ), muscle strength (Busse, Hughes, Wiles, & Rosser, ), as well as weight loss (Aziz et al., ) all occur in HD, the most debilitating symptoms are associated with CNS dysfunction. These symptoms typically emerge in the fourth or fifth decade of life and progress until death 10 or 15 years later.…”