Neurocardiovascular deficits in the Q175 mouse model of Huntington's disease. Issue 11 (2nd June 2017)

• Record Type: Journal Article
• Authors: Cutler, Tamara S.; Park, Saemi; Loh, Dawn H.; Jordan, Maria C.; Yokota, Tomohiro; Roos, Kenneth P.; Ghiani, Cristina A.; Colwell, Christopher S.
• Is Part Of: Physiological reports. Volume 5:Issue 11(2017)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2017-06-02
• Subjects: Autonomic nervous system -- baroreceptor reflex -- cardiovascular function -- circadian rhythms -- core body temperature -- echocardiograms -- electrocardiograms -- fibrosis -- heart rate variability -- Huntington's disease -- radio telemetry; Physiology -- Periodicals; 571
• DOI: 10.14814/phy2.13289
• Languages: English
• ISSNs: 2051-817X

Abstract

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. Abstract : Huntington's disease (HD) patients exhibit a high incidence of cardiovascular events leading to heart failure and death. Using the Q175 mouse model of HD, we uncover clear autonomic dysfunction that starts early in the disease progression. Importantly, many of the symptoms vary as a function of time of day and raise the possibility that the circadian cycle should be considered in the diagnosis and treatment of HD.