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

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 off...

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Autores principales: Cutler, Tamara S., Park, Saemi, Loh, Dawn H., Jordan, Maria C., Yokota, Tomohiro, Roos, Kenneth P., Ghiani, Cristina A., Colwell, Christopher S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471434/
https://www.ncbi.nlm.nih.gov/pubmed/28576852
http://dx.doi.org/10.14814/phy2.13289
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author Cutler, Tamara S.
Park, Saemi
Loh, Dawn H.
Jordan, Maria C.
Yokota, Tomohiro
Roos, Kenneth P.
Ghiani, Cristina A.
Colwell, Christopher S.
author_facet Cutler, Tamara S.
Park, Saemi
Loh, Dawn H.
Jordan, Maria C.
Yokota, Tomohiro
Roos, Kenneth P.
Ghiani, Cristina A.
Colwell, Christopher S.
author_sort Cutler, Tamara S.
collection PubMed
description 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.
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spelling pubmed-54714342017-06-21 Neurocardiovascular deficits in the Q175 mouse model of Huntington's disease Cutler, Tamara S. Park, Saemi Loh, Dawn H. Jordan, Maria C. Yokota, Tomohiro Roos, Kenneth P. Ghiani, Cristina A. Colwell, Christopher S. Physiol Rep Original Research 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. John Wiley and Sons Inc. 2017-06-02 /pmc/articles/PMC5471434/ /pubmed/28576852 http://dx.doi.org/10.14814/phy2.13289 Text en © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Research
Cutler, Tamara S.
Park, Saemi
Loh, Dawn H.
Jordan, Maria C.
Yokota, Tomohiro
Roos, Kenneth P.
Ghiani, Cristina A.
Colwell, Christopher S.
Neurocardiovascular deficits in the Q175 mouse model of Huntington's disease
title Neurocardiovascular deficits in the Q175 mouse model of Huntington's disease
title_full Neurocardiovascular deficits in the Q175 mouse model of Huntington's disease
title_fullStr Neurocardiovascular deficits in the Q175 mouse model of Huntington's disease
title_full_unstemmed Neurocardiovascular deficits in the Q175 mouse model of Huntington's disease
title_short Neurocardiovascular deficits in the Q175 mouse model of Huntington's disease
title_sort neurocardiovascular deficits in the q175 mouse model of huntington's disease
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471434/
https://www.ncbi.nlm.nih.gov/pubmed/28576852
http://dx.doi.org/10.14814/phy2.13289
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