UCLA

The circadian system coordinates rhythms of behavior, physiology and gene expression with the external cues of light and dark, and the dysfunction of this system leads to the development of disease. Huntington's disease patients experience circadian symptoms and are at an increased risk for serious cardiovascular events that often lead to death. We, therefore, explored circadian and cardiovascular dysfunction in the BACHD model of Huntington's disease (HD). Diurnal and circadian rhythms of heart rate (HR), heart rate variability (HRV) and body temperature were significantly blunted along with dysfunction of the autonomic nervous system as measured by baroreceptor reflex. Circadian disruption could be attributed to reduced Vasoactive Intestinal Peptide (VIP) signaling in HD, therefore, we examined whether cardiovascular rhythms were disrupted in the VIP-deficient mouse. We detected deficits in the diurnal and circadian rhythms of HR, HRV, body temperature and cage activity in VIP-deficient mice, suggesting that VIP is crucial for the circadian regulation of physiological outputs, including the cardiovascular system. Stabilization and realignment of the circadian system with the light/dark cycle may help decrease the risk of cardiovascular disease. Therefore, we explored the ability of scheduled exercise to drive and reorganize rhythms in behavior, physiology and gene expression in WT and VIP-deficient mice. Many of the deficits in diurnal rhythms displayed by VIP-deficient mice were rescued by exercise during the late night. In summary, these studies examined mechanisms by which the circadian system regulates the cardiovascular system using BACHD and VIP-deficient mice. We also introduced a new tool to help temporally restructure behavior, which improved various parameters of the circadian system in a circadian compromised mouse model. This tool could potentially be applied to humans with circadian symptoms, to help deter the development of cardiovascular disease associated with circadian disruption.