Circadian and cardiovascular dysfunction in the Huntington’s disease mouse models

Circadian and sleep disruptions have been shown to lead to an increased risk for cardiovascular (CV) events. Huntington’s disease (HD) patients are reported to have various symptoms including circadian and motor deficits. In addition, CV symptoms are implicated as the cause of death in over 30% of the HD patient population. However, very little is understood about the intersection between circadian disruption, CV disease, and HD. Here we utilized two mouse models, BACHD and Q175, to investigate CV pathology in HD. Reduced diurnal and circadian resting heart rate rhythms, heart rate variability, and baroreceptor reflex support that the autonomic regulation of the CV system is compromised in both HD mouse lines. In addition, age-dependent reduction in the heart function and cardiac fibrosis were observed. These results led us to test the hypothesis that reducing the mutant huntingtin (mHtt) expression in the cardiomyocytes is sufficient to rescue CV symptoms seen in BACHD mice by crossing with the cardiomyocyte-specific Cre, Myh6-Cre. Our results show that reduced mHtt expression in the cardiomyocytes help improve left ventricular ejection fraction, several heart disease markers, and grip strength, a behavioral marker of cardiovascular health in the BACHD mice. Together this data indicates that heart disease in HD patients is likely to be driven both by cardiomyocyte specific pathology as well as dysfunction in the ANS

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 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

Impact of Nicotine Exposure on Hair Cell Toxicity and Embryotoxicity During Zebrafish Development

Objectives Nicotine has various adverse effects including negative impacts associated with maternal exposure. In the current study, we examined nicotine-induced damage of hair cells and embryotoxicity during zebrafish development. Methods Zebrafish embryos were exposed to nicotine at several concentrations (5, 10, 20, and 40 μM) and embryotoxicity were evaluated at 72 hours, including hatching rate, mortality, teratogenicity rate, and heart rate. Hair cells within the supraorbital (SO1 and SO2), otic (O1), and occipital (OC1) neuromasts were identified at 120 hours. Apoptosis and mitochondrial damage of hair cells were analyzed using TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling) and DASPEI (2-[4-(dimethylamino)styryl]-N-ethylpyridinium iodide) assays, respectively, and changes of ultrastructure were observed by scanning electron microscopy. Results The control group without nicotine appeared normal with overall mortality and teratogenicity rate <5%. The hatching rate and mortality rate was not significantly different according to nicotine concentration (n=400 each). The abnormal morphology rate (n=400) increased and heart rate (n=150) decreased with increasing nicotine concentration (P<0.05). Nicotine-induced hair cell damage significantly increased as nicotine concentration increased. A significantly greater number of TUNEL-positive cells (P<0.01) and markedly smaller DASPEI area (P<0.01) were shown as nicotine concentration increased. Conclusion The current results suggest that nicotine induces dose-dependent hair cell toxicity in embryos by promoting apoptosis and mitochondrial and structural damage

Circadian and cardiovascular dysfunction in the Huntington’s disease mouse models

Circadian and sleep disruptions have been shown to lead to an increased risk for cardiovascular (CV) events. Huntington’s disease (HD) patients are reported to have various symptoms including circadian and motor deficits. In addition, CV symptoms are implicated as the cause of death in over 30% of the HD patient population. However, very little is understood about the intersection between circadian disruption, CV disease, and HD. Here we utilized two mouse models, BACHD and Q175, to investigate CV pathology in HD. Reduced diurnal and circadian resting heart rate rhythms, heart rate variability, and baroreceptor reflex support that the autonomic regulation of the CV system is compromised in both HD mouse lines. In addition, age-dependent reduction in the heart function and cardiac fibrosis were observed. These results led us to test the hypothesis that reducing the mutant huntingtin (mHtt) expression in the cardiomyocytes is sufficient to rescue CV symptoms seen in BACHD mice by crossing with the cardiomyocyte-specific Cre, Myh6-Cre. Our results show that reduced mHtt expression in the cardiomyocytes help improve left ventricular ejection fraction, several heart disease markers, and grip strength, a behavioral marker of cardiovascular health in the BACHD mice. Together this data indicates that heart disease in HD patients is likely to be driven both by cardiomyocyte specific pathology as well as dysfunction in the ANS

Aggregating multiple probability intervals to improve their calibration

Many empirical studies have shown that interval probability estimates are too narrow (overconfident). We show that the \u27Wisdom of Crowds\u27 can mitigate the bias and improve the accuracy of the estimates by combining individual intervals. We re-analyzed data from the studies of Glaser, Langer, and Weber (2012) and Soll and Klayman (2004) . We applied 5- Averaging, Median, Enveloping, Probability averaging, and Quartiles- to combine the upper and lower bounds of the individual judges. Several measures were implemented for evaluating the methods. All methods were able to correct for the common miscalibration at different degrees and Quartiles was the most beneficial securing accuracy and informativeness

Voltage- and Calcium-Activated Potassium Channel Voltage Sensor Remodeling by Modulatory Beta Subunits and Heme

Large-conductance voltage- and Ca2+-activated K+ channels (BK) have a broad distribution of expression in mammalian cells. BK channels are activated by the membrane depolarization and elevation of intracellular free calcium. When the channel is activated, it allows an increase in potassium permeability, which hyperpolarizes the membrane electrical potential, suppressing cellular excitability. This membrane hyperpolarization decreases the activity of voltage-gated channels, including Ca2+ channels: the latter confers a significant role of BK channels in the internal calcium homeostasis. BK channels are involved in various fundamental physiological processes including the control of blood pressure and neuronal excitability. The BK channel is a homotetramer consisting of four pore-forming alpha subunits, which encode for seven membrane-spanning domains (S0-S6) and two large intracellular domains, RCK1 and RCK2. S0-S4 segments are known as the voltage sensing domain (VSD); S5 and S6 form the pore region and are involved in ion selectivity, while the RCK domains assemble into the ligand-sensing Gating Ring superstructure. In different tissues, the activity of BK alpha subunits is tuned by their association with modulatory beta subunits, beta1-4. The first project investigated the voltage-dependent structural rearrangements of the human BK channel in the presence of beta1 subunit. The data showed that the association of beta 1 remodeled the VSD movements. It is postulated that the association with beta1 destabilizes the active conformation of the voltage sensor in the absence of Ca2+, thus producing an overall right shift in its voltage dependence. BK channels are also modulated by small cytosolic ligands such as heme. The RCK1-RCK2 linker possesses a conserved heme regulation motif (HRM) and exhibited structural homology to cytochrome C (CytC), a hemoprotein. In particular, BK Methionine-691 aligned with M80 of the CytC, the second axial ligand (outside the HRM) to the heme iron. The goal of the second project aimed to understand the role of M691 in the BK regulation by heme. The mutation M691A dramatically diminished the inhibition of BK channel opening by heme (100 nM) compared with the wild-type BK, suggesting that M691 is critical for heme binding

Do Disruptions in the Circadian Timing System Contribute to Autonomic Dysfunction in Huntington's Disease?

Huntington's disease (HD) patients suffer from a progressive neurodegenerative disorder that inflicts both motor and non-motor symptoms. HD is caused by a CAG repeat expansion within the first exon of the huntingtin (HTT) gene that produces a polyglutamine repeat that leads to protein misfolding, soluble aggregates, and inclusion bodies detected throughout the body. Both clinical and preclinical research indicate that cardiovascular dysfunction should be considered a core symptom in at least a subset of HD patients. There is strong evidence for dysautonomia (dysfunctional autonomic nervous system, ANS) in HD patients that can be detected early in the disease progression. The temporal patterning of ANS function is controlled by the circadian timing system based in the anterior hypothalamus. Patients with neurodegenerative diseases including HD exhibit disrupted sleep/wake cycle and, in preclinical models, there is compelling evidence that the circadian timing system is compromised early in the disease process. Here we review data from preclinical models of HD that explore the intersection between disruption of circadian rhythms and dysautonomia. This work will lead to new therapeutic strategies and standards of care for HD and other neurodegenerative diseases