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The Effect of Cicadian Therapies in Models of Neurodegenerative Disease
Get PDFHuntington’s Disease (HD) is an autosomal dominant disorder caused by excessive CAG repeats in the gene encoding the huntingtin protein which leads to progressive neurodegeneration that inflicts cognitive, psychiatric, cardiovascular and motor dysfunction. There is currently no treatment to prevent or delay the course of the disease. Neuronal loss in the striatum is thought to be responsible for the abnormal motor control present in HD patients, though the pathophysiology behind the non-motor symptoms is still unclear. Disturbances in sleep-wake cycles are common among HD patients with reports of delayed sleep onset, frequent bedtime awakenings, and excessive fatigue, and these disruptions are recapitulated in mouse models. Because circadian dysfunction manifests early in the disease in both patients and mouse models, we sought to determine if early interventions that improve circadian rhythmicity could benefit HD symptoms and delay disease progression. Evidence of altered histaminergic signaling in HD patients suggests that this pathway may contribute to disrupted rhythms in arousal. Utilizing the Q175 mouse model of HD, we demonstrated that nightly treatment with a histamine-3 receptor antagonist/inverse agonist improved several behavioral measures of HD including strengthening activity rhythms, cognitive performance, and mood, as well as reducing inappropriate activity during the normal sleep time. Our findings suggest that drugs targeting the histamine-3 receptor system may be beneficial as cognitive enhancers in the management of HD.One of the most powerful regulators of the circadian system is the daily feed/fast cycle, and in two separate studies we found that three months of time-restricted feeding (6-hours of feeding in the middle of the active phase followed by 18-hours fasting) improved the sleep/wake cycle, motor symptoms, and autonomic function in both the Q175 and BACHD mouse models.Finally, we sought to determine whether a ketogenic diet was sufficient to impart motor performance and sleep/wake rhythm benefits in BACHD mice similar to those observed under TRF. We found that the ketogenic diet improves circadian dysfunction as well as motor symptoms in the BACHD mouse model.Altogether, these studies support the hypothesis that early interventions that improve sleep/wake timing and circadian rhythmicity can ameliorate a range of symptoms of HD and related neurodegenerative disorders
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A study on circadian regulation of the cardiovascular system: dysfunction in the BACHD Huntington's Disease model and Vasoactive Intestinal Peptide-deficient mice and the use of scheduled exercise to rescue circadian deficits.
Get PDFThe 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
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The mechanisms underlying exacerbated autistic behavior induced by the circadian-disrupting environment of nightly illumination.
Get PDFAutism spectrum disorders (ASD) are a set challenging neurodevelopmental disorders with extremely high prevalence and expensive social cost. There is a good evidence for a genetic contribution to ASD but environment factors also play a role and interact with the genetic loads as a “second-hit” that further exacerbated the syndrome. The later raise the possibility that dysfunctional circadian rhythms may contribute to the disease improving these rhythms may offer a mechanism to help with the management of ASD symptoms. Robust circadian rhythms and good quality of sleep are restorative and critical for many of the same behaviors that are compromised in ASD. However, the possibility that circadian disruption is one of the environmental factors that contribute to the disease has not been well studied. Using the contactin associated protein-like 2 knock out (Cntnap2 KO) mouse model of ASD, this dissertation research addressed this issue by determine whether a mild circadian disruption caused by dim light at night (DLaN) impacts wild type (WT) and Cntnap2 KO mice. In the first study, I demonstrated that the Cntnap2 mutants are vulnerable to DLaN exposure by showing light-evoked disruptions in sleep/wake cycles, the social impairments, and repetitive grooming behavior. Nightly treatment with melatonin was effective in counteracting the negative effects of DLaN. Next, I examined the pathways by which DLaN was detected and specifically explored the role of the photopigment melanopsin in mediating DLaN consequences. The effects of DLaN on circadian behavior, social behavior, and repetitive behavior were prevented in a line of mice in which the cells expressing melanopsin are genetically ablated. In addition, knowing the melanopsin is largely sensitive to light in the blue/green wavelengths, a specialized LED-system was used that minimized the melanopsin activation while still providing illumination for vision. The illumination produced by this lighting system prevented the negative impacts of DLaN. In the third study, I aimed to evaluate the role of inflammation in mediating the effects of DLaN. The Cntnap2 mutation itself was found to alter the immune profiles in the plasma and the prefrontal cortex, and made the mutants even more vulnerable to the DLaN perturbation compared to the WT controls. Moreover, an inhibitor targeting COX-2 signaling effectively blocked DLaN-evoked inflammation as well as the behavioral changes caused by this environmental second hit. Together, this dissertation work supports a model in which DLaN activates inflammatory pathway. Increase in these inflammatory molecules drives behavioral changes. Widely used, inexpensive pharmacological treatments were found to prevent these adverse behavioral changes. Finally, in the last study, a second mouse model of ASD - the fragile X mental retardation 1 (Fmr1) KO mice, was used to test the principle hypothesis that circadian interventions can be beneficial to ASD
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Ionic mechanisms of circadian disruption
Get PDFThe temporal patterning of biological function is regulated by the circadian system on the cellular and systemic levels. In mammals, rhythmic neural output from the suprachiasmatic nucleus (SCN) of the hypothalamus provides the temporal cues needed to sustain synchronous cellular oscillations within tissues throughout the body, and coordinate those rhythms across systems to generate patterns of behavior and physiology essential for health and well-being. Genetic factors that may contribute to the dysfunction of the circadian system include sex, alterations in vasoactive intestinal peptide (VIP) signaling, and the Huntington’s disease (HD) causing mutation, all of which are associated with the increased prevalence of behavioral and physiological rhythm disruptions. By examining the SCN for patterns of electrical activity and alteration in the ionic mechanisms that regulate those activities, we determined sex differences in the balance between GABA excitation and inhibition may predispose females to circadian disruption. Secondly, disrupted electrical activity rhythms in animals lacking VIP is associated with deficits in rhythmic behavior/physiology and photic entrainment. Thirdly, reduced A-type/H and enhanced BK potassium currents are associated with the loss of rhythmic SCN electrical activity in the BACHD mouse model of HD
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Vasoactive intestinal peptide shapes photic communication across the circadian visual system
Get PDFCircadian rhythms affect human health and well-being by temporally organizing biological processes and fitting them to a 24 hour period. In mammals, circadian rhythm generation and organization are regulated by oscillatory networks in the heterogeneous suprachiasmatic nucleus (SCN) of the hypothalamus. Acute light resets the phase of these networks at night by an incompletely understood mechanism that involves changes in the transcriptional status of the immediate early gene c-fos and the clock gene Per1 in individual SCN cells. Neuropeptides, which anatomically define the SCN's functionally distinct core and shell subregions, have also emerged as important players in this light response pathway. The following set of studies examines how one such neuropeptide, vasoactive intestinal peptide (VIP), contributes to the gene expression changes across the SCN network during a successful phase shift. Experiments show that in response to a phase shifting light pulse, mice genetically deficient in VIP: 1) have acute, blunted molecular responses of c-FOS and Per1 in the SCN, 2) do not sustain gene expression changes in c-FOS and Per1 across SCN cells over time, and 3) lack gene expression changes of c-FOS and Per1 specifically in the SCN shell. Because these effects of VIP may be either acute or chronic due to an organizational or developmental role for VIP, experiments were also carried out to identify anatomical changes in the SCN of mice genetically deficient in VIP. Results suggest that specific changes to the light-input side of the circuit are altered when VIP is absent, indicating an organizational role for this neuropeptide. These changes include increased retinal afferent terminal branching and decreased androgen receptor expression in the retino-recipient region of the SCN. Interestingly, there did not appear to be changes in intra-SCN connectivity in mice lacking VIP, as determined by analysis of Golgi impregnated neurons. These data together suggest that VIP acts not only acutely to affect photic signaling, but it also plays a role in the structuring of the SCN to allow for the efficient flow of photic phase resetting information from retinal inputs across the circadian system
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Circadian and cardiovascular dysfunction in the Huntington’s disease mouse models
Get PDFCircadian 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
Hypertension Caused by Disruption of the Circadian System:Blood Pressure Regulation at Multiple Levels
No full textThe chapter begins with explaining the effects of deleting of Cry genes which causes complete loss of circadian rhythms and leads to hyperaldosteronism and salt‐sensitive hypertension. Aldosterone induces reabsorption of ions and water in the kidneys, thereby increasing blood volume, leading to higher blood pressure. Since primary aldosteronism (PA) carries a higher risk of developing cardiovascular complications, accurate diagnosis and treatment of idiopathic hyperaldosteronism are particularly important. The pathological conditions of Cry‐null mice may play an important role in unraveling the pathophysiology of PA and salt‐sensitive hypertension in humans. Intriguingly, Miyajima et al. (1991) reports that muscle sympathetic nerve activity increases in essential hypertension and renovascular hypertension but decreases in PA. Baroreflex is very important for rapid regulation of blood pressure. The regulation of blood pressure is crucially important and, thus, is controlled by multilayered regulatory systems
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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Corticosterone and carbenoxolone effects on neural cell proliferation in the adult songbird
Get PDFAcute and/or chronic stress can negatively affect neurogenesis of mammals and birds via action of the stress hormone and glucocorticoid, corticosterone (CORT). The zebra finch ventricular zone (VZ) has persistent neurogenesis during adulthood. Our lab previously reported that the adult female VZ is protected from stress-induced declines in neurogenesis in contrast to males. 11-beta hydroxysteroid dehydrogenases (11β HSDs) regulate CORT, with the type 2 isoform de-activating it. In this study, we tested the hypothesis that inhibiting this enzyme with carbenoxolone will reduce neurogenesis in females and further decrease it males. We measured cell proliferation using the mitotic marker 5’-bromo-2’deoxyuridine (BrdU) and treated brain slices with CORT reflecting increasing stress levels with or without carbenoxolone. We found no effect of CORT or CORT paired with CBX on either male or female neurogenesis. Our findings indicate that perhaps 11β HSD2 does not mediate the previously-observed sex differences in adult neurogenesis
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