The Circadian Biology of Heart Failure.

Driven by autonomous molecular clocks that are synchronized by a master pacemaker in the suprachiasmatic nucleus, cardiac physiology fluctuates in diurnal rhythms that can be partly or entirely circadian. Cardiac contractility, metabolism, and electrophysiology, all have diurnal rhythms, as does the neurohumoral control of cardiac and kidney function. In this review, we discuss the evidence that circadian biology regulates cardiac function, how molecular clocks may relate to the pathogenesis of heart failure, and how chronotherapeutics might be applied in heart failure. Disrupting molecular clocks can lead to heart failure in animal models, and the myocardial response to injury seems to be conditioned by the time of day. Human studies are consistent with these findings, and they implicate the clock and circadian rhythms in the pathogenesis of heart failure. Certain circadian rhythms are maintained in patients with heart failure, a factor that can guide optimal timing of therapy. Pharmacologic and nonpharmacologic manipulation of circadian rhythms and molecular clocks show promise in the prevention and treatment of heart failure.

HDAC6 regulates glucocorticoid receptor signaling in serotonin pathways with critical impact on stress resilience.

Genetic variations in certain components of the glucocorticoid receptor (GR) chaperone complex have been associated with the development of stress-related affective disorders and individual variability in therapeutic responses to antidepressants. Mechanisms that link GR chaperoning and stress susceptibility are not well understood. Here, we show that the effects of glucocorticoid hormones on socioaffective behaviors are critically regulated via reversible acetylation of Hsp90, a key component of the GR chaperone complex. We provide pharmacological and genetic evidence indicating that the cytoplasmic lysine deacetylase HDAC6 controls Hsp90 acetylation in the brain, and thereby modulates Hsp90-GR protein-protein interactions, as well as hormone- and stress-induced GR translocation, with a critical impact on GR downstream signaling and behavior. Pet1-Cre-driven deletion of HDAC6 in serotonin neurons, the densest HDAC6-expressing cell group in the mouse brain, dramatically reduced acute anxiogenic effects of the glucocorticoid hormone corticosterone in the open-field, elevated plus maze, and social interaction tests. Serotonin-selective depletion of HDAC6 also blocked the expression of social avoidance in mice exposed to chronic social defeat and concurrently prevented the electrophysiological and morphological changes induced, in serotonin neurons, by this murine model of traumatic stress. Together, these results identify HDAC6 inhibition as a potential new strategy for proresilience and antidepressant interventions through regulation of the Hsp90-GR heterocomplex and focal prevention of GR signaling in serotonin pathways. Our data thus uncover an alternate mechanism by which pan-HDAC inhibitors may regulate stress-related behaviors independently of their action on histones.

Caloric restriction experience reprograms stress and orexigenic pathways and promotes binge eating.

Long-term weight management by dieting has a high failure rate. Pharmacological targets have focused on appetite reduction, although less is understood as to the potential contributions of the stress state during dieting in long-term behavioral modification. In a mouse model of moderate caloric restriction in which a 10-15% weight loss similar to human dieting is produced, we examined physiological and behavioral stress measures. After 3 weeks of restriction, mice showed significant increases in immobile time in a tail suspension test and stress-induced corticosterone levels. Increased stress was associated with brain region-specific alterations of corticotropin-releasing factor expression and promoter methylation, changes that were not normalized with refeeding. Similar outcomes were produced by high-fat diet withdrawal, an additional component of human dieting. In examination of long-term behavioral consequences, previously restricted mice showed a significant increase in binge eating of a palatable high-fat food during stress exposure. Orexigenic hormones, melanin-concentrating hormone (MCH) and orexin, were significantly elevated in response to the high-fat diet only in previously restricted mice. Furthermore, administration of the MCH receptor-1 antagonist GSK-856464 [4-(4-ethyl-5-methylsulfanyl-1,2,4-triazol-3-yl)pyridine] significantly reduced total caloric intake in these mice during high-fat access. These results reveal reprogramming of key central pathways involved in regulating stress responsivity and orexigenic drives by moderate caloric restriction experience. In humans, such changes would be expected to reduce treatment success by promoting behaviors resulting in weight regain, and suggest that management of stress during dieting may be beneficial in long-term maintenance.

Considerations for the Safe Operation of Schools During the Coronavirus Pandemic.

During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, providing safe in-person schooling has been a dynamic process balancing evolving community disease burden, scientific information, and local regulatory requirements with the mandate for education. Considerations include the health risks of SARS-CoV-2 infection and its post-acute sequelae, the impact of remote learning or periods of quarantine on education and well-being of children, and the contribution of schools to viral circulation in the community. The risk for infections that may occur within schools is related to the incidence of SARS-CoV-2 infections within the local community. Thus, persistent suppression of viral circulation in the community through effective public health measures including vaccination is critical to in-person schooling. Evidence suggests that the likelihood of transmission of SARS-CoV-2 within schools can be minimized if mitigation strategies are rationally combined. This article reviews evidence-based approaches and practices for the continual operation of in-person schooling.

Dysregulated editing of serotonin 2C receptor mRNAs results in energy dissipation and loss of fat mass.

RNA editing that converts adenosine to inosine replaces the gene-encoded Ile, Asn, and Ile (INI) of serotonin [5-hydroxytryptamine (5-HT)] receptor 2C (5-HT(2C)R) with Val, Gly, and Val (VGV). Up to 24 different 5-HT(2C)R isoforms are detected in different brain regions (Burns et al., 1997; Fitzgerald et al., 1999; Wang et al., 2000). To elucidate the physiological significance of 5-HT(2C)R mRNA editing, we derived mutant mouse lines harboring a knock-in INI or VGV allele, resulting in sole expression of one of two extremely different editing isoforms 5-HT(2C)R-INI (editing blocked) or -VGV (fully edited). Although INI mice grew normally, VGV mice had a severely reduced fat mass, despite compensatory hyperphagia, as a result of constitutive activation of the sympathetic nervous system and increased energy expenditure. Furthermore, serotonergic neurotransmission was oversensitized in VGV mice, most likely because of the increased cell surface expression of VGV receptors. Melanocortin 4 receptor (MC4R) regulates energy homeostasis (Balthasar et al., 2005; Heisler et al., 2006; Lam et al., 2008), and Mc4r(-/-) mice are obese because of hyperphagia and reduced energy expenditure (Huszar et al., 1997). However, the elevated energy expenditure of VGV mice could not be rescued in the Mc4r(-/-) background, indicating the presence of a distinct signaling pathway mediated via 5-HT(2C)R-VGV that dominates the MC4R-dependent pathway in control of energy expenditure. Our results highlight the importance of regulated 5-HT(2C)R mRNA editing, because dysregulation could result in the pathological consequences such as growth retardation seen in VGV mice.

Effects of stress on dietary preference and intake are dependent on access and stress sensitivity.

Recent studies support a link between stress and the increased consumption of palatable foods. However, there has been a noted lack of genetic models to examine predisposing factors of overweight, obesity, and binge eating, particularly the role that stress sensitivity might play in the development of these conditions. We have examined the effects of chronic stress exposure on macronutrient choice preferences in a genetic mouse model of stress sensitivity (corticotropin-releasing factor receptor-2 deficient mice). Mice were provided with high fat, high protein, and high carbohydrate diets during exposure to chronic variable stress (CVS). Mice given free access to these diets during CVS selected a greater proportion of their calories in the form of the high fat diet compared to non-stressed mice. Apparent genotypic differences in high protein and high carbohydrate preferences were also diminished during the stress exposure. Stress-sensitive mice showed reduced weight gain and caloric efficiency during CVS, indicating a role for this phenotype in energy balance. When the preferred high fat diet was provided under limited access, stress-sensitive mice showed an increase in high fat consumption during CVS that was not observed in wild type mice, indicating a potential role for stress sensitivity in stress-induced bingeing. These studies support an involvement of stress pathways in macronutrient selection where stress selectively elevates the intake of a preferred high fat diet. Based on the alterations in caloric efficiency, increases in stress sensitivity may further predispose an organism toward altered energy balance in times of stress.

Decreases in dietary preference produce increased emotionality and risk for dietary relapse.

BACKGROUND: Obesity is a modern health epidemic, with the overconsumption of highly palatable, calorically dense foods as a likely contributor. Despite the known consequences of obesity, behavioral noncompliance remains high, supporting the powerful rewarding properties of such foods. We hypothesized that exposure to preferred diets would result in an amelioration of stress responsivity via activation of reward pathways that would be reversed during dietary withdrawal, increasing the risk for relapse and treatment failure. METHODS: Mice were exposed to preferred diets high in fat or carbohydrates for 4 weeks and then were withdrawn to house chow. Behavioral, physiologic, and biochemical assays were performed to examine changes in stress and reward pathways. RESULTS: These studies revealed significant changes in arousal and anxiety-like behaviors, limbic corticotropin-releasing factor expression, and expression of reward-related signaling molecules in response to the highly preferred high-fat diet that was reversed by withdrawal. In a dietary-reinstatement model, mice withdrawn from the high-fat diet endured an aversive environment to gain access to the preferred food. CONCLUSIONS: Exposure to a highly preferred diet high in fat reduces stress sensitivity, whereas acute withdrawal from such a diet elevates the stress state and reduces reward, contributing to the drive for dietary relapse.

Enhancement of stress resilience through histone deacetylase 6-mediated regulation of glucocorticoid receptor chaperone dynamics.

BACKGROUND: Acetylation of heat shock protein 90 (Hsp90) regulates downstream hormone signaling via the glucocorticoid receptor (GR), but the role of this molecular mechanism in stress homeostasis is poorly understood. We tested whether acetylation of Hsp90 in the brain predicts and modulates the behavioral sequelae of a mouse model of social stress. METHODS: Mice subjected to chronic social defeat stress were stratified into resilient and vulnerable subpopulations. Hypothalamic-pituitary-adrenal axis function was probed using a dexamethasone/corticotropin-releasing factor test. Measurements of Hsp90 acetylation, Hsp90-GR interactions, and GR translocation were performed in the dorsal raphe nucleus. To manipulate Hsp90 acetylation, we pharmacologically inhibited histone deacetylase 6, a known deacetylase of Hsp90, or overexpressed a point mutant that mimics the hyperacetylated state of Hsp90 at lysine K294. RESULTS: Lower acetylated Hsp90, higher GR-Hsp90 association, and enhanced GR translocation were observed in dorsal raphe nucleus of vulnerable mice after chronic social defeat stress. Administration of ACY-738, a histone deacetylase 6-selective inhibitor, led to Hsp90 hyperacetylation in brain and in neuronal culture. In cell-based assays, ACY-738 increased the relative association of Hsp90 with FK506 binding protein 51 versus FK506 binding protein 52 and inhibited hormone-induced GR translocation. This effect was replicated by overexpressing the acetylation-mimic point mutant of Hsp90. In vivo, ACY-738 promoted resilience to chronic social defeat stress, and serotonin-selective viral overexpression of the acetylation-mimic mutant of Hsp90 in raphe neurons reproduced the behavioral effect of ACY-738. CONCLUSIONS: Hyperacetylation of Hsp90 is a predictor and causal molecular determinant of stress resilience in mice. Brain-penetrant histone deacetylase 6 inhibitors increase Hsp90 acetylation and modulate GR chaperone dynamics offering a promising strategy to curtail deleterious socioaffective effects of stress and glucocorticoids.

Delta FosB-mediated alterations in dopamine signaling are normalized by a palatable high-fat diet.

BACKGROUND: Sensitivity to reward has been implicated as a predisposing factor for behaviors related to drug abuse as well as overeating. However, the underlying mechanisms contributing to reward sensitivity are unknown. We hypothesized that a dysregulation in dopamine signaling might be an underlying cause of heightened reward sensitivity whereby rewarding stimuli could act to normalize the system. METHODS: We used a genetic mouse model of increased reward sensitivity, the Delta FosB-overexpressing mouse, to examine reward pathway changes in response to a palatable high-fat diet. Markers of reward signaling in these mice were examined both basally and following 6 weeks of palatable diet exposure. Mice were examined in a behavioral test following high-fat diet withdrawal to assess the vulnerability of this model to removal of rewarding stimuli. RESULTS: Our results demonstrate altered reward pathway activation along the nucleus accumbens-hypothalamic-ventral tegmental area circuitry resulting from overexpression of Delta FosB in the nucleus accumbens and striatal regions. Levels of phosphorylated cyclic adenosine monophosphate (cAMP) response element binding protein (pCREB), brain-derived neurotrophic factor (BDNF), and dopamine and cyclic adenosine monophosphate regulated phosphoprotein with a molecular mass of 32 kDa (DARPP-32) in the nucleus accumbens were reduced in Delta FosB mice, suggestive of reduced dopamine signaling. Six weeks of high-fat diet exposure completely ameliorated these differences, revealing the potent rewarding capacity of a palatable diet. Delta FosB mice also showed a significant increase in locomotor activity and anxiety-related responses 24 hours following high-fat withdrawal. CONCLUSIONS: These results establish an underlying sensitivity to changes in reward related to dysregulation of Delta FosB and dopamine signaling that can be normalized with palatable diets and may be a predisposing phenotype in some forms of obesity.