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

Modulation of stress and reward signaling by high fat diet and withdrawal

Interactions between neural stress and reward pathways underlie a number of modern health problems, including substance abuse and overeating. This work was designed to elucidate the mechanisms by which stress and reward influence palatable diet consumption, and how interactions between these systems contribute to behaviors related to food intake and preference. We utilized genetic models of heightened stress and reward sensitivity as well as environmental models of high fat diet withdrawal and early life exposure to investigate the effects of a natural reward, high fat diet, on neural pathways and behavior. Using a genetic model of increased stress sensitivity, we found that chronic variable stress leads to an increased preference for a high fat diet and an increased risk for binge-type eating. We built upon this study by showing that when access to a previously consumed high fat diet is removed, mice exhibit signs of increased emotionality and stress and decreased reward signaling. These changes are associated with an increased motivation to consume high fat diet in our dietary reinstatement paradigm. In subsequent mechanistic studies using a genetic model of increased reward sensitivity, we found evidence that increased motivation for reward is associated with reduced markers of basal dopamine signaling, and that consumption of a high fat diet ameliorates these deficits. We have shown that an increased vulnerability to dietary reinstatement persists for 4-6 weeks following diet withdrawal and is associated with changes in stress and reward signaling. Finally, in our early exposure model, we demonstrated that exposure to a high fat during early life leads to changes in gene expression in reward systems that persist for months following diet exposure and are associated with an increased preference for high fat diet. This work demonstrates the powerful effects of a natural reward, high fat diet, on stress and reward systems in the brain, and suggests possible therapeutic strategies designed to reduce stress and elevate brain dopamine levels in order to reduce the risk of relapse to high fat diet consumption

The Circadian Biology of Heart Failure

El Jamal N, Lordan R, Teegarden SL, Grosser T, FitzGerald G. The Circadian Biology of Heart Failure. Circulation Research. 2023;132(2):223-237.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

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