Temporal control of the integrated stress response by a stochastic molecular switch

Stress granules (SGs) are formed in the cytosol as an acute response to environmental cues and activation of the integrated stress response (ISR), a central signaling pathway controlling protein synthesis. Using chronic virus infection as stress model, we previously uncovered a unique temporal control of the ISR resulting in recurrent phases of SG assembly and disassembly. Here, we elucidate the molecular network generating this fluctuating stress response, by integrating quantitative experiments with mathematical modeling, and find that the ISR operates as a stochastic switch. Key elements controlling this switch are the cooperative activation of the stress-sensing kinase PKR, the ultrasensitive response of SG formation to the phosphorylation of the translation initiation factor eIF2alpha, and negative feedback via GADD34, a stress-induced subunit of protein phosphatase 1. We identify GADD34 mRNA levels as the molecular memory of the ISR that plays a central role in cell adaptation to acute and chronic stress.

Proteomic and metabolomic profiling of acute and chronic stress events associated with military exercises

Saliva collected from military personnel during training yields potential biomarkers that could be utilized to differentiate types of stress, specifically chronic versus acute.

A Deletion of the Nuclear Localization Signal Domain in the Fus Protein Induces Stable Post-stress Cytoplasmic Inclusions in SH-SY5Y Cells

Mutations in Fused-in-Sarcoma (FUS) gene involving the nuclear localization signal (NLS) domain lead to juvenile-onset Amyotrophic Lateral Sclerosis (ALS). The mutant protein mislocalizes to the cytoplasm, incorporating it into Stress Granules (SG). Whether SGs are the first step to the formation of stable FUS-containing aggregates is still unclear. In this work, we used acute and chronic stress paradigms to study the SG dynamics in a human SH-SY5Y neuroblastoma cell line carrying a deletion of the NLS domain of the FUS protein (homozygous: ΔNLS–/–; heterozygous: ΔNLS+/–). Wild-type (WT) cells served as controls. We evaluated the subcellular localization of the mutant protein through immunoblot and immunofluorescence, in basal conditions and after acute stress and chronic stress with sodium arsenite (NaAsO2). Cells were monitored for up to 24 h after rescue. FUS was expressed in both nucleus and cytoplasm in the ΔNLS+/– cells, whereas it was primarily cytoplasmic in the ΔNLS–/–. Acute NaAsO2 exposure induced SGs: at rescue,>90% of ΔNLS cells showed abundant FUS-containing if compared to less than 5% of the WT cells. The proportion of FUS-positive SGs remained 15–20% at 24 h in mutant cells. Cycloheximide did not abolish the long-lasting SGs in mutant cells. Chronic exposure to NaAsO2 did not induce significant SGs formation. A wealth of research has demonstrated that ALS-associated FUS mutations at the C-terminus facilitate the incorporation of the mutant protein into SGs. We have shown here that mutant FUS-containing SGs tend to fail to dissolve after stress, facilitating a liquid-to-solid phase transition. The FUS-containing inclusions seen in the dying motor neurons might therefore directly derive from SGs. This might represent an attractive target for future innovative therapies.

Endocannabinoids and Heart Rate Variability Alterations after Exposure to Prolonged Intensive Physical Exercise of the Hellenic Navy SEALs

Background: Recent research indicates that both endocannabinoids (eCB) and heart rate variability (HRV) are associated with stress-induced experiences. However, these underlying mechanisms are not elucidated. The present study aims to investigate whether exposure to acute and chronic stress conditions can give rise to measurable changes, both to the peripheral eCB ligands and HRV. Methods: Thirteen candidates under intense preparation for their enlistment in the Hellenic Navy SEALs (HNS) participated in the study. All subjects underwent mental state examination, while HRV variables in time and frequency domain recordings were acquired. Furthermore, at baseline and 30 days after prolonged and intensive physical exercise, hair was collected to measure eCB ligands, such as anandamide (AEA), 2-arachidonoylglycerol (2-AG), and the N-acyl ethanolamine (NAE) molecules: palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). Results: Comparing basal hair concentrations of eCB ligands before and after intense physical exercise, we found that AEA, PEA, and OEA were notably increased, whereas no differences were observed regarding the ligand 2-AG. Furthermore, there were observed associations between the concentrations of peripheral eCB ligands, both at baseline and after the prolonged physical exercise and the time and frequency domains of HRV. Conclusions: These findings suggest that endocannabinoid–HRV interrelations might share a short-term, and long-term adaptability of the changes in self-regulation associated with stress. Further studies will be required to determine the validity of peripheral eCB signaling and HRV as a biomarker for different aspects of the stress response.

Clinical Features of Patients With Heart Failure After the 2016 Kumamoto Earthquakes

Objective: Acute and chronic stress after severe earthquakes can contribute to cardiovascular events, including heart failure (HF). On April 14, 2016, magnitude 7 earthquakes occurred in the Aso region in the western part of Japan. This study aimed to investigate the clinical characteristics of HF in this area after these earthquakes. Methods: We investigated the clinical characteristics and 1-y mortality rate of patients with HF. Nutritional status was evaluated with the Geriatric Nutritional Risk Index (GNRI) and the Prognostic Nutritional Index (PNI). Results: Among a total of 58 cardiovascular events, HF was the most frequently observed (n = 28). The mean age of individuals with HF was 85.5 y. The total incidence of HF was significantly higher compared with the average of the prior 2 y. Disaster influence on mental health was suggested by patient history in 20 patients (71%). The 1-y mortality rate among patients with HF was 50%. Among those who died, 93% had malnutrition status (GNRI <92 and /or PNI ≤38). Conclusions: Our results demonstrated the poor prognosis of patients with HF following the disaster. The prevalence of malnutrition was high in those patients. Careful follow-up is necessary, especially for older people with frailty.

Home Care Resiliency during the COVID-19 Pandemic: Older Adult-Home Care Aide Dyads’ Perspectives

Homecare has increased its value as an alternative to nursing homes and adapted to evolving COVID-19 challenges. However, little is known about how COVID-19 has impacted community-dwelling older adults who need assistance with daily activities, including dressing, cooking, and shopping. Guided by the stress process framework, this mixed-method study examined how older homecare recipients experienced the acute and chronic stress during the first eight months of the pandemic, focusing on the role of home care aides (HCAs) in the context of Medicaid-funded in-home services. Thirty-five dyads of care recipients and HCAs participated in a COVID telephone survey as part of a larger study. Care recipients were typically older minority (40% African American, 31% Latinx) women (77%). Their COVID-related anxiety level, assessed by a 6-item Spielberger State Anxiety Inventory (1 “not at all” to 4 “very much”), was 2.2 (SD=0.9). While COVID-19 drastically reduced contacts with family members and healthcare providers, HCAs continued to provide care in person. One care recipient said, “Fortunately, I still have my HCA come and that keeps me sane.” HCAs showed resilience while facing their own family- and work-related stress: “I have followed the rules and just adapted. (COVID) did not affect the activities for my client.” Some dyads, however, experienced care disruptions because of COVID infection or fear in one or both parties. COVID-19 has demonstrated homecare resilience at the person-, dyad-, and organization-levels, calling for equitable, sustainable home-based care for a growing number of older adults who desire to stay in the home.

Evaluating Experiences of Stress and Coping Among African American Women During the COVID-19 Pandemic to Inform Future Interventions

Background African American (AA) women experience disproportionate levels of chronic disease, which is theorized to be driven by greater exposure to acute and chronic stress. The coronavirus (COVID-19) pandemic has further exacerbated existing health disparities among AA communities. Understanding how AA women have experienced and responded to stress during the pandemic may help to inform how future interventions can better address physical and mental well-being in AA communities. Aims Drawing from stress and coping models and an ecological framework, the present study conducted a theory-based qualitative assessment of stress-related experiences during the pandemic among a cohort of AA women, including (1) sources of stress, (2) coping strategies, (3) perceptions of health-related behaviors, (4) the role of community, and (5) recommendations for future interventions. Method After completing a group-based physical activity intervention program during the COVID-19 pandemic, a cohort of AA women ( N =17, Mage= 49.3 ± 11.24) completed individual interviews. Sessions were conducted by phone, audiotaped, transcribed, and coded by independent raters ( rs = .71–.73). Themes were identified using deductive and inductive approaches. Results Among sources of stress directly related to the pandemic, being at home, getting sick, and homeschooling/parenting were the most frequently discussed themes. Participants engaged in active coping (problem and emotion-focused), with health behaviors, social support, and religion/spirituality, emerging as frequently discussed themes. Although some participants reported passive coping strategies (e.g., avoidance), this approach was less pronounced. Conclusions These qualitative results are used to guide suggestions for future interventions that jointly address stress and health-related behaviors in order to improve translation of research into practice and policy for future pandemics and disasters.

Opposing Changes in Synaptic and Extrasynaptic N-Methyl-D-Aspartate Receptor Function in Response to Acute and Chronic Restraint Stress

A pertinent mechanism by which stress impacts learning and memory is through stress-induced plastic changes in glutamatergic transmission in the hippocampus. For instance, acute stress has been shown to alter the expression, binding, and function of the ionotropic glutamate N-methyl-D-aspartate receptor (NMDAR). However, the consequences of chronic stress, which could lead to various stress-related brain disorders, on NMDAR function remain unclear. While most studies on NMDARs focused on these receptors in synapses (synaptic NMDARs or sNMDARs), emerging findings have revealed functional roles of NMDARs outside synapses (extrasynaptic NMDARs or exNMDARs) that are distinct from those of sNMDARs. Using a restraint stress paradigm in adult rats, the objective of the current study is to examine whether sNMDARs and exNMDARs in the hippocampus are differentially regulated by acute and chronic stress. We examined sNMDAR and exNMDAR function in dorsal CA1 hippocampal neurons from brain slices of adult rats that were acutely (1 episode) or chronically (21 daily episodes) stressed by restraint (30 min). We found that acute stress increases sNMDAR but suppresses exNMDAR function. Surprisingly, we only observed a reduction in exNMDAR function after chronic stress. Taken together, our findings suggest that sNMDARs and exNMDARs may be differentially regulated by acute and chronic stress. Most importantly, the observed suppression in exNMDAR function by both acute and chronic stress implies crucial but overlooked roles of hippocampal exNMDARs in stress-related disorders.

Integrated Regulation of PKA by Fast and Slow Neurotransmission in the Nucleus Accumbens Controls Plasticity and Stress Responses

Cortical glutamate and midbrain dopamine neurotransmission converge to mediate striatum-dependent behaviors, while maladaptations in striatal circuitry contribute to mental disorders. Here we uncover a molecular mechanism by which glutamatergic and dopaminergic signaling integrate to regulate cAMP-dependent protein kinase (PKA) via phosphorylation of the PKA regulatory subunit, RIIβ. We find that glutamate-dependent reduction in Cdk5-dependent RIIβ phosphorylation alters the PKA holoenzyme auto-inhibitory state to increase PKA signaling in response to dopamine. Disruption of RIIβ phosphorylation by Cdk5, consequently, enhances cortico-ventral striatal synaptic plasticity. Acute and chronic stress in rats inversely modulates RIIβ phosphorylation and ventral striatal infusion of a small interfering peptide that selectively targets RIIβ regulation by Cdk5 improves behavioral response to stress. This new signaling mechanism integrating ventral striatal glutamate and dopamine neurotransmission is likely important to brain function, may contribute to neuropsychiatric conditions, and serves as a possible target for the development of novel therapeutics for stress-related disorders.