Maladaptive Stress Responses Research Articles

Glucocorticoids induce a maladaptive epithelial stress response to aggravate acute kidney injury.

Acute kidney injury (AKI) is a frequent and challenging clinical condition associated with high morbidity and mortality and represents a common complication in critically ill patients with COVID-19. In AKI, renal tubular epithelial cells (TECs) are a primary site of damage, and recovery from AKI depends on TEC plasticity. However, the molecular mechanisms underlying adaptation and maladaptation of TECs in AKI remain largely unclear. Here, our study of an autopsy cohort of patients with COVID-19 provided evidence that injury of TECs by myoglobin, released as a consequence of rhabdomyolysis, is a major pathophysiological mechanism for AKI in severe COVID-19. Analyses of human kidney biopsies, mouse models of myoglobinuric and gentamicin-induced AKI, and mouse kidney tubuloids showed that TEC injury resulted in activation of the glucocorticoid receptor by endogenous glucocorticoids, which aggravated tubular damage. The detrimental effect of endogenous glucocorticoids on injured TECs was exacerbated by the administration of a widely clinically used synthetic glucocorticoid, dexamethasone, as indicated by experiments in mouse models of myoglobinuric- and folic acid-induced AKI, human and mouse kidney tubuloids, and human kidney slice cultures. Mechanistically, studies in mouse models of AKI, mouse tubuloids, and human kidney slice cultures demonstrated that glucocorticoid receptor signaling in injured TECs orchestrated a maladaptive transcriptional program to hinder DNA repair, amplify injury-induced DNA double-strand break formation, and dampen mTOR activity and mitochondrial bioenergetics. This study identifies glucocorticoid receptor activation as a mechanism of epithelial maladaptation, which is functionally important for AKI.

Senescence suppresses the integrated stress response and activates a stress-remodeled secretory phenotype.

Senescence is a state of indefinite cell-cycle arrest associated with aging, cancer, and age-related diseases. Here, we find that translational deregulation, together with a corresponding maladaptive integrated stress response (ISR), is a hallmark of senescence that desensitizes senescent cells to stress. We present evidence that senescent cells maintain high levels of eIF2α phosphorylation, typical of ISR activation, but translationally repress production of the stress response activating transcription factor 4 (ATF4) by ineffective bypass of the inhibitory upstream open reading frames (uORFs). Surprisingly, ATF4 translation remains inhibited even after acute proteotoxic and amino acid starvation stressors, resulting in a highly diminished stress response. We also find that stress augments the senescence-associated secretory phenotype with sustained remodeling of inflammatory factors expression that is suppressed by non-uORF carrying ATF4 mRNA expression. Our results thus show that senescent cells possess a unique response to stress, which entails an increase in their inflammatory profile.

A new framework for understanding stress and disease: the developmental model of stress as applied to multiple sclerosis.

This paper proposes a new model of stress that integrates earlier models and adds insights from developmental psychology. Previous models describe the behavioral and physical effects of stress events, but have not explained the translation of experiences into stress itself. The Developmental Model of Stress shows how psychosocial developmental challenges in childhood create persistent negative beliefs and behaviors that increase threat perception and maladaptive stress responses. These developmental challenges produce early psychological and physiological predispositions for increased stress responses over time. Ongoing stress leads to dysregulation of physical stress-response systems (allostatic load), which is associated with multiple diseases. High allostatic load provides the necessary preconditions for the diathesis-stress model, which says the addition of an acute stressor to a weakened or predisposed system can lead to disease development. The paper also documents the evolving measurement of stress to better understand the stress-disease relationship, helping to resolve conflicting results between studies. The Developmental Model of Stress was combined with clinician insight and patient reports to build an integrative framework for understanding the role of stress in the development and progression of multiple sclerosis (MS). It includes the first mapping of maladaptive beliefs and behaviors arising from developmental challenges that are common to people with MS. An initial comparison shows these may be distinct from those of people with other chronic diseases. These beliefs and behaviors form the predisposing factors and contribute to the triggering factors, which are the acute stressors triggering disease onset. These often took two forms, a prolonged incident experienced as feeling trapped or stuck, and threat of a breach in a relationship. The reinforcing factors add the stress of a chronic disease with a poor prognosis and seemingly random symptom fluctuation, still managed with the same beliefs and behaviors developed in childhood, increasing physiological dysregulation and symptom severity. A pilot study is described in which these three categories of stress factors in MS were explicitly addressed. This study noted clinically important improvements in physical and mental well-being, providing preliminary support for the Developmental Model. Future research might expand on the pilot using a more robust sample and design.

Abnormal Morphology and Synaptogenic Signaling in Astrocytes Following Prenatal Opioid Exposure.

In recent decades, there has been a dramatic rise in the rates of children being born after in utero exposure to drugs of abuse, particularly opioids. Opioids have been shown to have detrimental effects on neurons and glia in the central nervous system (CNS), but the impact of prenatal opioid exposure (POE) on still-developing synaptic circuitry is largely unknown. Astrocytes exert a powerful influence on synaptic development, secreting factors to either promote or inhibit synapse formation and neuronal maturation in the developing CNS. Here, we investigated the effects of the partial µ-opioid receptor agonist buprenorphine on astrocyte synaptogenic signaling and morphological development in cortical cell culture. Acute buprenorphine treatment had no effect on the excitatory synapse number in astrocyte-free neuron cultures. In conditions where neurons shared culture media with astrocytes, buprenorphine attenuated the synaptogenic capabilities of astrocyte-secreted factors. Neurons cultured from drug-naïve mice showed no change in synapses when treated with factors secreted by astrocytes from POE mice. However, this same treatment was synaptogenic when applied to neurons from POE mice, indicating a complex neuroadaptive response in the event of impaired astrocyte signaling. In addition to promoting morphological and connectivity changes in neurons, POE exerted a strong influence on astrocyte development, disrupting their structural maturation and promoting the accumulation of lipid droplets (LDs), suggestive of a maladaptive stress response in the developing CNS.

USING THE METHOD OF PSYCHOCONSTITUTIONAL THERAPY IN THE EARLY ACUTE PERIOD OF POST-TRAUMATIC DISORDER

In this study, we investigated the effectiveness of psychoconstitutional therapy (PCT) in the early acute phase of Post-Traumatic Stress Disorder (PTSD) within a biopsychosocial framework, considering individual psychological and constitutional differences. Participants were categorized into "Flowers," "Pots," and "Gardeners" based on their stress response behaviours and received tailored interventions aimed at modulating amygdala activity and revising maladaptive stress responses. The results showed statistically significant improvements in stress response behaviours, PTSD symptomatology across various clusters, and overall psychological well-being, as measured by the Psychological General Well-Being Index. This study highlights the potential of psychoconstitutional therapy not only to reduce PTSD symptoms but also to enhance general mental health. It supports the inclusion of this therapy in current psychiatric practices and aligns with the growing trend towards personalized treatment approaches, offering new hope for effective PTSD management

Recapitulating and reversing human brain ribosomopathy defects via the maladaptive integrated stress response.

Animal or human models recapitulating brain ribosomopathies are incomplete, hampering development of urgently needed therapies. Here, we generated genetic mouse and human cerebral organoid models of brain ribosomopathies, caused by mutations in small nucleolar RNA (snoRNA) SNORD118. Both models exhibited protein synthesis loss, proteotoxic stress, and p53 activation and led to decreased proliferation and increased death of neural progenitor cells (NPCs), resulting in brain growth retardation, recapitulating features in human patients. Loss of SNORD118 function resulted in an aberrant upregulation of p-eIF2α, the mediator of integrated stress response (ISR). Using human iPSC cell-based screen, we identified small-molecule 2BAct, an ISR inhibitor, which potently reverses mutant NPC defects. Targeting ISR by 2BAct mitigated ribosomopathy defects in both cerebral organoid and mouse models. Thus, our SNORD118 mutant organoid and mice recapitulate human brain ribosomopathies and cross-validate maladaptive ISR as a key disease-driving mechanism, pointing to a therapeutic intervention strategy.

The brain, gut, and bladder health nexus: A conceptual model linking stress and mental health disorders to overactive bladder in women.

A small, but growing literature links stressors and mental health disorders (MHDs) across the life course to overactive bladder (OAB) and urinary incontinencesymptoms. Mechanisms by which stressors and MHDs may impact bladder health are not fully understood, limiting novel prevention and treatment efforts. Moreover, potential biopsychosocial mechanisms involving the brain and gut have not been considered in an integrated, comprehensive fashion. Members of the prevention of lower urinary tract symptomsResearch Consortium developed conceptual models to inform research on biopsychosocial mechanisms through which stress and MDHs may impact bladder health among girls and women, focusing on brain and gut physiology. Two conceptual models were developed-one to explain central (brain-based) and peripheral (gut-based) mechanisms linking stressors and MHDs to OAB and bladder health, and one to highlight bidirectional communication between the brain, gut, and bladder. Traumatic events, chronic stressors, and MHDs may lead to a maladaptive stress response, including dysregulated communication and signaling between the brain, gut, and bladder. Gut bacteria produce molecules and metabolites that alter production of neurotransmitters, amino acids, short-chain fatty acids, and inflammatory immune response molecules that mediate communication between the gut and brain. Microbiota signal neurogenesis, microglia maturation, and synaptic pruning; they also calibrate brain-gut-bladder axis communication through neurotransmission and synaptogenesis, potentially influencing bladder symptom development. Life course trajectories of risk may be prevented or interrupted by central and peripheral resources for neuropsychological resilience. Depicted pathways, including brain-gut-bladder communication, have implications for research and development of novel prevention and treatment approaches.

P02.26.B METABOLIC PLASTICITY IN GLIOBLASTOMA TUMOR-INITIATING CELL AND RESISTANCE TO LSD1-DIRECTED THERAPY

Abstract BACKGROUND Glioblastoma (GBM), the most common primary brain tumor in adults, remains incurable despite multimodal therapy. There is a pressing unmet medical need for new therapeutic strategies, especially because patients experience only short-term benefit after primary treatment and the vast majority inevitably relapse. Adaptation to harsh microenvironmental conditions, including nutrient deprivation, proteostasis perturbation, hypoxia and drug treatment, induce molecular and metabolic changes in glioblastoma that lead to the acquisition of a tolerance to stress and resistance to drug. In this context, we demonstrated that Lysine-specific histone demethylase 1 (LSD1) is a regulator of tumor-initiating cell (TICs) survival, adaptation and recovery from stress. LSD1 pharmacological inhibition with a specific and brain penetrant inhibitor (LSD1i) induces a maladaptive integrated stress response (ISR) which leads to the death of TICs exposed to ER stress or nutrient deficiency. MATERIAL AND METHODS Given the high GBM heterogeneity, we analyzed different patient-derived TICs grown in vitro as sphere and characterized for their genetic landscape and in vitro/in vivo stem cell-like features. We applied mechanistically different strategies, including biological, metabolic and pharmacological approaches, as well as transcriptomic and proteomic profiling. Zebrafish and GBM xenografts have been exploited as in vivo models. RESULTS LSD1i treatment induces physical and functional rearrangements of mitochondria, culminating into their enhanced bioenergetic activity and ATP production that predispose to cell death. Interestingly, only a subset of patient-derived TICs benefits from LSD1i therapy. These samples are largely dependent on glycolysis and, upon LSD1i administration, they are unable to further enhance it when mitochondrial energy production is inhibited. The samples resistant to LSD1i maintain their cellular behavior unaltered even upon prolonged treatment. They display reduced susceptibility to the stressful cues represented by either LSD1i and the known ER stressors Thapsigargin and Tunicamycin, by efficiently restoring energy homeostasis and properly activating the Activating Transcription Factor 4 (ATF4)-dependent ISR. Remarkably, LSD1i resistant samples display metabolic flexibility and switch between glycolytic and oxidative metabolism to ensure their survival. CONCLUSION The identification of specific metabolic vulnerabilities could offer unique opportunities for therapeutic intervention: the selective LSD1i vulnerability relies on the preferential dependence on glycolysis, while the great metabolic plasticity of LSD1i resistant TICs coordinates changes that favor their adaptation to stressful microenvironments and therapeutic insults.

Utility of Continuous Paravertebral Block After Retroperitoneal Abdominal Aortic Aneurysm Repair

Open abdominal aortic aneurysm (AAA) repairs can be associated with significant pain and morbidity. Previous studies have demonstrated utility of adjunctive epidural analgesia (EA) in addition to general anesthesia (GA) to reduce pain and blunt the maladaptive surgical stress response. However, EA may be complicated by epidural hematomas and severe hypotension. Recently, we started using continuous paravertebral block (PVB) for perioperative analgesia after retroperitoneal AAA repair. PVB has some distinct advantages over EA such as unilateral localization, reduced risk of hypotension, and minimal risk of epidural hematoma in the setting of systemic heparinization. This study aimed to examine the utility of PVB by comparing total opioid consumption in the postoperative period among patients who received GA+PVB and those who received GA alone. This retrospective matched cohort study included 62 patients who underwent elective retroperitoneal AAA repair between January 2019 and August 2022. Thirty-one subjects managed with GA+PVB were compared with 31 control subjects treated with GA alone, matched on following criteria: age, sex, and cross-clamp location. Outcome measures included total opioid analgesics administered during their inhospital postoperative course, time to extubation, time to return to baseline activity, time to normal bowel function, and length of stay. Opioid doses were converted to morphine milligram equivalents (MMEs). The GA+PVB group required significantly less opioid analgesics (81±53 MME) than the GA group (171±121 MME) (P<0.001). Compared to GA alone, GA+PVB was superior in every clinical metric examined: time to extubation (3 vs. 1hr, P<0.001), recovery of bowel function (3 vs. 2days, P=0.002), recovery of baseline physical activity (4 vs. 2days, P=0.019), and length of stay (5 vs. 3days, P<0.001). Continuous paravertebral block provides better pain management with significantly decreased opioid requirements in the postoperative period compared to GA-alone for patients undergoing elective retroperitoneal AAA repair.

Diet- and salinity-induced modifications of the gut microbiota are associated with differential physiological responses to ranavirus infection in Rana sylvatica.

Greater knowledge of how host-microbiome interactions vary with anthropogenic environmental change and influence pathogenic infections is needed to better understand stress-mediated disease outcomes. We investigated how increasing salinization in freshwaters (e.g. due to road de-icing salt runoff) and associated increases in growth of nutritional algae influenced gut bacterial assembly, host physiology and responses to ranavirus exposure in larval wood frogs (Rana sylvatica). Elevating salinity and supplementing a basic larval diet with algae increased larval growth and also increased ranavirus loads. However, larvae given algae did not exhibit elevated kidney corticosterone levels, accelerated development or weight loss post-infection, whereas larvae fed a basic diet did. Thus, algal supplementation reversed a potentially maladaptive stress response to infection observed in prior studies in this system. Algae supplementation also reduced gut bacterial diversity. Notably, we observed higher relative abundances of Firmicutes in treatments with algae-a pattern consistent with increased growth and fat deposition in mammals-that may contribute to the diminished stress responses to infection via regulation of host metabolism and endocrine function. Our study informs mechanistic hypotheses about the role of microbiome mediation of host responses to infection that can be tested in future experiments in this host-pathogen system. This article is part of the theme issue 'Amphibian immunity: stress, disease and ecoimmunology'.

The Role of The Rostral Ventromedial Medulla in Stress Responses.

The rostral ventromedial medulla (RVM) is a brainstem structure critical for the descending pain modulation system involved in both pain facilitation and inhibition through its projection to the spinal cord. Since the RVM is well connected with pain- and stress-engaged brain structures, such as the anterior cingulate cortex, nucleus accumbens, and amygdala, its involvement in stress responses has become a matter of great interest. While chronic stress has been proposed as a trigger of pain chronification and related psychiatric comorbidities due to maladaptive stress responses, acute stress triggers analgesia and other adaptative responses. Here we reviewed and highlighted the critical role of the RVM in stress responses, mainly in acute stress-induced analgesia (SIA) and chronic stress-induced hyperalgesia (SIH), providing insights into pain chronification processes and comorbidity between chronic pain and psychiatric disorders.

Loss of Tyro3 causes anxiety-relevant behavioural changes in female mice.

White-matter brain abnormalities have been found across a variety of psychiatric disorders. The extent of white matter pathology is proposed to be predictive of the severity of anxiety disorders. However, it is still unknown whether disruptions of white matter integrity precede, and are sufficient to give rise to, the behavioural symptoms. Interestingly, mood disturbances feature prominently in central demyelinating diseases such as multiple sclerosis. It is unclear whether the greater frequency of neuropsychiatric symptoms is linked to underlying neuropathology. In this study, we characterised male and female Tyro3 knockout (KO) mice using a variety of behavioural paradigms. Anxiety-related behaviours were assessed with the elevated-plus maze and light-dark box. Fear memory processing was assessed using fear conditioning and extinction paradigms. Finally, we assessed immobility time in the Porsolt swim test as a measure of depression-related behavioural despair. Surprisingly, loss of Tyro3 did not lead to manifestation of major shifts in baseline behaviour. We noted significant differences in habituation to novel environments and post-conditioning freezing levels of female Tyro3 KO mice, which are consistent with the female bias in anxiety disorders and could be indicative of maladaptive stress-responses. This study has demonstrated that white matter pathology related to a loss of Tyro3 is associated with pro-anxiety behavioural responses of female mice. Future studies could probe their contribution to increased risk for neuropsychiatric disorders when combined with stressful triggering events.

MP03-11 THE BRAIN, GUT &amp; BLADDER HEALTH NEXUS UNDERLYING STRESS &amp; MENTAL HEALTH DISORDERS IN WOMEN

You have accessJournal of UrologyCME1 Apr 2023MP03-11 THE BRAIN, GUT & BLADDER HEALTH NEXUS UNDERLYING STRESS & MENTAL HEALTH DISORDERS IN WOMEN Ariana Smith, Amanda Berry, Linda Brubaker, Shayna Cunningham, Sheila Gahagan, Lisa Kane Low, Margaret Mueller, Siobhan Sutcliffe, Beverly Williams, and Brady Sonya Ariana SmithAriana Smith More articles by this author , Amanda BerryAmanda Berry More articles by this author , Linda BrubakerLinda Brubaker More articles by this author , Shayna CunninghamShayna Cunningham More articles by this author , Sheila GahaganSheila Gahagan More articles by this author , Lisa Kane LowLisa Kane Low More articles by this author , Margaret MuellerMargaret Mueller More articles by this author , Siobhan SutcliffeSiobhan Sutcliffe More articles by this author , Beverly WilliamsBeverly Williams More articles by this author , and Brady SonyaBrady Sonya More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003214.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The relationship between the brain, gut and bladder is complex. To aid further studies to understand the relationship between specific stressors and mental health disorders (MHD), intestinal sequelae and lower urinary tract symptoms (LUTS) we aim to identify potential mechanisms and biological processes that explain brain-gut-bladder associations in women. METHODS: Identification of mechanisms followed guidelines of conceptual model development. RESULTS: Traumatic events, chronic stressors and MHD may lead to a maladaptive stress response with implications for communication and signaling between the brain, gut and bladder. Figure 1 depicts three bidirectional axes; the gut, brain and bladder are key actors engaged in “communication” across the life course. Each organ function is guided by key inputs that ideally assist in maintaining health but also can initiate or exacerbate dysfunction. The gut can communicate with the brain and bladder in ways that shape trajectories of MHD, neuropsychological resilience, central physiological dysregulation and the likelihood of developing and experiencing persistent LUTS. Psychological stressors influence communication between the gut and the brain with accompanying alterations in gut metabolites, neurotransmitters and microbiota. Gut bacteria produce molecules and metabolites that alter production of neurotransmitters (serotonin, dopamine), amino acids (tryptophan), short chain fatty acids (butyrate, acetate) and amyloid proteins that influence the brain (neuronal, blood, immune pathways), thus mediating communication between the gut and brain. Gut bacteria also alter inflammatory immune response via endotoxins, conferring vulnerability or resistance to bladder infections. Microbiota signal neurogenesis, microglia maturation and synaptic pruning; they also calibrate brain-gut-bladder axis communication through neurotransmission, synaptogenesis & the vagus nerve. CONCLUSIONS: Some neurotransmitter alterations seen with stress may not be caused directly by perceptions of stress, but rather by stress-related alteration in intestinal bacteria. The brain-gut-bladder axis has implications for research as well as novel prevention and treatment approaches. An intriguing area for research is how the microbiome may influence the brain & bladder. Source of Funding: The Prevention of Lower Urinary Tract Symptoms (PLUS) Research Consortium is supported by the National Institutes of Health (NIH) through cooperative agreements (grants U24DK106786, U01DK106853, U01DK106858, U01DK106898, U01DK106893, U01DK106827, U01DK106908, U01DK106892, U01DK126045) © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e26 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ariana Smith More articles by this author Amanda Berry More articles by this author Linda Brubaker More articles by this author Shayna Cunningham More articles by this author Sheila Gahagan More articles by this author Lisa Kane Low More articles by this author Margaret Mueller More articles by this author Siobhan Sutcliffe More articles by this author Beverly Williams More articles by this author Brady Sonya More articles by this author Expand All Advertisement PDF downloadLoading ...

Retinal ganglion cells adapt to ionic stress in experimental glaucoma.

Identification of early adaptive and maladaptive neuronal stress responses is an important step in developing targeted neuroprotective therapies for degenerative disease. In glaucoma, retinal ganglion cells (RGCs) and their axons undergo progressive degeneration resulting from stress driven by sensitivity to intraocular pressure (IOP). Despite therapies that can effectively manage IOP many patients progress to vision loss, necessitating development of neuronal-based therapies. Evidence from experimental models of glaucoma indicates that early in the disease RGCs experience altered excitability and are challenged with dysregulated potassium (K+) homeostasis. Previously we demonstrated that certain RGC types have distinct excitability profiles and thresholds for depolarization block, which are associated with sensitivity to extracellular K+. Here, we used our inducible mouse model of glaucoma to investigate how RGC sensitivity to K+ changes with exposure to elevated IOP. In controls, conditions of increased K+ enhanced membrane depolarization, reduced action potential generation, and widened action potentials. Consistent with our previous work, 4 weeks of IOP elevation diminished RGC light-and current-evoked responses. Compared to controls, we found that IOP elevation reduced the effects of increased K+ on depolarization block threshold, with IOP-exposed cells maintaining greater excitability. Finally, IOP elevation did not alter axon initial segment dimensions, suggesting that structural plasticity alone cannot explain decreased K+ sensitivity. Thus, in response to prolonged IOP elevation RGCs undergo an adaptive process that reduces sensitivity to changes in K+ while diminishing excitability. These experiments give insight into the RGC response to IOP stress and lay the groundwork for mechanistic investigation into targets for neuroprotective therapy.

An RDoC-based approach to adolescent self-injurious thoughts and behaviors: The interactive role of social affiliation and cardiac arousal.

Recent theoretical models have posited that increases in self-injurious thoughts and behaviors (SITBs) during adolescence may be linked to failures in biological stress regulation in contexts of social stress. However, there is a lack of data examining this hypothesis during the transition to adolescence, a sensitive period of development characterized by changes across socioaffective and psychophysiological domains. Building on principles from developmental psychopathology and the RDoC framework, the present study used a longitudinal design in a sample of 147 adolescents to test whether interactions among experiences of social (i.e., parent and peer) conflict and cardiac arousal (i.e., resting heart rate) predicted adolescents' engagement in SITBs (i.e., nonsuicidal self-injury, NSSI; and suicidal ideation; SI) across 1-year follow-up. Prospective analyses revealed that adolescents experiencing a combination of greater peer, but not family, conflict and higher cardiac arousal at baseline showed significant longitudinal increases in NSSI. In contrast, social conflict did not interact with cardiac arousal to predict future SI. Findings indicate that greater peer-related interpersonal stress in adolescents may increase risk for future NSSI among youth with physiological vulnerabilities (i.e., higher resting heart rate) that may be markers of maladaptive stress responses. Future research should examine these processes at finer timescales to elucidate whether these factors are proximal predictors of within-day SITBs.

Early Life Stress, Coping, and Cardiovascular Reactivity to Acute Social Stress.

Early life stress (ELS) occurring during childhood and adolescence is an established risk factor for later cardiovascular disease and dysregulated reactivity to acute social stress. This study examined whether ELS associations with baseline cardiovascular functioning, cardiovascular stress reactivity and recovery, and emotional stress reactivity vary across levels of emotion-oriented, task-oriented, and avoidant coping styles. The sample included 1027 adolescents and young adults (mean age = 19.29 years; 50% female; 64% Black, 34% non-Hispanic White) who reported on their ELS exposure and coping styles. Participants completed a standardized acute social stress test (the Trier Social Stress Test [TSST]), with heart rate (HR) and blood pressure (BP) measured before, during, and after the TSST. Self-reports of negative emotions during the TSST indexed emotional stress reactivity. Multiple regression models adjusting for demographic factors and body mass index showed that ELS was associated with lower HR stress reactivity, avoidant coping was related to lower systolic BP and diastolic BP during stress and lower systolic BP during recovery, and higher emotion-oriented coping and lower task-oriented coping predicted greater emotional stress reactivity. A consistent pattern emerged where emotion-oriented coping amplified the associations between ELS and maladaptive stress responses (blunted cardiovascular stress reactivity and recovery; enhanced emotional stress reactivity), whereas lower levels of emotion-oriented coping were associated with resilient profiles among those who experienced ELS (lower resting HR, lower emotional stress reactivity, average HR and BP stress reactivity and recovery). However, low levels of emotion-oriented coping also conferred a risk of higher BP during recovery for those with high levels of ELS. These results suggest that low to moderate levels of emotion-oriented coping promote optimal cardiovascular and emotional reactivity to acute stress among individuals exposed to ELS.

GluN2D expression is regulated by restraint stress and supports active stress coping bouts

Stress coping strategies represent critical responses to environmental challenges, and active coping has been linked to stress resilience in humans. Understanding the neuroadaptations that support these strategies may provide insights into adaptive and maladaptive stress responses. NMDA receptors (NMDARs) play key roles in neuroadaptation, and NMDARs have been specifically implicated in stress responsiveness. Constitutive knockout mice have been used to implicate the GluN2D NMDAR subunit in regulation of stress-sensitive and affective behavior, but the brain regions in which GluN2D expression changes drive these effects remain unknown. Here we report that following an acute restraint stressor, GluN2D subunit expression is specifically decreased in the bed nucleus of the stria terminalis (BNST), a key region involved in stress processing, in male but not female mice, with no differences found in the thalamus or ventral hippocampus in either sex. Rodents engage in active struggling events during restraint stress that may represent active coping strategies to stress. Thus, we assessed active coping bouts during acute and chronic restraint stress sessions in GluN2D knockout mice. During the first restraint session, GluN2D knockout mice exhibited a pronounced decrease in struggling bouts during restraint stress relative to wild-type littermates, consistent with a role of GluN2D in active coping responses to stress. Repeated, daily restraint sessions revealed a sex-specific role of GluN2D expression on certain aspects of active coping behaviors, with male GluN2D KO mice exhibiting a decrease in total coping bouts measured across five sessions. However, BNST-specific knockdown of GluN2D in male mice did not alter active coping bouts, suggesting either a multi-synaptic role of GluN2D and/or a developmental role of GluN2D in this behavior. Altogether, these data are consistent with a growing literature suggesting that exploration of GluN2D control of stress circuit actions may lead to a novel therapeutic target to consider for stress-related mood disorders.

Distinct forms of regret linked to resilience versus susceptibility to stress are regulated by region-specific CREB function in mice.

Regret describes recognizing alternative actions could have led to better outcomes. It remains unclear whether regret derives from generalized mistake appraisal or instead comprises dissociable, action-specific processes. Using a neuroeconomic task, we found that mice were sensitive to fundamentally distinct types of regret following exposure to chronic social defeat stress or manipulations of CREB, a transcription factor implicated in stress action. Bias to make compensatory decisions after rejecting high-value offers (regret type I) was unique to stress-susceptible mice. Bias following the converse operation, accepting low-value offers (regret type II), was enhanced in stress-resilient mice and absent in stress-susceptible mice. CREB function in either the prefrontal cortex or nucleus accumbens was required to suppress regret type I but bidirectionally regulated regret type II. We provide insight into how maladaptive stress response traits relate to distinct forms of counterfactual thinking, which could steer therapy for mood disorders, such as depression, toward circuit-specific computations through a careful description of decision narrative.

Coping with COVID Stress: Maladaptive and Adaptive Response Styles Predicting College Student Internalizing Symptom Dimensions.

The COVID-19 pandemic significantly disrupted daily life for undergraduates and introduced new stressors (e.g., campus closures). How individuals respond to stressors can interact with stress to increase disorder risk in both unique and transdiagnostic ways. The current study examined how maladaptive and adaptive stress response styles moderated the perceived severity of COVID-related stressors effect on general and specific internalizing dimensions at the beginning of the COVID-19 pandemic in a combined undergraduate sample across two universities (N = 451) using latent bifactor modeling and LASSO modeling to identify optimal predictors. Results showed that perceived stress severity and maladaptive response styles (not adaptive response styles or interactions between stress and response styles) were associated with both common and specific internalizing dimensions. Results suggest additive associations of stress severity and maladaptive coping with internalizing symptoms during the pandemic’s beginning, and provide important insights for screening, prevention, and intervention during future public health crises.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10862-022-09975-7.

Neural correlates of repetitive negative thinking: Dimensional evidence across the psychopathological continuum

Repetitive negative thinking (RNT) captures an important transdiagnostic factor that predisposes to a maladaptive stress response and contributes to diverse psychiatric disorders. Although RNT can best be seen as a continuous symptom dimension that cuts across boundaries from health to various psychiatric disorders, the neural mechanisms underlying RNT have almost exclusively been studied in health and stress-related disorders, such as depression and anxiety disorders. We set out to study RNT from a large-scale brain network perspective in a diverse population consisting of healthy subjects and patients with a broader range of psychiatric disorders. We studied 46 healthy subjects along with 153 patients with a stress-related and/or neurodevelopmental disorder. We focused on three networks, that are associated with RNT and diverse psychiatric disorders: the salience network, default mode network (DMN) and frontoparietal network (FPN). We investigated the relationship of RNT with both network connectivity strength at rest and with the stress-induced changes in connectivity. Across our whole sample, the level of RNT was positively associated with the connectivity strength of the left FPN at rest, but negatively associated with stress-induced changes in DMN connectivity. These findings may reflect an upregulation of the FPN in an attempt to divert attention away from RNT, while the DMN result may reflect a less flexible adaptation to stress, related to RNT. Additionally, we discuss how our findings fit into the non-invasive neurostimulation literature. Taken together, our results provide initial insight in the neural mechanisms of RNT across the spectrum from health to diverse psychiatric disorders.