The neuroimmunology of social-stress-induced sensitization.

Myriad clinical findings provide links between chronic stressors, inflammation, and mood disorders. Furthermore, traumatic or chronic exposure to psychological stressors may promote stress sensitization, in which individuals have long-term complications, including increased vulnerability to subsequent stressors. Post-traumatic stress disorder (PTSD) is a clinically relevant example of stress sensitization. PTSD alters neuronal circuitry and mood; however, the mechanisms underlying long-term stress sensitization within this disorder are unclear. Rodent models of chronic social defeat recapitulate several key physiological, immunological, and behavioral responses associated with psychological stress in humans. Repeated social defeat (RSD) uniquely promotes the convergence of neuronal, central inflammatory (microglial), and peripheral immune (monocyte) pathways, leading to prolonged anxiety, social withdrawal, and cognitive impairment. Moreover, RSD promotes stress sensitization, in which mice are highly sensitive to subthreshold stress exposure and recurrence of anxiety weeks after the cessation of stress. Therefore, the purpose of this Review is to discuss the influence of social-defeat stress on the immune system that may underlie stress sensitization within three key cellular compartments: neurons, microglia, and monocytes. Delineating the mechanisms of stress sensitization is critical in understanding and treating conditions such as PTSD.

A synergistic mindsets intervention protects adolescents from stress.

Social-evaluative stressors-experiences in which people feel they could be judged negatively-pose a major threat to adolescent mental health1-3 and can cause young people to disengage from stressful pursuits, resulting in missed opportunities to acquire valuable skills. Here we show that replicable benefits for the stress responses of adolescents can be achieved with a short (around 30-min), scalable 'synergistic mindsets' intervention. This intervention, which is a self-administered online training module, synergistically targets both growth mindsets4 (the idea that intelligence can be developed) and stress-can-be-enhancing mindsets5 (the idea that one's physiological stress response can fuel optimal performance). In six double-blind, randomized, controlled experiments that were conducted with secondary and post-secondary students in the United States, the synergistic mindsets intervention improved stress-related cognitions (study 1, n = 2,717; study 2, n = 755), cardiovascular reactivity (study 3, n = 160; study 4, n = 200), daily cortisol levels (study 5, n = 118 students, n = 1,213 observations), psychological well-being (studies 4 and 5), academic success (study 5) and anxiety symptoms during the 2020 COVID-19 lockdowns (study 6, n = 341). Heterogeneity analyses (studies 3, 5 and 6) and a four-cell experiment (study 4) showed that the benefits of the intervention depended on addressing both mindsets-growth and stress-synergistically. Confidence in these conclusions comes from a conservative, Bayesian machine-learning statistical method for detecting heterogeneous effects6. Thus, our research has identified a treatment for adolescent stress that could, in principle, be scaled nationally at low cost.

Unraveling how the third-party brain under stress responds to injustices.

How third-party individuals respond to injustices is important for resolving conflict in society. A study in PLOS Biology shows that individuals experiencing acute stress prefer to aid victims over punishing offenders, an opposite pattern to non-stress conditions.

Acute stress during witnessing injustice shifts third-party interventions from punishing the perpetrator to helping the victim.

People tend to intervene in others' injustices by either punishing the transgressor or helping the victim. Injustice events often occur under stressful circumstances. However, how acute stress affects a third party's intervention in injustice events remains open. Here, we show a stress-induced shift in third parties' willingness to engage in help instead of punishment by acting on emotional salience and central-executive and theory-of-mind networks. Acute stress decreased the third party's willingness to punish the violator and the severity of the punishment and increased their willingness to help the victim. Computational modeling revealed a shift in preference of justice recovery from punishment the offender toward help the victim under stress. This finding is consistent with the increased dorsolateral prefrontal engagement observed with higher amygdala activity and greater connectivity with the ventromedial prefrontal cortex in the stress group. A brain connectivity theory-of-mind network predicted stress-induced justice recovery in punishment. Our findings suggest a neurocomputational mechanism of how acute stress reshapes third parties' decisions by reallocating neural resources in emotional, executive, and mentalizing networks to inhibit punishment bias and decrease punishment severity.

Neural control of affiliative touch in prosocial interaction.

The ability to help and care for others fosters social cohesiveness and is vital to the physical and emotional well-being of social species, including humans1-3. Affiliative social touch, such as allogrooming (grooming behaviour directed towards another individual), is a major type of prosocial behaviour that provides comfort to others1-6. Affiliative touch serves to establish and strengthen social bonds between animals and can help to console distressed conspecifics. However, the neural circuits that promote prosocial affiliative touch have remained unclear. Here we show that mice exhibit affiliative allogrooming behaviour towards distressed partners, providing a consoling effect. The increase in allogrooming occurs in response to different types of stressors and can be elicited by olfactory cues from distressed individuals. Using microendoscopic calcium imaging, we find that neural activity in the medial amygdala (MeA) responds differentially to naive and distressed conspecifics and encodes allogrooming behaviour. Through intersectional functional manipulations, we establish a direct causal role of the MeA in controlling affiliative allogrooming and identify a select, tachykinin-expressing subpopulation of MeA GABAergic (γ-aminobutyric-acid-expressing) neurons that promote this behaviour through their projections to the medial preoptic area. Together, our study demonstrates that mice display prosocial comforting behaviour and reveals a neural circuit mechanism that underlies the encoding and control of affiliative touch during prosocial interactions.

It matters what you see: Graphic media images of war and terror may amplify distress.

Media exposure to graphic images of violence has proliferated in contemporary society, particularly with the advent of social media. Extensive exposure to media coverage immediately after the 9/11 attacks and the Boston Marathon bombings (BMB) was associated with more early traumatic stress symptoms; in fact, several hours of BMB-related daily media exposure was a stronger correlate of distress than being directly exposed to the bombings themselves. Researchers have replicated these findings across different traumatic events, extending this work to document that exposure to graphic images is independently and significantly associated with stress symptoms and poorer functioning. The media exposure-distress association also appears to be cyclical over time, with increased exposure predicting greater distress and greater distress predicting more media exposure following subsequent tragedies. The war in Israel and Gaza, which began on October 7, 2023, provides a current, real-time context to further explore these issues as journalists often share graphic images of death and destruction, making media-based graphic images once again ubiquitous and potentially challenging public well-being. For individuals sharing an identity with the victims or otherwise feeling emotionally connected to the Middle East, it may be difficult to avoid viewing these images. Through a review of research on the association between exposure to graphic images and public health, we discuss differing views on the societal implications of viewing such images and advocate for media literacy campaigns to educate the public to identify mis/disinformation and understand the risks of viewing and sharing graphic images with others.

The impact of marriage equality campaigns on stress: Did a Swiss public vote get under the skin?

Lesbian, gay, bisexual, trans, intersex, and queer (LGBTIQ+) individuals encounter persistent structural inequalities and discrimination that can lead to detrimental psychological and physiological health outcomes. Amid evolving legal landscapes, little attention has been directed toward understanding the physiological health effects of societal shifts on these communities. This study aims to explore the impact of a national marriage equality vote and associated debates on psychological and biological stress among LGBTIQ+ individuals and cisgender, heterosexual, endosex individuals (termed cis-heterosexual) in Switzerland. We gathered longitudinal survey and biological data collected in hair samples among LGBTIQ+ and cis-heterosexual individuals before, during, and after the 2021 national vote (survey data: NT1T2 = 954; NT2T3 = 880; biological data: NT1T2 = 393; NT2T3 = 354). Preregistered analyses reveal a notable increase in biological stress levels (i.e., cortisol and cortisone levels), but not perceived stress, among both LGBTIQ+ as well as cis-heterosexual individuals who were close to them during the campaign. Results further point out the negative impacts of the campaign against marriage equality (i.e., no-campaign) on LGBTIQ+ individuals' biological stress levels as well as on those of their allies. These effects were, however, moderated by exposure to the campaign for marriage equality (i.e., yes-campaign), indicating the powerful buffering effects of the yes-campaign on the impact of discrimination on individuals' health. However, these positive effects appear to come at a cost, potentially impacting the well-being of individuals engaged in advocating for the yes-campaign. This research underscores the lasting impact of political campaigns on individuals' health.

Social stress induces autoimmune responses against the brain.

Clinical studies have revealed a high comorbidity between autoimmune diseases and psychiatric disorders, including major depressive disorder (MDD). However, the mechanisms connecting autoimmunity and depression remain unclear. Here, we aim to identify the processes by which stress impacts the adaptive immune system and the implications of such responses to depression. To examine this relationship, we analyzed antibody responses and autoimmunity in the chronic social defeat stress (CSDS) model in mice, and in clinical samples from patients with MDD. We show that socially stressed mice have elevated serum antibody concentrations. We also confirm that social stress leads to the expansion of specific T and B cell populations within the cervical lymph nodes, where brain-derived antigens are preferentially delivered. Sera from stress-susceptible (SUS) mice exhibited high reactivity against brain tissue, and brain-reactive immunoglobulin G (IgG) antibody levels positively correlated with social avoidance behavior. IgG antibody concentrations in the brain were significantly higher in SUS mice than in unstressed mice, and positively correlated with social avoidance. Similarly, in humans, increased peripheral levels of brain-reactive IgG antibodies were associated with increased anhedonia. In vivo assessment of IgG antibodies showed they largely accumulate around blood vessels in the brain only in SUS mice. B cell-depleted mice exhibited stress resilience following CSDS, confirming the contribution of antibody-producing cells to social avoidance behavior. This study provides mechanistic insights connecting stress-induced autoimmune reactions against the brain and stress susceptibility. Therapeutic strategies targeting autoimmune responses might aid in the treatment of patients with MDD featuring immune abnormalities.

Global trends in emotional distress.

In this study, we examined emotional distress using annual representative survey data from 1.53 million individuals surveyed in 113 countries from 2009 to 2021. Participants reported whether they had experienced worry, sadness, stress, or anger during a lot of the previous day. Within-country estimates showed that the prevalence of feelings of emotional distress increased from 25 to 31% between 2009 and 2021, with those with low levels of education and income experiencing the largest increases in distress. On a global level, the pandemic period was characterized by an initial increase in distress in 2020 followed by recovery in 2021.

A Prelimbic Cortex-Thalamus Circuit Bidirectionally Regulates Innate and Stress-Induced Anxiety-Like Behavior.

Anxiety-related disorders respond to cognitive behavioral therapies, which involved the medial prefrontal cortex (mPFC). Previous studies have suggested that subregions of the mPFC have different and even opposite roles in regulating innate anxiety. However, the specific causal targets of their descending projections in modulating innate anxiety and stress-induced anxiety have yet to be fully elucidated. Here, we found that among the various downstream pathways of the prelimbic cortex (PL), a subregion of the mPFC, PL-mediodorsal thalamic nucleus (MD) projection, and PL-ventral tegmental area (VTA) projection exhibited antagonistic effects on anxiety-like behavior, while the PL-MD projection but not PL-VTA projection was necessary for the animal to guide anxiety-related behavior. In addition, MD-projecting PL neurons bidirectionally regulated remote but not recent fear memory retrieval. Notably, restraint stress induced high-anxiety state accompanied by strengthening the excitatory inputs onto MD-projecting PL neurons, and inhibiting PL-MD pathway rescued the stress-induced anxiety. Our findings reveal that the activity of PL-MD pathway may be an essential factor to maintain certain level of anxiety, and stress increased the excitability of this pathway, leading to inappropriate emotional expression, and suggests that targeting specific PL circuits may aid the development of therapies for the treatment of stress-related disorders.

Neuritin Controls Axonal Branching in Serotonin Neurons: A Possible Mediator Involved in the Regulation of Depressive and Anxiety Behaviors via FGF Signaling.

Abnormal neuronal morphological features, such as dendrite branching, axonal branching, and spine density, are thought to contribute to the symptoms of depression and anxiety. However, the role and molecular mechanisms of aberrant neuronal morphology in the regulation of mood disorders remain poorly characterized. Here, we show that neuritin, an activity-dependent protein, regulates the axonal morphology of serotonin neurons. Male neuritin knock-out (KO) mice harbored impaired axonal branches of serotonin neurons in the medial prefrontal cortex and basolateral region of the amygdala (BLA), and male neuritin KO mice exhibited depressive and anxiety-like behaviors. We also observed that the expression of neuritin was decreased by unpredictable chronic stress in the male mouse brain and that decreased expression of neuritin was associated with reduced axonal branching of serotonin neurons in the brain and with depressive and anxiety behaviors in mice. Furthermore, the stress-mediated impairments in axonal branching and depressive behaviors were reversed by the overexpression of neuritin in the BLA. The ability of neuritin to increase axonal branching in serotonin neurons involves fibroblast growth factor (FGF) signaling, and neuritin contributes to FGF-2-mediated axonal branching regulation in vitro. Finally, the oral administration of an FGF inhibitor reduced the axonal branching of serotonin neurons in the brain and caused depressive and anxiety behaviors in male mice. Our results support the involvement of neuritin in models of stress-induced depression and suggest that neuronal morphological plasticity may play a role in controlling animal behavior.

The impact of psychosocial adversity on brain and behaviour: an overview of existing knowledge and directions for future research.

Environmental experiences play a critical role in shaping the structure and function of the brain. Its plasticity in response to different external stimuli has been the focus of research efforts for decades. In this review, we explore the effects of adversity on brain's structure and function and its implications for brain development, adaptation, and the emergence of mental health disorders. We are focusing on adverse events that emerge from the immediate surroundings of an individual, i.e., microenvironment. They include childhood maltreatment, peer victimisation, social isolation, affective loss, domestic conflict, and poverty. We also take into consideration exposure to environmental toxins. Converging evidence suggests that different types of adversity may share common underlying mechanisms while also exhibiting unique pathways. However, they are often studied in isolation, limiting our understanding of their combined effects and the interconnected nature of their impact. The integration of large, deep-phenotyping datasets and collaborative efforts can provide sufficient power to analyse high dimensional environmental profiles and advance the systematic mapping of neuronal mechanisms. This review provides a background for future research, highlighting the importance of understanding the cumulative impact of various adversities, through data-driven approaches and integrative multimodal analysis techniques.

Strength and resilience of developing brain circuits predict adolescent emotional and stress responses during the COVID-19 pandemic.

The COVID-19 pandemic has had profound but incompletely understood adverse effects on youth. To elucidate the role of brain circuits in how adolescents responded to the pandemic's stressors, we investigated their prepandemic organization as a predictor of mental/emotional health in the first ~15 months of the pandemic. We analyzed resting-state networks from n = 2,641 adolescents [median age (interquartile range) = 144.0 (13.0) months, 47.7% females] in the Adolescent Brain Cognitive Development study, and longitudinal assessments of mental health, stress, sadness, and positive affect, collected every 2 to 3 months from May 2020 to May 2021. Topological resilience and/or network strength predicted overall mental health, stress and sadness (but not positive affect), at multiple time points, but primarily in December 2020 and May 2021. Higher resilience of the salience network predicted better mental health in December 2020 (ß = 0.19, 95% CI = [0.06, 0.31], P = 0.01). Lower connectivity of left salience, reward, limbic, and prefrontal cortex and its thalamic, striatal, amygdala connections, predicted higher stress (ß = -0.46 to -0.20, CI = [-0.72, -0.07], P < 0.03). Lower bilateral robustness (higher fragility) and/or connectivity of these networks predicted higher sadness in December 2020 and May 2021 (ß = -0.514 to -0.19, CI = [-0.81, -0.05], P < 0.04). These findings suggest that the organization of brain circuits may have played a critical role in adolescent stress and mental/emotional health during the pandemic.

Trends in Psychological Distress and Outpatient Mental Health Care of Adults During the COVID-19 Era.

BACKGROUND: In addition to the physical disease burden of the COVID-19 pandemic, concern exists over its adverse mental health effects. OBJECTIVE: To characterize trends in psychological distress and outpatient mental health care among U.S. adults from 2018 to 2021 and to describe patterns of in-person, telephone, and video outpatient mental health care. DESIGN: Cross-sectional nationally representative survey of noninstitutionalized adults. SETTING: United States. PARTICIPANTS: Adults included in the Medical Expenditure Panel Survey Household Component, 2018 to 2021 (n = 86 658). MEASUREMENTS: Psychological distress was measured with the Kessler-6 scale (range of 0 to 24, with higher scores indicating more severe distress), with a score of 13 or higher defined as serious psychological distress, 1 to 12 as less serious distress, and 0 as no distress. Outpatient mental health care use was measured via computer-assisted personal interviews. RESULTS: Between 2018 and 2021, the rate of serious psychological distress among adults increased from 3.5% to 4.2%. Although the rate of outpatient mental health care increased from 11.2% to 12.4% overall, the rate decreased from 46.5% to 40.4% among adults with serious psychological distress. When age, sex, and distress were controlled for, a significant increase in outpatient mental health care was observed for young adults (aged 18 to 44 years) but not middle-aged (aged 45 to 64 years) and older (aged >65 years) adults and for employed adults but not unemployed adults. In 2021, 33.4% of mental health outpatients received at least 1 video visit, including a disproportionate percentage of young, college-educated, higher-income, employed, and urban adults. LIMITATION: Information about outpatient mental health service modality (in-person, video, telephone) was first fully available in the 2021 survey. CONCLUSION: These trends and patterns underscore the persistent challenges of connecting older adults, unemployed persons, and seriously distressed adults to outpatient mental health care and the difficulties faced by older, less educated, lower-income, unemployed, and rural patients in accessing outpatient mental health care via video. PRIMARY FUNDING SOURCE: None.

Reactivation of Early-Life Stress-Sensitive Neuronal Ensembles Contributes to Lifelong Stress Hypersensitivity.

Early-life stress (ELS) is one of the strongest lifetime risk factors for depression, anxiety, suicide, and other psychiatric disorders, particularly after facing additional stressful events later in life. Human and animal studies demonstrate that ELS sensitizes individuals to subsequent stress. However, the neurobiological basis of such stress sensitization remains largely unexplored. We hypothesized that ELS-induced stress sensitization would be detectable at the level of neuronal ensembles, such that cells activated by ELS would be more reactive to adult stress. To test this, we leveraged transgenic mice to genetically tag, track, and manipulate experience-activated neurons. We found that in both male and female mice, ELS-activated neurons within the nucleus accumbens (NAc), and to a lesser extent the medial prefrontal cortex, were preferentially reactivated by adult stress. To test whether reactivation of ELS-activated ensembles in the NAc contributes to stress hypersensitivity, we expressed hM4Dis receptor in control or ELS-activated neurons of pups and chemogenetically inhibited their activity during experience of adult stress. Inhibition of ELS-activated NAc neurons, but not control-tagged neurons, ameliorated social avoidance behavior following chronic social defeat stress in males. These data provide evidence that ELS-induced stress hypersensitivity is encoded at the level of corticolimbic neuronal ensembles.SIGNIFICANCE STATEMENT Early-life stress enhances sensitivity to stress later in life, yet the mechanisms of such stress sensitization are largely unknown. Here, we show that neuronal ensembles in corticolimbic brain regions remain hypersensitive to stress across the life span, and quieting these ensembles during experience of adult stress rescues stress hypersensitivity.

Nursing's Role in Psychosocial Health Management After a Stroke Event: A Scientific Statement From the American Heart Association.

INTRODUCTION: Stroke can have profound psychosocial health implications. These constructs are often overlooked and undertreated yet can be as devastating as the physical, functional, and cognitive consequences after stroke. AIM: This scientific statement aims to evaluate 5 important aspects of psychosocial health (depression, stress, anxiety, fatigue, and quality of life) after a stroke to provide a framework for related nursing care across the poststroke continuum. METHODS: A narrative review of the literature published from 2018 to 2023 was conducted with databases such as PubMed/MEDLINE, ClinicalTrials.gov, PsychInfo/EBSCOHost, PsychArticles, CINHAL, and the Cochrane Library. RESULTS: Findings reveal a gap in evidence-based nursing interventions for addressing poststroke psychosocial needs. Critical strategies for shaping therapeutic nursing care include enhanced screening with validated tools; educating stroke survivors, families, and staff on symptom recognition, prevention, and treatment; and ensuring appropriate pharmacological management and access to psychological and psychosocial interventions, including referrals to social services and other essential support systems. Care should be comprehensive and interdisciplinary. Nurse-led research can benefit from more inclusive inclusion, including individuals with recurrent strokes and preexisting psychosocial conditions, focusing on the impact of structural racism and care disparities and expanding evidence-based nursing interventions. CONCLUSIONS: Although there is limited high-level evidence on the nursing care for patients with suboptimal psychosocial health after stroke, nurses have a crucial role in addressing these needs. Enhanced screening, assessment, supportive services, and education are vital to ensure that patients receive the necessary treatment and care.