Acute Stress Paradigm Research Articles

Stress-induced cortisol response predicts empathy for pain: The role of task-based connectivity between the insula and sensorimotor cortex during acute stress

Empathy for pain is a key driver of prosocial behavior and is influenced by acute psychosocial stress. However, the role of task-based brain connectivity during acute stress have been neglected. Hence, we aimed to explore the relationship between the magnitude of cortisol response to acute stress and empathy for pain, as well as the neural connectivity mechanisms involved. In this study, 80 healthy participants (37 women and 43 men) were exposed to the acute psychosocial stress paradigm (ScanSTRESS) and were scanned by functional magnetic resonance imaging. Saliva samples were collected to measure the magnitude of cortisol stress response. Subsequently, the participants took part in a pain-video task to assess their empathy for pain. Six participants were excluded because of physical discomfort or excessive head movement in all runs during the task-dependent fMRI scan. Therefore, 33 women and 41 men were included in data analysis. We found that empathy for pain was negatively correlated with the magnitude of cortisol stress response (r = -0.268, p = 0.018) and that the task-based connectivity between the salience network and sensorimotor network, including its sub-network and sub-region, was negatively correlated with the magnitude of cortisol stress response, and positively correlated with empathy for pain. Furthermore, task-based connectivity between the insula and the paracentral lobule mediates the effect of the stress-induced cortisol response on empathy for pain (indirect effect = -0.0152, 95% CI = [- 0.036, -0.001], p = 0.036). Our research suggests that empathy is not only correlated with stress-induced glucocorticoids but also tied to the stress-induced reduced communication between basic and higher brain regions.

Complement C5a Receptor Signaling Alters Stress Responsiveness and Modulates Microglia Following Chronic Stress Exposure

BackgroundAccumulating evidence underscores the pivotal role of heightened inflammation in the pathophysiology of stress-related diseases, but the underlying mechanisms remain elusive. The complement system, a key effector of the innate immune system, produces the C5–cleaved activation product C5a upon activation, initiating inflammatory responses through the canonical C5a receptor 1 (C5aR1). While C5aR1 is expressed in stress-responsive brain regions, its role in stress responsiveness remains unknown. MethodsTo investigate C5a-C5aR1 signaling in stress responses, mice underwent acute and chronic stress paradigms. Circulating C5a levels and messenger RNA expression of C5aR1 in the hippocampus and adrenal gland were measured. C5aR1-deficient mice were used to elucidate the effects of disrupted C5a-C5aR1 signaling across behavioral, hormonal, metabolic, and inflammation parameters. ResultsChronic restraint stress elevated circulating C5a levels while reducing C5aR1 messenger RNA expression in the hippocampus and adrenal gland. Notably, the absence of C5aR1 signaling enhanced adrenal sensitivity to adrenocorticotropic hormone, concurrently reducing pituitary adrenocorticotropic hormone production and enhancing the response to acute stress. C5aR1-deficient mice exhibited attenuated reductions in locomotor activity and body weight under chronic stress. Additionally, these mice displayed increased glucocorticoid receptor sensitivity and disrupted glucose and insulin homeostasis. Chronic stress induced an increase in C5aR1-expressing microglia in the hippocampus, a response mitigated in C5aR1-deficient mice. ConclusionsC5a-C5aR1 signaling emerges as a key metabolic regulator during stress, suggesting that complement activation and dysfunctional C5aR1 signaling may contribute to neuroinflammatory phenotypes in stress-related disorders. The results advocate for further exploration of complement C5aR1 as a potential therapeutic target for stress-related conditions.

The role of personal, relational, and collective self-esteem in predicting acute salivary cortisol response and perceived stress.

Personal self-esteem (PSE) has been well recognized as a buffer against stress; however, the effects of other types of self-esteem, such as relational self-esteem (RSE) and collective self-esteem (CSE), on stress have not been adequately explored. This study investigated the roles of PSE, RSE, and CSE in reducing stress response. The Rosenberg, Relational, and Collective Self-Esteem Scales were adopted to assess PSE, RSE, and CSE, respectively. Participants underwent an acute social stress paradigm, and their acute stress response was assessed using subjective stress reports and salivary cortisol levels. Chronic stress level was estimated using the Perceived Stress Scale and hair cortisol concentration. The results showed that PSE was negatively correlated with salivary cortisol response during acute social stress; however, no significant associations were found between any type of self-esteem and subjective stress reports. For chronic stress, all types of self-esteem were negatively associated with perceived stress level, but not with hair cortisol concentration. Further hierarchical regression analyses suggested that only PSE negatively predicted acute salivary cortisol response and perceived stress level. Overall, the findings suggest the essential role of PSE in predicting acute salivary cortisol responses and perceived stress.

Microglia modulate sleep/wakefulness under baseline conditions and under acute social defeat stress in adult mice

Although sleep is tightly regulated by multiple neuronal circuits in the brain, nonneuronal cells such as glial cells have been increasingly recognized as crucial sleep regulators. Recent studies have shown that microglia may act to maintain wakefulness. Here, we investigated the possible involvement of microglia in the regulation of sleep quantity and quality under baseline and stress conditions through electroencephalography (EEG)/electromyography (EMG) recordings, and by employing pharmacological methods to eliminate microglial cells in the adult mouse brain. We found that severe microglial depletion induced by the colony-stimulating factor 1 receptor (CSF1R) antagonist PLX5622 (PLX) reversibly decreased the total wake time and the wake episode duration and increased the EEG slow-wave power during wakefulness under baseline conditions. To examine the role of microglia in sleep/wake regulation under mental stress, we used the acute social defeat stress (ASDS) paradigm, an ethological model for psychosocial stress. Sleep analysis under ASDS revealed that microglial depletion exacerbated the stress-induced decrease in the total wake time and increase in anxiety-like behaviors in the open field test. These results demonstrate that microglia actively modulate sleep quantity and architecture under both baseline and stress conditions. Our findings suggest that microglia may potentially provide resilience against acute psychosocial stress by regulating restorative sleep.

Different Chronic Stress Paradigms Converge on Endogenous TDP43 Cleavage and Aggregation

The TAR-DNA binding protein (TDP43) is a nuclear protein whose cytoplasmic inclusions are hallmarks of Amyotrophic Lateral Sclerosis (ALS). Acute stress in cells causes TDP43 mobilization to the cytoplasm and its aggregation through different routes. Although acute stress elicits a strong phenotype, is far from recapitulating the years-long aggregation process. We applied different chronic stress protocols and described TDP43 aggregation in a human neuroblastoma cell line by combining solubility assays, thioflavin-based microscopy and flow cytometry. This approach allowed us to detect, for the first time to our knowledge in vitro, the formation of 25 kDa C-terminal fragment of TDP43, a pathogenic hallmark of ALS. Our results indicate that chronic stress, compared to the more common acute stress paradigm, better recapitulates the cell biology of TDP43 proteinopathies. Moreover, we optimized a protocol for the detection of bona fide prions in living cells, suggesting that TDP43 may form amyloids as a stress response.

Sex differences in neuroendocrine, sympathetic nervous system, and affect responses to acute stress in cannabis users.

Cannabis is the most widely used illicit substance in the USA and is often reportedly used for stress reduction. Indeed, cannabinoids modulate signaling of the hypothalamic-pituitary-adrenal axis and sympathetic nervous system. However, the role of biological sex in this interaction between cannabis use and stress is poorly understood, despite sex differences in neurobiological stress responsivity, endocannabinoid signaling, and clinical correlates of cannabis use. The study aims to examine the role of biological sex in multisystem stress responsivity in cannabis users. Frequent cannabis users (> 3 times/week, n = 48, 52% male) and non-users (n = 41, 49% male) participated in an acute psychosocial stress paradigm. Saliva was collected at eight timepoints and analyzed for hypothalamic-pituitary-adrenal (cortisol) and sympathetic (alpha-amylase) indices of stress responsivity, and basal estradiol. Subjective ratings of negative affect, including distress, were collected at three timepoints. Cannabis users showed blunted pre-to-post-stress cortisol reactivity. Female cannabis users demonstrated greater blunted cortisol reactivity than their male counterparts. Sex moderated the effect of cannabis use on alpha-amylase responsivity over time, wherein female cannabis users showed flattened alpha-amylase responses across the stressor compared to male cannabis users and both non-user groups. Qualitatively, female cannabis users demonstrated the greatest pre-to-post-stress change in subjective distress. Differences in stress responding were not explained by estradiol or distress intolerance. Biological sex impacts multisystem stress responding in cannabis users. Paradoxically, female cannabis users showed the least physiological, but greatest subjective, responses to the stressor. Further research into sex differences in the effects of cannabis use is warranted to better understand mechanisms and clinical implications.

PACAP Controls Endocrine and Behavioral Stress Responses via Separate Brain Circuits

BackgroundThe neuropeptide PACAP (pituitary adenylate cyclase-activating polypeptide) is a master regulator of central and peripheral stress responses, yet it is not clear how PACAP projections throughout the brain execute endocrine and behavioral stress responses. MethodsWe used AAV (adeno-associated virus) neuronal tracing, an acute restraint stress (ARS) paradigm, and intersectional genetics, in C57BL/6 mice, to identify PACAP-containing circuits controlling stress-induced behavior and endocrine activation. ResultsPACAP deletion from forebrain excitatory neurons, including a projection directly from medial prefrontal cortex to hypothalamus, impairs c-fos activation and corticotropin-releasing hormone (CRH) messenger RNA elevation in the paraventricular nucleus after 2 hours of restraint, without affecting ARS-induced hypophagia, or c-fos elevation in nonhypothalamic brain. Elimination of PACAP within projections from lateral parabrachial nucleus to extended amygdala, on the other hand, attenuates ARS-induced hypophagia, along with extended amygdala fos induction, without affecting ARS-induced CRH messenger RNA elevation in the paraventricular nucleus. PACAP projections to extended amygdala terminate at protein kinase C delta type (PKCδ) neurons in both the central amygdala and the oval bed nucleus of the stria terminalis. Silencing of PKCδ neurons in the central amygdala, but not in the oval bed nucleus of the stria terminalis, attenuates ARS-induced hypophagia. Experiments were carried out in mice of both sexes with n ≥ 3 per group. ConclusionsA frontocortical descending PACAP projection controls paraventricular nucleus CRH messenger RNA production to maintain hypothalamic-pituitary-adrenal axis activation and regulate the endocrine response to stress. An ascending PACAPergic projection from the external lateral parabrachial nucleus to PKCδ neurons in the central amygdala regulates behavioral responses to stress. Defining two separate limbs of the acute stress response provides broader insight into the specific brain circuitry engaged by the psychogenic stress response.

A 2-hit model of early life stress and later life restraint stress: Susceptibility or resilience to anxiety and alcohol drinking?

Early life stress adversely influences neurodevelopment and has profound long-term effects on brain function and behavior. Here we measure endogenous stress hormone and determine locomotor, anxiogenic, and operant binge drinking behavior of rats exposed to a 2-hit model of maternal deprivation (MD) stress in infancy followed by acute (ARS) or chronic restraint stress (CRS) paradigms during adolescence/adulthood to determine resiliency or susceptibility to the second stress exposure. Adolescents (n=40) exhibited higher baseline corticosterone (CORT) levels than adults (n=40) and with CRS exposure, showed significantly elevated circulating CORT irrespective of MD exposure status. In adults, MD females had lower baseline CORT levels than controls, whereas MD and control male CORT were indistinguishable. For behavior, N=40 was used in total. In the open field, locomotion was significantly decreased upon ARS, with MD having a significant sustained impact on ambulatory measures with CRS. When tested for anxiety-like behavior on an elevated zero maze, ARS interacted with MD to induce protracted and more profound anxiogenic behavior. Upon CRS, MD anxiogenic behavior was reversed to baseline levels whereas controls, especially males, exceeded baseline levels to spend significantly more time in the open arms of the EZM. Finally, in testing for binge drinking behavior, MD rats lever-pressed significantly more for 10% ethanol on an operant apparatus and exhibited a 3-fold greater drinking baseline than controls. Binge drinking behavior was further elevated with ARS, but quickly returned to the MD baseline even prior to reaching CRS. By contrast, controls had much lower baseline but significantly elevated binge drinking behavior by 3–5-fold in response to ARS which remained elevated through CRS, stabilizing at MD baseline levels. Sex differences were most evident in controls where males exhibited accelerated binge drinking behavior at consistently higher rates than females until Day 21 of CRS where their binge drinking behaviors were similar. There was also a main effect of alcohol binge behavior for MD males, and not females. This study illustrates that, depending on the biobehavioral output, males and females differ in reactivity to stressors where MD stress may confer sex-dependent resilience to subsequent stressors, and males are differently impacted than females.

Under Pressure: Using Acute Stress Paradigms to Advance Our Understanding of the Effects of Stress on the Adolescent Brain

Under Pressure: Using Acute Stress Paradigms to Advance Our Understanding of the Effects of Stress on the Adolescent Brain

Antidepressant Effect of Neuropeptide Y in Models of Acute and Chronic Stress

The search for potential effective antidepressants with minimal side effects is necessary. Peptides are possible applicants for this role. We investigated the antidepressant effect of neuropeptide Y (NY), alone and in combination with clomipramine, in models of acute and chronic stress induced by ultrasound of variable frequencies. Rats were divided into the following groups: the control group, stress group, and stress groups with intranasal administration of NY (100 μg/kg) or clomipramine (7.5 mg/kg), or their combination. Rat behavior was evaluated using a sucrose preference test and forced swimming test in an acute stress model, and a sucrose preference test, forced swimming test, social interaction test, open field test, and Morris water maze test in a chronic stress model. The results of our experiment demonstrated a protective effect of intranasal NY in a model of acute stress, which was comparable to the antidepressant effect of clomipramine. When the same dose was chronically administered, NY also demonstrated an antidepressant action, although expressed in a lesser degree than clomipramine. The combination of NY and clomipramine was much less effective in the chronic stress paradigm compared to the separated drug administration, but was just as effective in the acute stress paradigm. Until now, there was no convincing evidence for the efficacy of the chronic administration of neuropeptide Y; we demonstrated its effectiveness in the animal model of depressive-like behavior. However, our hypothesis that neuropeptide Y can enhance the effect of a classical antidepressant was not confirmed.

Serum neurotransmitters level in response to acute restraint stress in perimenopausal female rats following L-arginine supplementation

Abstract Background: Reproductive aging in females is a continuous process involving progressive follicular depletion that begins at birth and extends through the menopausal transition. Objective: This study aimed to assess neurotransmitter interplay in L-arginine-supplemented perimenopausal female rats subjected to an acute restraint stress paradigm. Materials/Methods: Fifty-four female Sprague–Dawley rats were divided into three groups: Control rats (injected with Corn oil 2.5 μL/g BW); VCD rats (injected with 4-vinylcyclohexene diepoxide 160 mg/kg BW diluted in Corn oil) both for 15 days; and Aging rats (210 days old) left to age naturally. Sixty days after VCD/corn oil administration and 240 days in Aging group, rats were further divided into two subgroups: distilled water and L-arginine supplemented (100 mg/kg BW) for additional 30 days. At 130 days in Control and VCD groups, and 270 days in Aging group on diestrus morning, animals were decapitated at two different time points (“before” and “after”) restraint stress. Trunk blood was collected into plain tubes; centrifuged to extract serum which was stored at –80°C for dopamine, noradrenaline, and serotonin measurements using specialized high-sensitive ELISA kits from LDN immunoassay company, Germany). Results: Before and after restraint stress, serum dopamine and noradrenaline levels were significantly lower (P < 0.05) in the perimenopausal groups compared to Control group, whereas serum serotonin was not significantly different amongst the three groups. L-arginine supplementation after stress significantly reduced (P < 0.05) serum dopamine in VCD rats and significantly increased (P < 0.05) it in Aging rats. On the other hand, L-arginine supplementation significantly lowered (P < 0.05) serum noradrenaline in Control rats and significantly increased (P < 0.05) it in VCD rats. Furthermore, after stress, L-arginine supplementation also significantly lowered (P < 0.05) serum serotonin in VCD and Aging rats compared to the Control rats. Conclusion: L-arginine supplementation showed differential effects in an attempt to regulate neurotransmitters and this could be protective against hormonal fluctuations that occur during perimenopause.

The STRESS-NL database: A resource for human acute stress studies across the Netherlands

Stress initiates a cascade of (neuro)biological, physiological, and behavioral changes, allowing us to respond to a challenging environment. The human response to acute stress can be studied in detail in controlled settings, usually in a laboratory environment. To this end, many studies employ acute stress paradigms to probe stress-related outcomes in healthy and patient populations. Though valuable, these studies in themselves often have relatively limited sample sizes. We established a data-sharing and collaborative interdisciplinary initiative, the STRESS-NL database, which combines (neuro)biological, physiological, and behavioral data across many acute stress studies in order to accelerate our understanding of the human acute stress response in health and disease (www.stressdatabase.eu). Researchers in the stress field from 12 Dutch research groups of 6 Dutch universities created a database to achieve an accurate inventory of (neuro)biological, physiological, and behavioral data from laboratory-based human studies that used acute stress tests. Currently, the STRESS-NL database consists of information on 5529 individual participants (2281 females and 3348 males, age range 6–99 years, mean age 27.7 ± 16 years) stemming from 57 experiments described in 42 independent studies. Studies often did not use the same stress paradigm; outcomes were different and measured at different time points. All studies currently included in the database assessed cortisol levels before, during and after experimental stress, but cortisol measurement will not be a strict requirement for future study inclusion. Here, we report on the creation of the STRESS-NL database and infrastructure to illustrate the potential of accumulating and combining existing data to allow meta-analytical, proof-of-principle analyses. The STRESS-NL database creates a framework that enables human stress research to take new avenues in explorative and hypothesis-driven data analyses with high statistical power. Future steps could be to incorporate new studies beyond the borders of the Netherlands; or build similar databases for experimental stress studies in rodents. In our view, there are major scientific benefits in initiating and maintaining such international efforts.

Fight or flight: The effect of heart rate reactivity on acute stress-induced food intake

The ‘fight-or-flight-reaction’ describes the suppression of all irrelevant functions like food intake during the acute stress response. However, heart rate reactivity and food intake under acute stress has not been investigated. Therefore, the aim of this study was to investigate the effect of high and low heart rate reactivity on food intake following an acute laboratory stress paradigm in individuals with healthy weight. Fifty-six men and women with healthy weight (BMI: M = 21.82 ± 1.53 kg/m²) were categorized into high heart rate reactors (H-HRR) and low heart rate reactors (L-HRR). After the stress paradigm of the Trier Social Stress Test (TSST), total energy intake was measured in a standardized laboratory meal. H-HRR demonstrated a significantly lower appetite (z = -3.133, p≤ 0.01) and food intake (t(49.13) = 2.253, p≤ 0.05, d= 0.68) after the TSST compared to the L-HRR. No differences in the stress perception and cognitive appraisal could be found between the two reactor groups. These results suggest that the stress-induced heart rate reactivity might be a responsible factor in the stress-eating paradox. In view of the divergent results of stress-induced eating studies in laboratory setting with acute stressors, it is highly important to control the effect of the heart rate reactivity on food intake.

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.

Acute Maternal Stress Disrupts Infant Regulation of the Autonomic Nervous System and Behavior: A CASP Study.

Exposure to maternal stress is assumed to influence infant health and development across the lifespan. The autonomic nervous system (ANS) is especially sensitive to the effects of the early caregiving environment and linked to predictors of later mental health. Understanding how exposure to maternal stress adversely affects the developing ANS could inform prevention. However, there is no agreed upon definition of maternal stress making its study difficult. Here we use the Caretaker Acute Stress Paradigm (CASP) to study the effects of maternal stress in an experimentally controlled laboratory setting. The CASP has 5 episodes, a natural play, followed by a caretaker stressor (or control) condition, another play, a classic still face episode, followed by another play. A total of 104 4-months-old infants and their mothers were randomly assigned to either the caretaker-stress or caretaker-control condition. Changes in behavior, heart rate (HR), and respiratory sinus arrhythmia (RSA) before and after the introduction of the stressor (or control condition) were recorded and compared. Infants in the maternal stress condition showed significantly more behavioral distress [X2 = (1, N = 104) = 4.662, p = 0.031]. Moreover, infants whose mothers were in the stress condition showed an significant increase in heart rate after the caretaker condition [F(1, 102) = 9.81, p = 0.002]. Finally we observed a trend to faster RSA recovery in infants of the control condition [F(1, 75) = 3.539, p = 0.064]. Results indicate that exposure to acute maternal stress affects infant regulation of the autonomic nervous system and behavior.

Impact of bifrontal transcranial Direct Current Stimulation on decision-making and stress reactivity. A pilot study

Stress is an adaptive response with repercussions on the human health. The dorsolateral prefrontal cortex (DLPFC) is thought to be involved in stress regulation by contributing to limit its biological and behavioral pejorative consequences. Here, to investigate the contribution of the DLPFC in stress response, we applied transcranial Direct Current Stimulation (tDCS) over the DLPFC during acute stress exposure in healthy participants. We hypothesized that active tDCS compared to sham would impact top-down control of the DLPFC on goal-directed behavior and hypothalamo–pituitary–adrenal (HPA) axis activity.In a double-blind sham-controlled study, 30 healthy subjects were randomly allocated to receive either active (2 mA, n = 15) or sham tDCS (n = 15) with the anode over the left DLPFC and the cathode over the right DLFPC. During the 30-min stimulation period, participants faced an experimental acute stress paradigm. Changes in goal-directed behavior were measured with a decision-making task. HPA axis reactivity was assessed by repeated measures of salivary cortisol.Acute stress decreased appetite for immediate reward in the sham group (mean - 4.40%; p = 0.017) whereas no significant effect of stress was observed in the active group. During stress exposure, we observed a significant larger elevation of salivary cortisol (p = 0.045; Cohen's d = 0.431) in the sham tDCS group (+179.8%; Standard error of the mean (SEM) = 20.6) than in the active group (+138.5%; SEM = 14.2).Stimulating the DLPFC using bifrontal tDCS may prevent stress-induced acute effects on both biological and behavioral outcomes.

Does well-being associate with stress physiology? A systematic review and meta-analysis.

The current meta-analysis tested whether trait indicators of well-being associate with stressor-evoked physiological reactivity and recovery in healthy adults. Medline, PsycINFO, and PubMed were used to identify relevant articles. Articles were included if they (a) measured cardiovascular or neuroendocrine (but not immune) physiology during or after an acute laboratory stress paradigm (b) measured indicators of hedonic well-being, eudaimonic well-being, or optimism, and (c) included healthy adult participants. Laboratory stress tasks included frustrating cognitive tasks, emotional recall tasks, and tasks involving social evaluation. Physiological variables were aggregated across cardiac (heart rate and cardiac output), hemodynamic (mean arterial pressure, systolic blood pressure, and diastolic blood pressure), HPA (cortisol), and autonomic (high frequency heart rate variability, skin conductance, and catecholamines) markers. Twenty-seven studies were included (n = 3,390; 54.6% women). Effect sizes and confidence intervals were estimated using a random-effects model with pooled variance. Contrary to expectations, optimism was associated with greater cardiac reactivity to cognitive stressors but did not associate with stress recovery. By contrast, hedonic well-being was associated with enhanced hemodynamic recovery following laboratory stressors but was not associated with stress reactivity. Hedonic well-being, but not optimism, could potentially buffer against the effects of psychological stressors on physiological responding by relating to more complete recovery. Identifying the mechanisms contributing to these patterns of association may provide insights into psychological interventions for well-being and stress-related disease risk. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Early social deprivation does not affect cortisol response to acute and chronic stress in zebrafish

Social isolation is a well-established technique for inducing early adversity but, in rodent models, the need of parental care makes it difficult to distinguish the effects of social deprivation from the consequences of nutritional deficiencies. Zebrafish do not require parental care, allowing separation of social deprivation from nutritional deprivation, and have emerged as a promising model to study ontogeny of normal and pathological behaviors relevant for human neuropsychological disorders. Previous reports of life-long isolation in zebrafish showed some consistency with mammalian literature, depicting later social deficits and locomotor hyperactivity. However, unlike reports of higher anxiety and stress behavior in isolated rodents and primates, behavioral responses were tapered in isolated fish. To examine whether life-long developmental isolation has a dampening effect on zebrafish endocrine stress response, we applied stressors to zebrafish siblings that were either isolated or socialized, and compared their whole-body cortisol levels with non-stressed control siblings kept in low-housing densities. Utilizing previously validated paradigms (exposure to novel tank and unpredictable chronic stress), we exposed separate groups (n = 9–14, mixed-sex) of social and isolated zebrafish to acute and chronic stressors and measured their cortisol levels. A univariate ANOVA and post-hoc Tukey’s HSD tests confirmed that compared to socially raised control fish, developmental isolation did not increase baseline cortisol levels in zebrafish. Additionally, compared to the non-stressed condition, application of both acute and chronic stressors significantly increased cortisol levels in isolated fish and, to a similar degree, to socially raised fish. Our findings suggest that zebrafish isolation studies may help separate effects of social deprivation from nonsocial aspects of early adversity. These studies further substantiate the use of developmental isolation in zebrafish, particularly with acute and chronic stress paradigms, for modeling neuropsychological disorders. LAY SUMMARY A difficult childhood can make humans react more frequently or severely to later stress and modeling this effect in animals can help explain how and why early stress affects subsequent mental and physical health. Early social isolation does not affect later response to stressful situations in adult zebrafish, providing us with a model of psychiatric disorders that allows separation of effects of poor physical environments (lacking food, shelter, etc.) from poor social environments (lack of appropriate socialization).

Risk and Resilience in an Acute Stress Paradigm: Evidence From Salivary Cortisol and Time-Frequency Analysis of the Reward Positivity

Both abnormal stress and reward responsivity are consistently linked to multiple forms of psychopathology; however, the nature of the associations between stress and reward sensitivity remains poorly understood. In the present study, we examined associations between the hypothalamic-pituitary-adrenal-axis stress response and event-related potentials sensitive to the receipt of reward-related feedback in a pre–post experimental paradigm. Neural responses were recorded while male participants completed a simple monetary-reward guessing task before and after the Montreal Imaging Stress Task. Results demonstrated that acute psychosocial stress significantly reduced the magnitude of neural responses to feedback in the reward-sensitive delta-frequency band but not the loss-sensitive theta-frequency band. In addition, a larger delta-frequency response to rewards at baseline predicted reduced overall cortisol response in the stress condition. These findings suggest, therefore, that neural reward circuitry may be associated with both risk for and resilience to stress-related psychopathology.

Anxiolytic Mechanism(S) and Corticosterone-Attenuating Effect of Hydroalcoholic Leaf Extract of Tapinanthus globiferus Mistletoe Growing on Azadirachta indica Tree

Similar pharmacodynamic mechanism(s) often underlie drug actions and toxicities of anxiolytic agents and medicinal extracts. Extracts of Tapinanthus globiferus and related plant species have been reported with anxiolytic activities. But mechanistic evaluations on these plant extracts are few. This study investigated the anxiolytic mechanism(s), including the corticosterone-attenuating effect, of hydroalcoholic Tapinanthus globiferus (HATG) leaf extract harvested from Azadirachta indica host tree in the mouse elevated zero-maze and restraint-induced acute stress paradigms using per cent open segment time (%OST) and brain/plasma corticosterone levels as endpoints, respectively. The results show that anxiolytic activity (%OST) of 150 mg/kg HATG leaf extract was reversed by pretreatment with 5 mg/kg caffeine (HATG alone, 10.90±1.73;HATG+Caffeine, 8.66±1.74), 2 mg/kg methysergide (MTD) (HATG alone, 98.70±14.98; HATG+MTD, 74.20±10.82) and 5 mg yohimbine (HATG alone, 120.10±10.72; HATG+Yohimine, 78.44±13.92) but not by 0.5 m/kg atropine (HATG alone, 104.60±25.31; HATG+Atropine, 105.40±11.85), 0.5 mg/kg flumazenil (HATG alone,80.27±9.69; HATG+Flumazenil, 80.75±10.19), 2 mg/kg cyproheptadine (HATG alone, 88.67±16.44; HATG+Cyproheptadine, 92.11±12.58), 0.2 mg/kg haloperidol (HATG alone, 74.11±17.33; HATG+Haloperidol, 94.00±32.54) and 5 mg/kg naloxone (HATG alone, 94.30±10.84; HATG+Naloxone, 95.30±6.86). The results also indicate HATG leaf extract (at 50, 150, 500 and 1500 mg/kg) caused largely dose-dependent and significant (p<0.05) attenuations in brain/plasma corticosterone levels (5.64±0.66/3.91±0.44,3.78±0.39/3.39±0.38, 4.26±0.34/3.22±0.18 and 2.74±0.51/2.74±0.22), respectively, in extract- compared to distilled water- (5.93±0.60/4.56±0.37) and diazepam-treated (2.34±0.19/2.44±0.29) mice subjected to restraint-induced acute stress. These findings suggest anxiolytic mechanism(s) of the extract may involve its interactions with the adenosine, non-5HT2 serotonin, alpha (α)2 receptors and the hypothalamus-pituitary-adrenal (HPA) axis. This study may constitute the first mechanistic and corticosterone modulation report on the extracts of this parasitic medicinal plant and may benefit from confirmatory radio-labelled binding assays in subsequent studies.