Sex differences in acute early life stress-enhanced fear learning in adult rats.

Patients diagnosed with posttraumatic stress disorder (PTSD) present with a spectrum of debilitating anxiety symptoms resulting from exposure to trauma. Women are twice as likely to be diagnosed with anxiety and PTSD compared to men; however, the reason for this vulnerability remains unknown. We conducted four experiments where we first demonstrated a female vulnerability to stress-enhanced fear learning (SEFL) with a moderate, acute early life stress (aELS) exposure (4 footshocks in a single session), compared to a more intense aELS exposure (15 footshocks in a single session) where males and females demonstrated comparable SEFL. Next, we demonstrated that this female vulnerability does not result from differences in footshock reactivity or contextual fear conditioning during the aELS exposure. Finally, using gonadectomy or sham surgeries in adult male and female rats, we showed that circulating levels of gonadal steroid hormones at the time of adult fear conditioning do not explain the female vulnerability to SEFL. Additional research is needed to determine whether this vulnerability can be explained by organizational effects of gonadal steroid hormones or differences in sex chromosome gene expression. Doing so is critical for a better understanding of increased female vulnerability to certain psychiatric diseases.

Cumulative lifetime stressor exposure impairs stimulus-response but not contextual learning.

Greater exposure to stressors over the life course is believed to promote striatum-dependent over hippocampus-dependent learning and memory processes under stressful conditions. However, little research in this context has actually assessed lifetime stressor exposure and, moreover, it remains unknown whether greater cumulative lifetime stressor exposure exerts comparable effects on striatum-dependent learning and hippocampus-dependent learning in non-stressful contexts. To investigate this issue, we used the Stress and Adversity Inventory for Adults (Adult STRAIN) and Multicued Search Task to investigate the relation between cumulative lifetime stressor exposure and striatum-dependent stimulus-response learning and hippocampus-dependent contextual learning under non-stressful conditions among healthcare professionals (N = 205; 157 females, 48 males; Age: M = 34.23, SD 9.3, range 20-59 years). Individuals with moderate, but not low, cumulative lifetime stressor exposure exhibited impaired learning for stimulus-response associations. In contrast, learning for context associations was unrelated to participants' lifetime stressor exposure profiles. These results thus provide first evidence that cumulative lifetime stressor exposure may have negative consequences on human striatum-dependent stimulus-response learning under non-stressful environmental conditions.

Computed tomography myocardial perfusion imaging to detect myocardial ischemia in patients with anxiety and obstructive coronary heart disease post-exposure to mental stressors.

This study aims to measure myocardial blood flow (MBF) using dynamic CT- myocardial perfusion imaging (CT-MPI) combined with mental stressors in patients with obstructive coronary artery disease (OCAD) and in patients with anxiety and no obstructive coronary artery disease (ANOCAD). A total of 30 patients with OCAD with 30 patients with ANOCAD were included in this analysis. Using the 17-segment model, the rest and stress phase MBF of major coronary arteries in participants were recorded respectively. Compared with ANOCAD patients, OCAD patients were more likely to have localized reduction of MBF (p < 0.05). For patients with ANOCAD, both global MBF and MBF of the main coronary arteries in the stress phase were lower than those in the rest phase (all p < 0.05), but there was no significant difference in MBF among the main coronary arteries in the rest or stress phase (p = 0.25, p = 0.15). For patients with OCAD, the MBF of the target area was lower than that of the non-target area in both the rest and stress phase, and the MBF of the target area in the stress phase was lower than that in the rest phase (all p < 0.05). However, there was no significant difference in MBF between the rest or stress phase in the non-target area (p = 0.73). Under mental stress, the decrease in MBF in ANOCAD patients was diffuse, while the decrease in MBF in OCAD patients was localized. Dynamic CT-MPI combined with mental stressors can be used to detect MBF changes in anxiety patients.

Unique and interactive effects of threat and deprivation on latent trait cortisol among emerging adults.

Though considerable work supports the Dimensional Model of Adversity and Psychopathology, prior research has not tested whether the dimensions-threat (e.g., abuse) and deprivation (e.g., neglect)-are uniquely related to salivary trait indicators of hypothalamic pituitary adrenal (HPA) axis activity. We examined the unique and interactive effects of threat and deprivation on latent trait cortisol (LTC)-and whether these effects were modified by co-occurring adversities. Emerging adults (n = 90; Mage = 19.36 years; 99.88% cisgender women) provided salivary cortisol samples four times a day (waking, 30 min and 45 min postwaking, bedtime) over three 3-day measurement waves over 13 weeks. Contextual life stress interviews assessed early adversity. Though the effects varied according to the conceptualization of early adversity, overall, threat-but not deprivation, nor other co-occurring adversities-was uniquely associated with the across-wave LTC. Specifically, the incidence and frequency of threat were each negatively related to the across-wave LTC. Threat severity was also associated with the across-wave LTC, but only among those with no deprivation. Finally, the effects of threat were modified by other co-occurring adversities. Findings suggest that threat has unique implications for individual differences in HPA axis activity among emerging adults, and that co-occurring adversities modify such effects.

Flexible processing of distractor stimuli under stress.

Acute stress is assumed to affect executive processing of stimulus information, although extant studies have yielded heterogeneous findings. The temporal flanker task, in which a target stimulus is preceded by a distractor of varying utility, offers a means of investigating various components involved in the adjustment of information processing and conflict control. Both behavioral and EEG data obtained with this task suggest stronger distractor-related response activation in conditions associated with higher predictivity of the distractor for the upcoming target. In two experiments we investigated distractor-related processing and conflict control after inducing acute stress (Trier Social Stress Test). Although the stressed groups did not differ significantly from unstressed control groups concerning behavioral markers of attentional adjustment (i.e., Proportion Congruent Effect), or event-related sensory components in the EEG (i.e., posterior P1 and N1), the lateralized readiness potential demonstrated reduced activation evoked by (predictive) distractor information under stress. Our results suggest flexible adjustment of attention under stress but hint at decreased usage of nominally irrelevant stimulus information for biasing response selection.

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.

Cold pressor stress effects on cardiac repolarization.

The cold pressor test (CPT) elicits strong cardiovascular reactions via activation of the sympathetic nervous system (SNS), yielding subsequent increases in heart rate (HR) and blood pressure (BP). However, little is known on how exposure to the CPT affects cardiac ventricular repolarization. Twenty-eight healthy males underwent both a bilateral feet CPT and a warm water (WW) control condition on two separate days, one week apart. During pre-stress baseline and stress induction cardiovascular signals (ECG lead II, Finometer BP) were monitored continuously. Salivary cortisol and subjective stress ratings were assessed intermittently. Corrected QT (QTc) interval length and T-wave amplitude (TWA) were assessed for each heartbeat and subsequently aggregated individually over baseline and stress phases, respectively. CPT increases QTc interval length and elevates the TWA. Stress-induced changes in cardiac repolarization are only in part and weakly correlated with cardiovascular and cortisol stress-reactivity. Besides its already well-established effects on cardiovascular, endocrine, and subjective responses, CPT also impacts on cardiac repolarization by elongation of QTc interval length and elevation of TWA. CPT effects on cardiac repolarization share little variance with the other indices of stress reactivity, suggesting a potentially incremental value of this parameter for understanding psychobiological adaptation to acute CPT stress.

Stress in autism (STREAM): A study protocol on the role of circadian activity, sleep quality and sensory reactivity.

Mental health issues are markedly increased in individuals with autism, making it the number one research priority by stakeholders. There is a crucial need to use personalized approaches to understand the underpinnings of mental illness in autism and consequently, to address individual needs. Based on the risk factors identified in typical mental research, we propose the following themes central to mental health issues in autism: sleep difficulties and stress. Indeed, the prevalence of manifold circadian disruptions and sleep difficulties in autism, alongside stress related to sensory overload, forms an integral part of autistic symptomatology. This proof-of-concept study protocol outlines an innovative, individualised approach towards investigating the interrelationships between stress indices, sleep and circadian activation patterns, and sensory sensitivity in autism. Embracing an individualized methodology, we aim to collect 14 days of data per participant from 20 individuals with autism diagnoses and 20 without. Participants' sleep will be monitored using wearable EEG headbands and a sleep diary. Diurnal tracking of heart rate and electrodermal activity through wearables will serve as proxies of stress. Those objective data will be synchronized with subjective experience traces collected throughout the day using the Temporal Experience Tracing (TET) method. TET facilitates the quantification of relevant aspects of individual experience states, such as stress or sensory sensitivities, by providing a continuous multidimensional description of subjective experiences. Capturing the dynamics of subjective experiences phase-locked to neural and physiological proxies both between and within individuals, this approach has the potential to contribute to our understanding of critical issues in autism, including sleep problems, sensory reactivity and stress. The planned strives to provide a pathway towards developing a more nuanced and individualized approach to addressing mental health in autism.

The impact of virtual reality scenes on stress response characteristics of individuals with different personality traits.

Virtual reality based physical stress (VRPS) paradigms could eliminate the influence of social factors on participants, and it may be a desirable tool to explore the impact of personality traits on stress levels. In this study, we attempt to explore the effects of VRPS on stress response among individuals with different personality traits. Forty male participants with an average age of 22.79 ± 0.41 years were divided into two groups based on Harm Avoidance (HA) scores of Tridimensional Personality Questionnaire (TPQ), referred to as the Low-HA group and the High-HA group. The stress levels of the participants were assessed using salivary α-amylase (sAA) activity and heart rate variability (HRV) indices pre- and post-stress. The influence of personality traits on stress response among different groups was analyzed. VRPS significantly affected the sAA activity and HRV indicators of both groups. During and after stress, there were significant differences in sAA activity and HRV indicators between the two groups. The sAA levels and HRV indices of the Low-HA group were lower than those of the High-HA group. Furthermore, sAA levels and HRV indices were correlated with the scores of TPQ. VRPS scenarios elicit different stress responses on individuals with different harm avoidance personality traits. Stress evaluation based on VR scenarios presents potential in personality trait assessments, particularly for distinguishing between individuals with low and high HA tendencies.

Cortico-limbic interactions and carotid atherosclerotic burden during chronic stress exposure.

BACKGROUND AND AIMS: Chronic stress associates with cardiovascular disease, but mechanisms remain incompletely defined. Advanced imaging was used to identify stress-related neural imaging phenotypes associated with atherosclerosis. METHODS: Twenty-seven individuals with post-traumatic stress disorder (PTSD), 45 trauma-exposed controls without PTSD, and 22 healthy controls underwent 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI). Atherosclerotic inflammation and burden were assessed using 18F-FDG PET (as maximal target-to-background ratio, TBR max) and MRI, respectively. Inflammation was assessed using high-sensitivity C-reactive protein (hsCRP) and leucopoietic imaging (18F-FDG PET uptake in spleen and bone marrow). Stress-associated neural network activity (SNA) was assessed on 18F-FDG PET as amygdala relative to ventromedial prefrontal cortex (vmPFC) activity. MRI diffusion tensor imaging assessed the axonal integrity (AI) of the uncinate fasciculus (major white matter tract connecting vmPFC and amygdala). RESULTS: Median age was 37 years old and 54% of participants were female. There were no significant differences in atherosclerotic inflammation between participants with PTSD and controls; adjusted mean difference in TBR max (95% confidence interval) of the aorta 0.020 (-0.098, 0.138), and of the carotids 0.014 (-0.091, 0.119). Participants with PTSD had higher hsCRP, spleen activity, and aorta atherosclerotic burden (normalized wall index). Participants with PTSD also had higher SNA and lower AI. Across the cohort, carotid atherosclerotic burden (standard deviation of wall thickness) associated positively with SNA and negatively with AI independent of Framingham risk score. CONCLUSIONS: In this study of limited size, participants with PTSD did not have higher atherosclerotic inflammation than controls. Notably, impaired cortico-limbic interactions (higher amygdala relative to vmPFC activity or disruption of their intercommunication) associated with carotid atherosclerotic burden. Larger studies are needed to refine these findings.

Acute psychosocial stress modulates neural and behavioral substrates of cognitive control.

Acute psychosocial stress affects learning, memory, and attention, but the evidence for the influence of stress on the neural processes supporting cognitive control remains mixed. We investigated how acute psychosocial stress influences performance and neural processing during the Go/NoGo task-an established cognitive control task. The experimental group underwent the Trier Social Stress Test (TSST) acute stress induction, whereas the control group completed personality questionnaires. Then, participants completed a functional magnetic resonance imaging (fMRI) Go/NoGo task, with self-report, blood pressure and salivary cortisol measurements of induced stress taken intermittently throughout the experimental session. The TSST was successful in eliciting a stress response, as indicated by significant Stress > Control between-group differences in subjective stress ratings and systolic blood pressure. We did not identify significant differences in cortisol levels, however. The stress induction also impacted subsequent Go/NoGo task performance, with participants who underwent the TSST making fewer commission errors on trials requiring the most inhibitory control (NoGo Green) relative to the control group, suggesting increased vigilance. Univariate analysis of fMRI task-evoked brain activity revealed no differences between stress and control groups for any region. However, using multivariate pattern analysis, stress and control groups were reliably differentiated by activation patterns contrasting the most demanding NoGo trials (i.e., NoGo Green trials) versus baseline in the medial intraparietal area (mIPA, affiliated with the dorsal attention network) and subregions of the cerebellum (affiliated with the default mode network). These results align with prior reports linking the mIPA and the cerebellum to visuomotor coordination, a function central to cognitive control processes underlying goal-directed behavior. This suggests that stressor-induced hypervigilance may produce a facilitative effect on response inhibition which is represented neurally by the activation patterns of cognitive control regions.

Neural Correlates of Stress and Alcohol Cue-Induced Alcohol Craving and of Future Heavy Drinking: Evidence of Sex Differences.

OBJECTIVE: Stress and alcohol cue reactivity are associated with poor treatment outcomes in alcohol use disorder (AUD), but sex-specific neural correlates of stress and alcohol cue-induced craving compared with neutral cue-induced craving and of heavy drinking outcomes in AUD have not been examined. Thus, this study prospectively examined these associations and assessed sex differences. METHODS: Treatment-seeking adults with AUD (N=77; 46 men and 31 women) completed a functional MRI task involving stress, alcohol, and neutral cue exposure with repeated assessments of alcohol craving. Most of these participants (N=72; 43 men and 29 women) then participated in an 8-week standardized behavioral AUD treatment program, during which the percentage of heavy drinking days was assessed. RESULTS: Significant increases in both stress and alcohol cue-induced craving relative to neutral cue-induced craving were observed, with a greater alcohol-neutral contrast in craving relative to the stress-neutral contrast among men and equivalent stress-neutral and alcohol-neutral contrasts in craving among women. Whole-brain voxel-based regression analyses showed craving-associated hyperactivation in the neutral condition, but hypoactive prefrontal (ventromedial and lateral prefrontal, supplementary motor, and anterior cingulate regions) and striatal responses during exposure to stressful images (stress-neutral contrast) and alcohol cues (alcohol-neutral contrast), with significant sex differences. Additionally, a higher percentage of heavy drinking days was associated with hypoactivation of the subgenual anterior cingulate cortex and the bed nucleus of the stria terminalis in the stress-neutral contrast among women, hyperactivation of the hypothalamus in the stress-neutral contrast among men, and hyperactivation of the hippocampus in the alcohol-neutral contrast among men. CONCLUSIONS: Sex differences in stress- and alcohol cue-induced responses in the cortico-striatal-limbic network related to subjective alcohol craving and to heavy drinking indicated that distinct brain circuits underlie alcohol use outcomes in women and men. These findings underscore the need for sex-specific therapeutics to address this neural dysfunction effectively.

Prenatal restraint stress affects early neurobehavioral response and oxidative stress in mice pups.

Prenatal stress (PS), in both humans and animals, presents a potential risk to the mother and her fetus throughout gestation. PS is always associated with physiological changes that alter embryonic development and predispose the individual to lifelong health problems, including susceptibility to mental illness. This study aims to identify the harmful effects of prenatal restraint stress (PRS), commonly employed to induce stress painlessly and without any lasting debilitation during gestation. This stress is applied to pregnant Swiss albino mice from E7.5 to delivery for three hours daily. Our results show that PS affects dams' weight gain during the gestational period; moreover, the PS dams prefer passive nursing, exhibit a lower percentage of licking and grooming, and impair other maternal behaviors, including nesting and pup retrieval. Concerning the offspring, this stress induces neurobehavioral impairments, including a significant increase in the time of recovery of the young stressed pups in the surface righting reflex, the latency to avoid the cliff in the cliff avoidance test, longer latencies to accomplish the task in negative geotaxis, and a lower score in swimming development. These alterations were accompanied by increased Malondialdehyde activity (MDA) at PND17 and 21 and downregulation of AchE activity in the whole brain of pups on postnatal days 7 and 9. These findings demonstrated that PS causes deleterious neurodevelopmental impairments that can alter various behaviors later in life.

The Stress Phenotyping Framework: A multidisciplinary biobehavioral approach for assessing and therapeutically targeting maladaptive stress physiology.

Although dysregulated stress biology is becoming increasingly recognized as a key driver of lifelong disparities in chronic disease, we presently have no validated biomarkers of toxic stress physiology; no biological, behavioral, or cognitive treatments specifically focused on normalizing toxic stress processes; and no agreed-upon guidelines for treating stress in the clinic or evaluating the efficacy of interventions that seek to reduce toxic stress and improve human functioning. We address these critical issues by (a) systematically describing key systems and mechanisms that are dysregulated by stress; (b) summarizing indicators, biomarkers, and instruments for assessing stress response systems; and (c) highlighting therapeutic approaches that can be used to normalize stress-related biopsychosocial functioning. We also present a novel multidisciplinary Stress Phenotyping Framework that can bring stress researchers and clinicians one step closer to realizing the goal of using precision medicine-based approaches to prevent and treat stress-associated health problems.

Protective role of TRPV2 in synaptic plasticity through the ERK1/2-CREB-BDNF pathway in chronic unpredictable mild stress rats.

PURPOSE: Chronic stress is a significant risk factor for mood disorders such as depression, where synaptic plasticity plays a central role in pathogenesis. Transient Receptor Potential Vanilloid Type-2 (TRPV2) Ion Channels are implicated in hypothalamic-pituitary-adrenal axis disorders. Previous proteomic analysis indicated a reduction in TRPV2 levels in the chronic unpredictable mild stress (CUMS) rat model, yet its role in synaptic plasticity during depression remains to be elucidated. This study aims to investigate TRPV2's role in depression and its underlying mechanisms. METHODS: In vivo and in vitro experiments were conducted using the TRPV2-specific agonist probenecid and ERK1/2 inhibitors SCH772984. In vivo, rats underwent six weeks of CUMS before probenecid administration. Depressive-like behaviors were assessed through behavioral tests. ELISA kits measured 5-HT, DA, NE levels in rat hippocampal tissues. Hippocampal morphology was examined via Nissl staining. In vitro, rat hippocampal neuron cell lines were treated with ERK1/2 inhibitors SCH772984 and probenecid. Western blot, immunofluorescence, immunohistochemical staining, and RT-qPCR assessed TRPV2 expression, neurogenesis-related proteins, synaptic markers, and ERK1/2-CREB-BDNF signaling proteins. RESULTS: Decreased hippocampal TRPV2 levels were observed in CUMS rats. Probenecid treatment mitigated depressive-like behavior and enhanced hippocampal 5-HT, NE, and DA levels in CUMS rats. TRPV2 activation countered CUMS-induced synaptic plasticity inhibition. Probenecid activated the ERK1/2-CREB-BDNF pathway, suggesting TRPV2's involvement in this pathway via ERK1/2. CONCLUSION: These findings indicate that TRPV2 activation offers protective effects against depressive-like behaviors and enhances hippocampal synaptic plasticity in CUMS rats via the ERK1/2-CREB-BDNF pathway. TRPV2 emerges as a potential therapeutic target for depression.

REM Sleep Preserves Affective Response to Social Stress-Experimental Study.

Sleep's contribution to affective regulation is insufficiently understood. Previous human research has focused on memorizing or rating affective pictures and less on physiological affective responsivity. This may result in overlapping definitions of affective and declarative memories and inconsistent deductions for how rapid eye movement sleep (REMS) and slow-wave sleep (SWS) are involved. Literature associates REMS theta (4-8 Hz) activity with emotional memory processing, but its contribution to social stress habituation is unknown. Applying selective sleep stage suppression and oscillatory analyses, we investigated how sleep modulated affective adaptation toward social stress and retention of neutral declarative memories. Native Finnish participants (N = 29; age, M = 25.8 years) were allocated to REMS or SWS suppression conditions. We measured physiological (skin conductance response, SCR) and subjective stress response and declarative memory retrieval thrice: before laboratory night, the next morning, and after 3 d. Linear mixed models were applied to test the effects of condition and sleep parameters on emotional responsivity and memory retrieval. Greater overnight increase in SCR toward the stressor emerged after suppressed SWS (intact REMS) relative to suppressed REMS (20.1% vs 6.1%; p = 0.016). The overnight SCR increase was positively associated with accumulated REMS theta energy irrespective of the condition (r = 0.601; p = 0.002). Subjectively rated affective response and declarative memory recall were comparable between the conditions. The contributions of REMS and SWS to habituation of social stress are distinct. REMS theta activity proposedly facilitates the consolidation of autonomic affective responses. Declarative memory consolidation may not have greater dependence on intact SWS relative to intact REMS.

From Social Stress and Isolation to Autonomic Nervous System Dysregulation in Suicidal Behavior.

PURPOSE OF REVIEW: In this narrative review we wanted to describe the relationship of autonomic nervous system activity with social environment and suicidal spectrum behaviors. RECENT FINDINGS: Patients with suicidal ideation/suicide attempt have higher sympathetic nervous system (SNS) and lower parasympathetic nervous system (PNS) activity in resting conditions and during acute stress tasks compared with patients without suicidal ideation/suicide attempt. Death by suicide and violent suicide attempt also are related to SNS hyperactivation. Similarly, a SNS/PNS imbalance has been observed in people with childhood trauma, stressful life events or feelings of loneliness and isolation. Social support seems to increase PNS control and resilience. Due to the importance of the social context and stressful life events in suicidal behavior, SNS/PNS imbalance could act as a mediator in this relationship and be a source of relevant biomarkers. Childhood trauma and stressful life events may impair the autonomic nervous system response in suicidal patients. Loneliness, isolation and social support may act as moderators in acute stress situations.

The role of preterm birth in stress-induced sodium excretion in young adults.

BACKGROUND: Early-life programming due to prematurity and very low birth weight (VLBW, <1500 g) is believed to contribute to development of hypertension, but the mechanisms remain unclear. Experimental data suggest that altered pressure natriuresis (increased renal perfusion pressure promoting sodium excretion) may be a contributing mechanism. We hypothesize that young adults born preterm will have a blunted pressure natriuresis response to mental stress compared with those born term. METHODS: In this prospective cohort study of 190 individuals aged 18-23 years, 156 born preterm with VLBW and 34 controls born term with birth weight at least 2500 g, we measured urine sodium/creatinine before and after a mental stress test and continuous blood pressure before and during the stress test. Participants were stratified into groups by the trajectory at which mean arterial pressure (MAP) increased following the test. The group with the lowest MAP trajectory was the reference group. We used generalized linear models to assess poststress urine sodium/creatinine relative to the change in MAP trajectory and assessed the difference between groups by preterm birth status. RESULTS: Participants' mean age was 19.8 years and 57% were women. Change in urine sodium/creatinine per unit increase in MAP when comparing middle trajectory group against the reference group was greater in those born preterm [ß 5.4%, 95% confidence interval (95% CI) -11.4 to 5.3] than those born term (ß 38.5%, 95% CI -0.04 to 92.0), interaction term P = 0.002. CONCLUSION: We observed that, as blood pressure increased following mental stress, young adults born preterm exhibited decreased sodium excretion relative to term-born individuals.

Role of the prefrontal cortical protease TACE/ADAM17 in neurobehavioral responses to chronic stress during adolescence.

INTRODUCTION: Chronic adolescent stress profoundly affects prefrontal cortical networks regulating top-down behavior control. However, the neurobiological pathways contributing to stress-induced alterations in the brain and behavior remain largely unknown. Chronic stress influences brain growth factors and immune responses, which may, in turn, disrupt the maturation and function of prefrontal cortical networks. The tumor necrosis factor alpha-converting enzyme/a disintegrin and metalloproteinase 17 (TACE/ADAM17) is a sheddase with essential functions in brain maturation, behavior, and inflammatory responses. This study aimed to determine the impact of stress on the prefrontal cortex and whether TACE/ADAM17 plays a role in these responses. METHODS: We used a Lewis rat model that incorporates critical elements of chronic psychosocial stress, such as uncontrollability, unpredictability, lack of social support, and re-experiencing of trauma. RESULTS: Chronic stress during adolescence reduced the acoustic startle reflex and social interactions while increasing extracellular free water content and TACE/ADAM17 mRNA levels in the medial prefrontal cortex. Chronic stress altered various ethological behavioral domains in the observation home cages (decreased ingestive behaviors and increased walking, grooming, and rearing behaviors). A group of rats was injected intracerebrally either with a novel Accell™ SMARTpool TACE/ADAM17 siRNA or a corresponding siRNA vehicle (control). The RNAscope Multiplex Fluorescent v2 Assay was used to visualize mRNA expression. Automated puncta quantification and analyses demonstrated that TACE/ADAM17 siRNA administration reduced TACE/ADAM17 mRNA levels in the medial prefrontal cortex (59% reduction relative to control). We found that the rats that received prefrontal cortical TACE/ADAM17 siRNA administration exhibited altered eating patterns (e.g., increased food intake and time in the feeding zone during the light cycle). CONCLUSION: This study supports that the prefrontal cortex is sensitive to adolescent chronic stress and suggests that TACE/ADAM17 may be involved in the brain responses to stress.