Juvenile mild traumatic brain injury elicits distinct spatiotemporal astrocyte responses.

Mild-traumatic brain injury (mTBI) represents ~80% of all emergency room visits and increases the probability of developing long-term cognitive disorders in children. To date, molecular and cellular mechanisms underlying post-mTBI cognitive dysfunction are unknown. Astrogliosis has been shown to significantly alter astrocytes' properties following brain injury, potentially leading to significant brain dysfunction. However, such alterations have never been investigated in the context of juvenile mTBI (jmTBI). A closed-head injury model was used to study jmTBI on postnatal-day 17 mice. Astrogliosis was evaluated using glial fibrillary acidic protein (GFAP), vimentin, and nestin immunolabeling in somatosensory cortex (SSC), dentate gyrus (DG), amygdala (AMY), and infralimbic area (ILA) of prefrontal cortex in both hemispheres from 1 to 30 days postinjury (dpi). In vivo T2-weighted-imaging (T2WI) and diffusion tensor imaging (DTI) were performed at 7 and 30 dpi to examine tissue level structural alterations. Increased GFAP-labeling was observed up to 30 dpi in the ipsilateral SSC, the initial site of the impact. However, vimentin and nestin expression was not perturbed by jmTBI. The morphology of GFAP positive cells was significantly altered in the SSC, DG, AMY, and ILA up to 7 dpi that some correlated with magnetic resonance imaging changes. T2WI and DTI values were significantly altered at 30 dpi within these brain regions most prominently in regions distant from the impact site. Our data show that jmTBI triggers changes in astrocytic phenotype with a distinct spatiotemporal pattern. We speculate that the presence and time course of astrogliosis may contribute to pathophysiological processes and long-term structural alterations following jmTBI.

Stress Management Training Improves Overall Performance during Critical Simulated Situations: A Prospective Randomized Controlled Trial.

BACKGROUND: High-fidelity simulation improves participant learning through immersive participation in a stressful situation. Stress management training might help participants to improve performance. The hypothesis of this work was that Tactics to Optimize the Potential, a stress management program, could improve resident performance during simulation. METHODS: Residents participating in high-fidelity simulation were randomized into two parallel arms (Tactics to Optimize the Potential or control) and actively participated in one scenario. Only residents from the Tactics to Optimize the Potential group received specific training a few weeks before simulation and a 5-min reactivation just before beginning the scenario. The primary endpoint was the overall performance during simulation measured as a composite score (from 0 to 100) combining a specific clinical score with two nontechnical scores (the Ottawa Global Rating Scale and the Team Emergency Assessment Measure scores) rated for each resident by four blinded independent investigators. Secondary endpoints included stress level, as assessed by the Visual Analogue Scale during simulation. RESULTS: Of the 134 residents randomized, 128 were included in the analysis. The overall performance (mean ± SD) was higher in the Tactics to Optimize the Potential group (59 ± 10) as compared with controls ([54 ± 10], difference, 5 [95% CI, 1 to 9]; P = 0.010; effect size, 0.50 [95% CI, 0.16 to 0.91]). After specific preparation, the median Visual Analogue Scale was 17% lower in the Tactics to Optimize the Potential group (52 [42 to 64]) than in the control group (63 [50 to 73]; difference, -10 [95% CI, -16 to -3]; P = 0.005; effect size, 0.44 [95% CI, 0.26 to 0.59]. CONCLUSIONS: Residents coping with simulated critical situations who have been trained with Tactics to Optimize the Potential showed better overall performance and a decrease in stress level during high-fidelity simulation. The benefits of this stress management training may be explored in actual clinical settings, where a 5-min Tactics to Optimize the Potential reactivation is feasible prior to delivering a specific intervention.

Acute stress delays brain mitochondrial permeability transition pore opening.

Since emotional stress elicits brain activation, mitochondria should be a key component of stressed brain response. However, few studies have focused on mitochondria functioning in these conditions. In this work, we aimed to determine the effects of an acute restraint stress on rat brain mitochondrial functions, with a focus on permeability transition pore (PTP) functioning. Rats were divided into two groups, submitted or not to an acute 30-min restraint stress (Stress, S-group, vs. Control, C-group). Brain was removed immediately after stress. Mitochondrial respiration and enzymatic activities (complex I, complex II, hexokinase) were measured. Changes in PTP opening were assessed by the Ca(2+) retention capacity. Cell signaling pathways relevant to the coupling between mitochondria and cell function (adenosine monophosphate-activated protein kinase, phosphatidylinositol 3-kinase, glycogen synthase kinase 3 beta, MAPK, and cGMP/NO) were measured. The effect of glucocorticoids was also assessed in vitro. Stress delayed (43%) the opening of PTP and resulted in a mild inhibition of complex I respiratory chain. This inhibition was associated with significant stress-induced changes in adenosine monophosphate-activated protein kinase signaling pathway without changes in brain cGMP level. In contrast, glucocorticoids did not modify PTP opening. These data suggest a rapid adaptive mechanism of brain mitochondria in stressed conditions, with a special focus on PTP regulation. In a rat model of acute restraint stress, we observed substantial changes in brain mitochondria functioning. Stress significantly (i) delays (43%) the opening of permeability transition pore (PTP) by the calcium (Ca(2+) ), its main inductor and (ii) results in an inhibition of complex I in electron transport chain associated with change in AMPK signaling pathway. These data suggest an adaptive mechanism of brain mitochondria in stressed condition, with a special focus on PTP regulation.

Effect of a high-fat--high-fructose diet, stress and cinnamon on central expression of genes related to immune system, hypothalamic-pituitary-adrenocortical axis function and cerebral plasticity in rats.

The intake of a high-fat/high-fructose (HF/HFr) diet is described to be deleterious to cognitive performances, possibly via the induction of inflammatory factors. An excess of glucocorticoids is also known to exert negative effects on cerebral plasticity. In the present study, we assessed the effects of an unbalanced diet on circulating and central markers of inflammation and glucocorticoid activity, as well as their reversal by dietary cinnamon (CN) supplementation. A group of male Wistar rats were subjected to an immune challenge with acute lipopolysaccharide under a HF/HFr or a standard diet. Another group of Wistar rats were fed either a HF/HFr or a control diet for 12 weeks, with or without CN supplementation, and with or without restraint stress (Str) application before being killed. We evaluated the effects of such regimens on inflammation parameters in the periphery and brain and on the expression of actors of brain plasticity. To assess hypothalamic-pituitary-adrenocortical axis activity, we measured the plasma concentrations of corticosterone and the expression of central corticotrophin-releasing hormone, mineralocorticoid receptor, glucocorticoid receptor and 11ß-hydroxysteroid dehydrogenase. We found that the HF/HFr diet induced the expression of cytokines in the brain, but only after an immune challenge. Furthermore, we observed the negative effects of Str on the plasma concentrations of corticosterone and neuroplasticity markers in rats fed the control diet but not in those fed the HF/HFr diet. Additionally, we found that CN supplementation exerted beneficial effects under the control diet, but that its effects were blunted or even reversed under the HF/HFr diet. CN supplementation could be beneficial under a standard diet. [corrected].

Low-frequency stimulation of the ventral hippocampus facilitates extinction of contextual fear.

Difficulties to treat fear-associated disorders, including posttraumatic stress disorder, are thought to result from dysfunction in fear extinction learning and/or memory. Animal studies on extinction modulation are therefore promising for the development of new treatments. Recent rat studies, including ones using low-frequency stimulation (LFS), have demonstrated that the ventral hippocampus (VH) modulates extinction memory. The present study explores whether the VH also modulates extinction learning. For this, rats were implanted with stimulating electrodes in the VH and experienced contextual fear conditioning, followed 6 or 24 h later by VH LFS and three sessions of extinction training. We found that, whatever the delay used (6 or 24 h), animals that received VH LFS displayed persistent low levels of freezing from the second extinction session, whereas control rats showed low levels of freezing only during the third session. In animals submitted to a stress condition (provoked by a single inescapable foot-shock followed by three sessions of situational reminders) prior to fear conditioning, VH LFS also reduced freezing levels, which, in contrast, remained high in control rats during the course of extinction training. These data suggest that LFS, targeting the VH, may be useful in reducing fear responses during extinction learning.

Sleep biomarkers for stress-induced vulnerability to depression.

Stress can push individuals close to the threshold to depression. An individual's intrinsic vulnerability before a stressful event determines how close they come to the threshold of depression. Identification of vulnerability biomarkers at early (before the stressful event) and late (close to the threshold after the stressful event) stages would allow for corrective actions. Social defeat is a stressful event that triggers vulnerability to depression in half of exposed rats. We analyzed the sleep properties of rats before (baseline) and after (recovery) social defeat by telemetry electroencephalogram recordings. Using Gaussian partitioning, we identified three non-rapid eye movement stages (N-S1, N-S2, and N-S3) in rats based on a sleep depth index (relative δ power) and a cortical activity index (fractal dimension). We found (1) that, at baseline, N-S3 lability and high-θ relative power in wake identified, with 82% accuracy, the population of rats that will become vulnerable to depression after social defeat, and (2) that, at recovery, N-S1 instability identified vulnerable rats with 83% accuracy. Thus, our study identified early and late sleep biomarkers of vulnerability to depression, opening the way to the development of treatments at a prodromal stage for high sensitivity to stress, and for stress-induced vulnerability to depression.

Steady electrocorticogram characteristics predict specific stress-induced behavioral phenotypes.

Introduction: Depending on the individual, exposure to an intense stressor may, or may not, lead to a stress-induced pathology. Predicting the physiopathological evolution in an individual is therefore an important challenge, at least for prevention. In this context, we developed an ethological model of simulated predator exposure in rats: we call this the multisensorial stress model (MSS). We hypothesized that: (i) MSS exposure can induce stress-induced phenotypes, and (ii) an electrocorticogram (ECoG) recorded before stress exposure can predict phenotypes observed after stress. Methods: Forty-five Sprague Dawley rats were equipped with ECoG telemetry and divided into two groups. The Stress group (n = 23) was exposed to an MSS that combined synthetic fox feces odor deposited on filter paper, synthetic blood odor, and 22 kHz rodent distress calls; the Sham group (n = 22) was not exposed to any sensorial stimulus. Fifteen days after initial exposure, the two groups were re-exposed to a context that included a filter paper soaked with water as a traumatic object (TO) reminder. During this re-exposure, freezing behavior and avoidance of the filter paper were measured. Results: Three behaviors were observed in the Stress group: 39% developed a fear memory phenotype (freezing, avoidance, and hyperreactivity); 26% developed avoidance and anhedonia; and 35% made a full recovery. We also identified pre-stress ECoG biomarkers that accurately predicted cluster membership. Decreased chronic 24 h frontal Low θ relative power was associated with resilience; increased frontal Low θ relative power was associated with fear memory; and decreased parietal ß2 frequency was associated with the avoidant-anhedonic phenotype. Discussion: These predictive biomarkers open the way to preventive medicine for stress-induced diseases.

Heterogeneity of Psychological Profiles in French Army Units and Psychological Changes Between Pre- and Post-deployment: Two Pilot Studies.

INTRODUCTION: Over the past two decades, overseas deployments of the French Army have been characterized by the exposure of its service personnel to sustained, high levels of combat stress. There is a need to assess their mental health throughout the deployment cycle, identify risk factors associated with stress-related disorders, and characterize the factors that promote long-term well-being. METHODS: We conducted two pilot studies within four units of the French Army: a conventional combat unit, a counterterrorist unit, a combat service support unit, and a medical support unit. Study 1 (n = 65) analyzed the psychological functioning of service personnel with respect to their personality and stress management characteristics. Study 2 (n = 40) analyzed the impact of overseas deployment on stress-related psychological outcomes. RESULTS: Overall, results from study 1 showed that service personnel have a protective psychological functioning, which is particularly developed in the counterterrorist unit. In study 2, although no stress-related disorder symptoms were observed with the psychometric tools used, a certain degree of psychological dysfunction (social dysfunction and lower positive affect) was detected post-deployment. CONCLUSIONS: These two complementary studies are key elements in developing a better understanding of unmet, medico-military needs that lie on the pathway that links exposure to stressors to impaired health. Certain personnel enrolled in the French Army (notably, the counterterrorist unit) were found to have a high level of protective psychological functioning, largely due to the training they receive. Nevertheless, overall, overseas deployment was associated with poorer psychological functioning and the emergence of social dysfunction, especially in units responsible for the care of service personnel (medical support and combat service support units).

Psychophysiological dynamics of emotional reactivity: Interindividual reactivity characterization and prediction by a machine learning approach.

The fast reaction of the autonomic nervous system (ANS) to an emotional challenge (EC) is the result of a functional coupling between parasympathetic (PNS) and sympathetic (SNS) branches. This coupling can be characterized by measures of cross-correlations between electrodermal activity (EDA) (under the influence of the SNS) and the RR interval (the interval between R peaks) (under the influence of the PNS and the SNS). Significant interindividual variability has previously been reported in SNS-PNS coupling in emotional situations, and the present study aimed to identify interindividual cross-correlation variability in ANS reactivity. We therefore studied EDA and the RR interval in 62 healthy subjects, recorded during a 24-minute EC. A Gaussian Mixture Model was used to cluster tonic EDA-RR cross-correlations during the EC. This identified two clusters that were characterized by significant or non-significant cross-correlations (SCC and NCC clusters, respectively). The SCC cluster reported higher negative emotion after the EC, while the NCC cluster reported higher scores on the Center for Epidemiologic Studies-Depression scale. The latter finding suggests that NCC is a pathological mood pattern with altered negative perception. Furthermore, a machine learning model that included three parameters indexing the functionality of both branches of the ANS, measured at baseline, predicted cluster membership. Our results are a first step in detecting dysfunctional ANS reactivity in general population.

The Relationship between Allostasis and Mental Health Patterns in a Pre-Deployment French Military Cohort.

(1) Background: While a number of studies among military personnel focus on specific pathologies such as post-traumatic stress disorder (PTSD), anxiety, and depression, they do not address the cumulative impact on mental health of stressors related to the profession. The present study aims to determine the relationship between allostatic load and mental health status in a cohort of fit-for-duty soldiers prior to their deployment to Afghanistan. The aim is to better-define the consequences of stressor adjustment. (2) Methods: A cohort of 290 soldiers was evaluated in a cross-sectional study with respect to psychopathology (PTSD, anxiety, depression), psychological functioning (stress reactivity, psychological suffering), and allostatic profile (urinary cortisol and 8-iso-PGF2α, blood cortisol and BDNF). A hierarchical cluster analysis was used to identify allostatic patterns. (3) Results: Around 10% of the cohort reported high scores for psychopathology, and biological alterations were identified. For the remainder, four allostatic profiles could be identified by their psychological functioning. (4) Conclusions: Both biological and psychological assessments are needed to characterize subthreshold symptomatology among military personnel. The psychological significance of allostatic load should be considered as a way to improve health outcomes.

The heartbeat evoked potential does not support strong interoceptive sensibility in trait mindfulness.

The enhancement of body awareness is proposed as one of the cognitive mechanisms that characterize mindfulness. To date, this hypothesis is supported by self-report and behavioral measures but still lacks physiological evidence. The current study investigated relation between trait mindfulness (i.e., individual differences in the ability to be mindful in daily life) and body awareness in combining a self-report measure (Multidimensional Assessment of Interoceptive Awareness [MAIA] questionnaire) with analysis of the heartbeat evoked potential (HEP), which is an event-related potential reflecting the cortical processing of the heartbeat. The HEP data were collected from 17 healthy participants under five minutes of resting-state condition. In addition, each participant completed the Freiburg Mindfulness Inventory and the MAIA questionnaire. Taking account of the important variability of HEP effects, analyses were replicated with the same participants three times (in three distinct sessions). First, group-level analyses showed that HEP amplitude and trait mindfulness do not correlate. Secondly, we observed that HEP amplitude could positively correlate with self-reported body awareness; however, this association was unreliable over time. Interestingly, we found that HEP measure shows very poor reliability over time at the individual level, potentially explaining the lack of reliable association between HEP and psychological traits. Lastly, a reliable positive correlation was found between self-reported trait mindfulness and body awareness. Taken together, these findings provide preliminary evidence that the HEP might not support the increased subjective body awareness in trait mindfulness, thus suggesting that perhaps objective and subjective measures of body awareness could be independent.

Subsurface Confinement: Evidence from Submariners of the Benefits of Mindfulness.

OBJECTIVES: The subsurface ballistic missile nuclear submarine (SSBN) is an extreme professional environment in which personnel are both isolated and confined during patrols, which can last longer than 2 months. This environment is known to degrade submariners' mood and cognition. METHODS: This exploratory, empirical study followed a cohort of 24 volunteer submariners. Dispositional mindfulness was assessed with the Freiburg Mindfulness Inventory, in order to identify two groups (mindful and non-mindful) and compare change in emotional state, interoception, and health behaviors during the patrol. RESULTS: Overall, psychological health deteriorated during the patrol. However, mindful submariners demonstrated better psychological adaptation and interoception than the non-mindful group. This was associated with better subjective health behaviors (sleeping and eating). CONCLUSIONS: Dispositional mindfulness appears to protect against the negative effects of long-term containment in a professional environment, such as a submarine patrol. Our work highlights that mindfulness may help individuals to cope with stress in such situations. Developing mindfulness could also be an important preventive healthcare measure during quarantine imposed by the outbreak of a serious infectious disease.

Toward a Refined Mindfulness Model Related to Consciousness and Based on Event-Related Potentials.

Neuroimaging, behavioral, and self-report evidence suggests that there are four main cognitive mechanisms that support mindfulness: (a) self-regulation of attention, (b) improved body awareness, (c) improved emotion regulation, and (d) change in perspective on the self. In this article, we discuss these mechanisms on the basis of the event-related potential (ERP). We reviewed the ERP literature related to mindfulness and examined a data set of 29 articles. Our findings show that the neural features of mindfulness are consistently associated with the self-regulation of attention and, in most cases, reduced reactivity to emotional stimuli and improved cognitive control. On the other hand, there appear to be no studies of body awareness. We link these electrophysiological findings to models of consciousness and introduce a unified, mechanistic mindfulness model. The main idea in this refined model is that mindfulness decreases the threshold of conscious access. We end with several working hypotheses that could direct future mindfulness research and clarify our results.

Interoceptive Abilities in Inflammatory Bowel Diseases and Irritable Bowel Syndrome.

Alexithymia is usually described by three main dimensions difficulty identifying feelings (DIF), difficulty describing feelings (DDF), and externally oriented thinking (EOT). The most commonly used questionnaire investigating alexithymia, the Toronto Alexithymia Scale (TAS-20), supports this three-factor structure. One important assumption is that alexithymia severity is associated to vulnerability to somatic diseases, among them gastrointestinal disorders. However, the association between alexithymia and gastrointestinal disorders is not systematic, thus questioning the role of alexithymia as a vulnerability factor for those illnesses. A recent factor analysis suggested another four-factor structure for the TAS-20: difficulties in awareness of feelings (DAF), difficulties in interoceptive abilities (DIA), externally oriented thinking (EOT), and poor affective sharing (PAS). We assume that DIA and DAF might be more relevant to investigate the association between alexithymia and gastrointestinal disorders. The rationale is that DIA and DAF reflect impairments in emotion regulation that could contribute to an inappropriate autonomic and HPA axis homeostasis in irritable bowel syndrome (IBS), ulcerative colitis (UC), or Crohn's disease (CD). The aim of this study was to investigate whether DIA and DAF are associated with the presence of IBS, UC or CD, while checking for anxiety, depression, parasympathetic (vagus nerve) activity and cortisol levels. We recruited control participants (n=26), and patients in remission who were diagnosed with IBS (n=24), UC (n=18), or CD (n=21). Participants completed questionnaires to assess anxiety, depression, and alexithymia. A blood sample and an electrocardiogram were used to measure the level of cortisol and parasympathetic activity, respectively. Logistic regressions with the four-factor structure of the TAS-20 revealed that DIA was a significant predictor of IBS (W(1)=6.27, p=.01). Conversely, DIA and DAF were not significant predictors in CD and UC patients. However, low cortisol level was a significant predictor of UC (W(1)=4.67, p=.035). Additional logistic regressions based on the original 3-factor structure of TAS-20 (DIF, DDF, and EOT) showed that only DDF was a significant predictor of CD [W(1)=6.16, p < .001]. The present study suggests that DIA is an important dimension for assessing potential risk for gastrointestinal diseases, in particular for IBS.

Neuropeptide S promotes wakefulness through the inhibition of sleep-promoting ventrolateral preoptic nucleus neurons.

STUDY OBJECTIVES: The regulation of sleep-wake cycles is crucial for the brain's health and cognitive skills. Among the various substances known to control behavioral states, intraventricular injection of neuropeptide S (NPS) has already been shown to promote wakefulness. However, the NPS signaling pathway remains elusive. In this study, we characterized the effects of NPS in the ventrolateral preoptic nucleus (VLPO) of the hypothalamus, one of the major brain structures regulating non-rapid eye movement (NREM) sleep. METHODS: We combined polysomnographic recordings, vascular reactivity, and patch-clamp recordings in mice VLPO to determine the NPS mode of action. RESULTS: We demonstrated that a local infusion of NPS bilaterally into the anterior hypothalamus (which includes the VLPO) significantly increases awakening and specifically decreases NREM sleep. Furthermore, we established that NPS application on acute brain slices induces strong and reversible tetrodotoxin (TTX)-sensitive constriction of blood vessels in the VLPO. This effect strongly suggests that the local neuronal network is downregulated in the presence of NPS. At the cellular level, we revealed by electrophysiological recordings and in situ hybridization that NPSR mRNAs are only expressed by non-Gal local GABAergic neurons, which are depolarized by the application of NPS. Simultaneously, we showed that NPS hyperpolarizes sleep-promoting neurons, which is associated with an increased frequency in their spontaneous IPSC inputs. CONCLUSION: Altogether, our data reveal that NPS controls local neuronal activity in the VLPO. Following the depolarization of local GABAergic neurons, NPS indirectly provokes feed-forward inhibition onto sleep-promoting neurons, which translates into a decrease in NREM sleep to favor arousal.

Physiological and psychological effects of escape from a sunken submarine on shore and at sea.

INTRODUCTION: The stress effects induced by diverse military scenarios are usually studied under tightly controlled conditions, while only limited research has addressed realistic scenarios. This study was designed to compare the effects of two levels of realism in stressful training for escape from a sunken submarine. METHODS: Thirteen qualified submariners served as subjects. All had previously participated in underwater escape training using a simulated submarine in a land-based tank submerged at a depth of 6 m; for this study, they repeated the simulator escape, following which six of them executed escape from an actual submarine lying at a depth of 30 m on the sea floor. The men were studied before the exercises, immediately after surfacing, and 2 h later. Measured variables included sympathovagal balance, salivary cortisol, perceived mood, and sleep, as well as short-term and declarative memory. RESULTS: Compared to the simulator exercise in the tank, the escape at sea showed the following significant differences: 1) higher salivary cortisol values (6.33 +/- 3.9 nmol x L(-1) on shore and 13.38 +/- 7.5 nmol x L(-1) at sea); 2) greater adverse changes in mood, including vigor, tension, and ability to fall asleep; and 3) impairment in declarative memory. Responses were found to differ further for the five submariners who had prior experience of accident or injury while at sea. CONCLUSION: The psychophysiological and cognitive effects of military exercises may be influenced by the realism of conditions and by prior exposure to life-threatening situations.

Anxiety and Psycho-Physiological Stress Response to Competitive Sport Exercise.

Introduction: Sport is recognized as beneficial for health. In certain situation of practice, it nevertheless appears likely to induce a stress response. Anxiety is a stress response-modulating factor. Our objective is to characterize the role of anxiety in the stress response induced by a selective physical exercise. Method: Sixty-three young male military conducted a selective sporting running event (a 8-km commando-walk) and were recorded the day before, the day of the race, and the day after. The variables were psychometric [personality questionnaires, coping and anxious/stress state, and physiological (nocturnal heart rate variability and actigraphy)]. The subjects were classified, using scores on anxiety questionnaires at baseline, into two groups according to their anxious (G ANX) or non-anxious (G N-ANX). Results: Before the race, the G ANX was characterized by a lower level of self-esteem, higher scores in dysfunctional coping and a greater perceived stress compared to the G N-ANX. Compared to G N-ANX, the stress response to the exercise was higher in G ANX: G ANX exhibited (Selye, 1950) in immediate post-exercise, greater level in activation markers, and mental fatigue associated with a same level of physical fatigue and (Kim et al., 2018) in nocturnal post-exercise, an increase in sympathetic activation associated with a higher sleep fragmentation. Conclusion: A competition selection sport exercise causes a stress response, particularly for anxious subjects. Anxious status could be involved in the risk of emergence of overtraining in sport practice. These results must be taken into account when sport practice is used for anxiety management.

Stress-induced hippocampus Npas4 mRNA expression relates to specific psychophysiological patterns of stress response.

Neuronal Per-Arnt-Sim (PAS) domain protein 4 (Npas4) is a key protein that intervenes in GABA synapse scaling and neurotrophicity enhancing. Since GABA and neurotrophicity are implicated in stress response and Npas4-deficient rodents exhibit behavioral alterations, an investigation was designed in rats to verify whether stress-induced spontaneous hippocampus Npas4 mRNA expression would be associated with specific patterns of stress response. The rats were exposed to one of three stressor levels: no stress (CTL, n = 15), exposure to a footshock apparatus (Sham, S, n = 40) and footshock (F, n = 80). After stress exposure the S and F rats were tested in an activity cage, and subsequently in an elevated plus maze (EPM), just prior to the sacrifice. Using cluster analysis, the animals already assigned to a stress level were also distributed into 2 subgroups depending on their Npas4 mRNA levels. The low (L) and high (H) Npas4 expression subgroups were identified in the S and F groups, the CTL group being independent of the Npas4 levels. The Npas4 effect was studied through the interaction between stress (S and F) and Npas4 level (L and H). The biological stress response was similar in H and L rats, except blood corticosterone that was slightly lower in the H rats. The H rats were more active in the actimetry cage and presented higher levels of exploration in the EPM. They also exhibited higher hippocampus activation, as assessed by the c-fos, Egr1 and Arc mRNA levels. Therefore high Npas4 expression favors stress management.