UBE2M Is a Stress-Inducible Dual E2 for Neddylation and Ubiquitylation that Promotes Targeted Degradation of UBE2F.

UBE2M and UBE2F are two family members of neddylation E2 conjugating enzyme that, together with E3s, activate CRLs (Cullin-RING Ligases) by catalyzing cullin neddylation. However, whether and how two E2s cross-talk with each other are largely unknown. Here, we report that UBE2M is a stress-inducible gene subjected to cis-transactivation by HIF-1 and AP1, and MLN4924, a small molecule inhibitor of E1 NEDD8-activating enzyme (NAE), upregulates UBE2M via blocking degradation of HIF-1α and c-JUN. UBE2M is a dual E2 for targeted ubiquitylation and degradation of UBE2F, acting as a neddylation E2 to activate CUL3-Keap1 E3 under physiological conditions but as a ubiquitylation E2 for Parkin-DJ-1 E3 under stressed conditions. UBE2M-induced UBE2F degradation leads to CRL5 inactivation and subsequent NOXA accumulation to suppress the growth of lung cancer cells. Collectively, our study establishes a negative regulatory axis between two neddylation E2s with UBE2M ubiquitylating UBE2F, and two CRLs with CRL3 inactivating CRL5.

Genome-Wide Identification and Drought Stress Response Pattern of the NF-Y Gene Family in Cymbidium sinense.

Cymbidium sinense, a type of orchid plant, is more drought-resistant and ornamental than other terrestrial orchids. Research has shown that many members of the NUCLEAR FACTOR Y (NF-Y) transcription factor family are responsive to plant growth, development, and abiotic stress. However, the mechanism of the NF-Y gene family's response to abiotic stress in orchids has not yet been reported. In this study, phylogenetic analysis allowed for 27 CsNF-Y genes to be identified (5 CsNF-YAs, 9 CsNF-YBs, and 13 CsNF-YC subunits), and the CsNF-Ys were homologous to those in Arabidopsis and Oryza. Protein structure analysis revealed that different subfamilies contained different motifs, but all of them contained Motif 2. Secondary and tertiary protein structure analysis indicated that the CsNF-YB and CsNF-YC subfamilies had a high content of alpha helix structures. Cis-element analysis showed that elements related to drought stress were mainly concentrated in the CsNF-YB and CsNF-YC subfamilies, with CsNF-YB3 and CsNF-YC12 having the highest content. The results of a transcriptome analysis showed that there was a trend of downregulation of almost all CsNF-Ys in leaves under drought stress, while in roots, most members of the CsNF-YB subfamily showed a trend of upregulation. Additionally, seven genes were selected for real-time reverse transcription quantitative PCR (qRT-PCR) experiments. The results were generally consistent with those of the transcriptome analysis. The regulatory roles of CsNF-YB 1, 2, and 4 were particularly evident in the roots. The findings of our study may make a great contribution to the understanding of the role of CsNF-Ys in stress-related metabolic processes.

Reproductive disorders linked to the interaction between sex steroid and thyroid hormonal activities, oxidative stress responses, and the rate of metabolism of tris (1,3-dichloro-2-propyl) phosphate (TDCPP) in zebrafish.

The objective of this study was to assess the thyroid hormone disruption and reproductive dysfunction effects of the bioaccumulation and rate of mechanism in zebrafish exposed to tris(1,3-dichloro-2-propyl) phosphate (TDCPP), with stress responsiveness. The fish were exposed to test concentrations of TDCPP (0, 0.06, 0.3, 1.5 µg/mL) for 21 days, in accordance with no observed adverse effect level (i.e., < EC10) for zebrafish embryos. The bioaccumulation of TDCPP was found to be significantly higher in female zebrafish, while the metabolic rate was significantly higher in male zebrafish at all concentrations studied. The thyroid hormone (triiodothyronine [T3] and thyroxine [T4]) levels and sex steroid (i.e., estrogen, androgen, and progesterone) levels were significantly increased only in female zebrafish exposed to TDCPP, and no significant difference was observed in male zebrafish, although their cortisol levels increased. The response to TDCPP can, therefore, be considered sex-specific. The results of this study demonstrate for the first time, that the different response in the bioaccumulation and metabolic rate of TDCPP in males and females. The results also indicate that TDCPP alters thyroid hormone levels, furthermore, as steroidogenesis is related to reproductive function with differing response in males and females. TDCPP can be assumed to exert reproductive toxicity via disruption of thyroid and steroid synthesis through a slow metabolic rate in the whole body after exposure. Consequently, our proposed methodological approach to assess the interactions of thyroid and steroid biosynthesis and metabolic rate of TDCPP with reproductive toxicity will serve a testing strategy to examine the adverse outcomes of emerging environmental chemicals.

Genome-Wide Identification Analysis of the R2R3-MYB Transcription Factor Family in Cymbidium sinense for Insights into Drought Stress Responses.

Cymbidium sinense represents a distinctive Orchidaceae plant that is more tolerant than other terrestrial orchids. Studies have shown that many members of the MYB transcription factor (TF) family, especially the R2R3-MYB subfamily, are responsive to drought stress. This study identified 103 CsMYBs; phylogenetic analysis classified these genes into 22 subgroups with Arabidopsis thaliana. Structural analysis showed that most CsMYB genes contained the same motifs, three exons and two introns, and showed a helix-turn-helix 3D structure in each R repeat. However, the members of subgroup 22 contained only one exon and no intron. Collinear analysis revealed that C. sinense had more orthologous R2R3-MYB genes with wheat than A. thaliana and rice. Ka/Ks ratios indicated that most CsMYB genes were under purifying negative selection pressure. Cis-acting elements analysis revealed that drought-related elements were mainly focused on subgroups 4, 8, 18, 20, 21, and 22, and Mol015419 (S20) contained the most. The transcriptome analysis results showed that expression patterns of most CsMYB genes were upregulated in leaves in response to slight drought stress and downregulated in roots. Among them, members in S8 and S20 significantly responded to drought stress in C. sinense. In addition, S14 and S17 also participated in these responses, and nine genes were selected for the real-time reverse transcription quantitative PCR (RT-qPCR) experiment. The results were roughly consistent with the transcriptome. Our results, thus, provide an important contribution to understanding the role of CsMYBs in stress-related metabolic processes.

Baseline corticosterone is associated with parental care in virgin Japanese quail (Coturnix japonica).

Glucocorticoids (GCs) are thought to impact reproductive success, and ultimately fitness. In this study we focus specifically on the relationship between GCs and parental care. Captive bred Japanese quail (Coturnix japonica) do not show spontaneous parental care behavior, however this behavior can be induced through a sensitization procedure. We investigated how the GC status of Japanese quail relates to parental care in animals of both sexes exposed or not to a chick sensitization treatment. To assess GC status, we obtained baseline plasma and feather cort samples, and used the HPA-axis function test to assess stress responsiveness by examining the response to a standardized stressor as well as negative feedback efficacy through dexamethasone injection. Next, birds were either exposed to chicks overnight in a small enclosure (sensitization treatment) or were enclosed but not exposed to chicks (control). The following morning, adult behaviors were filmed in the presence of a fresh set of chicks for 20 min. A final serum GC sample was obtained to assess if exposure to novel chicks was perceived as stressful. In control animals, baseline GCs were associated with increased total parental care duration and decreased latency to first parental care event. Interestingly, the opposite relationship was found in the sensitization group. Finally, exposure to novel chicks was not associated with an increase in corticosterone in either group. Overall it appears that baseline GCs are correlated with parental care in captive bred Japanese quail, and that the relationship changes direction depending on whether or not sensitization has occurred.

Influence of prenatal transportation stress on innate immune response to an endotoxin challenge in weaned Brahman bull calves†,‡.

The objective of this study was to assess the influence of prenatal stress (PNS) on innate immune responses to an endotoxin challenge in weaned bull calves. Altered innate immune response to lipopolysaccharide (LPS), as characterized by changes in a range of variables was hypothesized in PNS bull calves. Brahman cows (n = 96; 48 stressed by transportation at five stages of gestation and 48 Controls) produced 85 calves, from which 16 uncastrated male (bull) calves from each PNS and Control treatment were selected for an LPS challenge period. Rectal temperature (RT), sickness behavior score (SBS), serum concentrations of cortisol, interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and complete blood count (CBC) variables were assessed in response to intravenous LPS (0.25 µg/kg body weight) administration. Each reported variable increased or decreased following LPS administration. Prior to LPS, PNS bull calves exhibited increased TNF-α, IL-6, and monocyte counts, but decreased IFN-γ, eosinophils, and basophils (p < .05). Compared with Control, in response to LPS, PNS bull calves exhibited greater circulating concentrations of cortisol. PNS bull calves exhibited lower (p < .05) eosinophil and basophil counts at time 0 (time of LPS administration) but similar counts to Control bull calves 2 h after LPS. PNS bull calves exhibited a greater change from baseline for IFN-γ and monocytes in response to LPS administration. No other variables were influenced by prenatal treatment (p > .05). These findings suggest that PNS did not adversely affect basal or induced components of the innate immune response to an immunological challenge. Lay summary Our laboratory studied the influence of prenatal stress (i.e., transportation of pregnant cows) on immune function of bull calves at 8 months of age. This was accomplished by studying aspects of their innate immune response to an immunological challenge. Prenatal stress did not adversely affect basal or induced components of the innate immune response to an immunological challenge.

Does the early social environment prepare individuals for the future? A match-mismatch experiment in female wild cavies.

BACKGROUND: The social environment that mothers experience during pregnancy and lactation has a strong effect on the developing offspring. Whether offspring can be adaptively shaped to match an environment that is similar to the maternal one is still a major question in research. Our previous work in wild cavies showed that females whose mothers lived in a stable social environment with few social challenges during pregnancy and lactation (SE-daughters) developed different behavioral phenotypes than females whose mothers lived in an unstable social environment with frequent social challenges during pregnancy and lactation (UE-daughters). In the present study we investigated whether SE-daughters are better adapted to a stable social environment, similar to their maternal one, than are UE-daughters, for which the stable social environment represents a mismatch with their maternal one. For this purpose, we established pairs of one UE- and one SE-daughter and housed them together under stable social conditions for one week. Dominance ranks, behavioral profiles, glucocorticoid levels, cortisol responsiveness and body weight changes were compared between the groups. We hypothesized that SE-daughters fare better in a stable social setting compared to UE-daughters. RESULTS: After one week of cohabitation in the stable social condition, UE-daughters had higher glucocorticoid levels, tended to gain less body weight within the first three days and displayed higher frequencies of energy-demanding behaviors such as rearing and digging than SE-daughters. However, there was no difference in cortisol responsiveness as well as in dominance ranks between UE- and SE-daughters. CONCLUSION: Higher glucocorticoid levels and less body weight gain imply that UE-daughters had higher energy demands than SE-daughters. This high energy demand of UE-daughters is further indicated by the increased display of rearing and digging behavior. Rearing implies increased vigilance, which is far too energy demanding in a stable social condition but may confer an advantage in an unstable social environment. Hence, SE-daughters seem to better match a stable social environment, similar to their maternal one, than do UE-daughters, who encountered a mismatch to their maternal environment. This data supports the environmental matching hypothesis, stating that individuals manage the best in environments that correspond to their maternal ones.

Age-related differences in stress responsiveness of the hypothalamic-pituitary-adrenal axis of nonhuman primates with various types of adaptive behavior.

Aging is characterized by disturbances in the functioning of the hypothalamic-pituitary-adrenal (HPA) axis, associated with disturbances in the adaptation processes and increase of the probability of the onset of post-stress syndrome. However, the individual features of age-related disorders stress reactivity of HPA axis have not been studied. The purpose was to study individual characteristics of the HPA axis responsiveness to acute psycho-emotional stress exposure (restraint, ASE) at different age periods on the model of the young adult and old physically healthy female rhesus monkeys that differ in their behavioral responses to stress, i.e., with depression-like and anxiety-like behavior (DAB) on the one hand and healthy standard (control) adaptive behavior (SB) on the other hand. No significant intergroup differences were observed in HPA axis responses to ASE in young animals. During aging the monkeys with SB showed reduced ACTH response to the ASE, whereas the monkeys with DAB demonstrated its increase. The old animals with DAB in response to ASE demonstrated the most pronounced HPA axis disorders, such as the highest levels of corticotrophin (ACTH), the lowest levels of dehydroepiandrosterone sulfate (DHEAS), reduced cortisol (F) levels and the highest values of the F/DHEAS molar ratio. The ratio F/DHEAS positively correlates with the malondialdehyde concentration in erythrocytes that is considered as the biomarker of oxidative stress. Thus, these data allow us to consider the old monkeys with DAB as individuals with higher vulnerability to the adverse effects of ASE. In addition, depression-like and anxiety-like behavior of aged primates under mild/moderate stress along with reduced DHEAS plasma concentration and increased values of F/DHEAS ratio can be used to identify individuals with increased vulnerability to ASE and accelerated aging.

Repeated restraint stress lowers the threshold for response to third ventricle CRF administration.

Rats and mice exposed to repeated stress or a single severe stress exhibit a sustained increase in energetic, endocrine, and behavioral response to subsequent novel mild stress. This study tested whether the hyper-responsiveness was due to a lowered threshold of response to corticotropin releasing factor (CRF) or an exaggerated response to a standard dose of CRF. Male Sprague-Dawley rats were subjected to 3h of restraint on each of 3 consecutive days (RRS) or were non-restrained controls. RRS caused a temporary hypophagia but a sustained reduction in body weight. Eight days after the end of restraint, rats received increasing third ventricle doses of CRF (0-3.0µg). The lowest dose of CRF (0.25µg) increased corticosterone release in RRS, but not control rats. Higher doses caused the same stimulation of corticosterone in the two groups of rats. Fifteen days after the end of restraint, rats were food deprived during the light period and received increasing third ventricle doses of CRF at the start of the dark period. The lowest dose of CRF inhibited food intake during the first hour following infusion in RRS, but not control rats. All other doses of CRF inhibited food intake to the same degree in both RRS and control rats. The lowered threshold of response to central CRF is consistent with the chronic hyper-responsiveness to CRF and mild stress in RRS rats during the post-restraint period.

Personality and innate immune defenses in a wild bird: Evidence for the pace-of-life hypothesis.

We tested the two main evolutionary hypotheses for an association between immunity and personality. The risk-of-parasitism hypothesis predicts that more proactive (bold, exploratory, risk-taking) individuals have more vigorous immune defenses because of increased risk of parasite exposure. In contrast, the pace-of-life hypothesis argues that proactive behavioral styles are associated with shorter lifespans and reduced investment in immune function. Mechanistically, associations between immunity and personality can arise because personality differences are often associated with differences in condition and stress responsiveness, both of which are intricately linked with immunity. Here we investigate the association between personality (measured as proactive exploration of a novel environment) and three indices of innate immune function (the non-specific first line of defense against parasites) in wild superb fairy-wrens Malurus cyaneus. We also quantified body condition, hemoparasites (none detected), chronic stress (heterophil:lymphocyte ratio) and circulating corticosterone levels at the end of the behavioral test (CORT, in a subset of birds). We found that fast explorers had lower titers of natural antibodies. This result is consistent with the pace-of-life hypothesis, and with the previously documented higher mortality of fast explorers in this species. There was no interactive effect of exploration score and duration in captivity on immune indices. This suggests that personality-related differences in stress responsiveness did not underlie differences in immunity, even though behavioral style did modulate the effect of captivity on CORT. Taken together these results suggest reduced constitutive investment in innate immune function in more proactive individuals.

Stress responsiveness and anxiety-like behavior: The early social environment differentially shapes stability over time in a small rodent.

The early social environment can profoundly affect behavioral and physiological phenotypes. We investigated how male wild cavy offspring, whose mothers had either lived in a stable (SE) or an unstable social environment (UE) during pregnancy and lactation, differed in their anxiety-like behavior and stress responsiveness. At two different time points in life, we tested the offspring's anxiety-like behavior in a dark-light test and their endocrine reaction to challenge in a cortisol reactivity test. Furthermore, we analyzed whether individual traits remained stable over time. There was no effect of the early social environment on anxiety-like behavior and stress responsiveness. However, at an individual level, anxiety-like behavior was stable over time in UE- but not in SE-sons. Stress responsiveness, in turn, was rather inconsistent in UE-sons and temporally stable in SE-sons. Conclusively, we showed for the first time that the early social environment differentially shapes the stability of behavioral and endocrine traits. At first glance, these results may be surprising, but they can be explained by the different functions anxiety-like behavior and stress responsiveness have.

Behavioural responses in a net restraint test predict interrenal reactivity in Arctic charr Salvelinus alpinus.

In this study, a 1 min net restraint test was evaluated as a method to predict stress-coping style in Arctic charr Salvelinus alpinus, by investigating the relationship between behaviour during the test and levels of plasma cortisol sampled after 30 min confinement. In two separate groups of S. alpinus, general linearized model revealed significant correlations between cortisol levels and principal component scores extracted from principal component analysis, combining measures of activity in the tests. With the use of glmulti, the model selection ruled out any effects of size, sex and order of capture on interrenal reactivity. In general, S. alpinus that were more active in the net restraint test also had low levels of circulating cortisol, suggesting a proactive coping style. The results from two repeated runs were not correlated, but both runs, performed eight days apart, show a negative correlation between post-stress cortisol level and activity in the net. The lack of consistency could be explained by different treatments before each run and individual differences in behavioural plasticity. The net restraint test is thus predictive of stress-coping style in S. alpinus, and has the benefit of being less time-consuming than the commonly used confinement stress test.

An oxidative stress-responsive electrospun polyester membrane capable of releasing anti-bacterial and anti-inflammatory agents for postoperative anti-adhesion.

Peritendinous adhesion, secondary to the repair surgery of tendon rupture or injury, is one of the most common causes of reoperation, owing to the proliferation of fibrous tissue and excessive collagen synthesis caused by the residing inflammatory cells. In this study, a smart oxidative stress-responsive electrospun polyester membrane (EPM) was fabricated as both physical barrier and reservoir of curcumin/celecoxib (CUR/CEL) to prevent peritendinous adhesion. The multicomponent EPM was designed to release the encapsulated drugs in response to oxidative stress of the local microenvironment induced by inflammation. Specifically, sulfides in the EPM were able to react with reactive oxygen species (ROS) and become hydrophilic sulfoxide or sulfone to accelerate the release rate of drugs and regulate oxidative stress level in the inflammatory site intelligently. The oxidation-sensitive multicomponent EPM loaded with CUR and CEL was tested for anti-adhesion capacity in vitro and in vivo. An excellent ROS-sensitive degradation behavior and good cytocompatibility with cell viability of above 85% were presented with the fabricated EPM. The CUR- or CEL-loaded EPM possessed a better anti-adhesion ability compared with EPM without the drugs. Nevertheless, they were inferior to the EPM simultaneously loaded with both drugs, where the adhesion rate and fibrous adhesion number in the EPM+CUR/CEL group were close to extremely low values of about zero, demonstrating that CUR and CEL could synergistically prevent peritendinous adhesion. More interestingly, the multicomponent EPM was able to react with the local oxidative stress, leading to a smart and sustained behavior of releasing approximately 80% of the drug within 20 days. Overall, the smart multicomponent EPM offers a promising barrier strategy to prevent peritendinous adhesion.

Knowledge of Biobehavioral Organization Can Facilitate Better Science: A Review of the BioBehavioral Assessment Program at the California National Primate Research Center.

Animals vary on intrinsic characteristics such as temperament and stress responsiveness, and this information can be useful to experimentalists for identifying more homogeneous subsets of animals that show consistency in risk for a particular research outcome. Such information can also be useful for balancing experimental groups, ensuring animals within an experiment have similar characteristics. In this review, we describe the BioBehavioral Assessment Program at the California National Primate Research Center, which, since its inception in 2001, has been providing quantitative information on intrinsic characteristics to scientists for subject selection and balancing, and to colony management staff for management purposes. We describe the program and review studies relating to asthma, autism, behavioral inhibition, etc., where the BBA Program was used to select animals. We also review our work, showing that factors such as rearing, ketamine exposure, and prenatal experience can affect biobehavioral organization in ways that some investigators might want to control for in their studies. Attention to intrinsic characteristics of subject populations is consistent with the growing interest in precision medicine and can lead to a reduction in animal numbers, savings in time and money for investigators, and reduced distress for the animals.

Male long-Evans rats: An outbred model of marked hypothalamic-pituitary-adrenal hyperactivity.

Rat and mouse strains differ in behavioral and physiological characteristics, and such differences can contribute to explain discrepant results between laboratories and better select the most appropriate strain for a particular purpose. Differences in the activity of the hypothalamic-pituitary-adrenal (HPA) axis are particularly important given the pivotal role of this system in determining consequences of exposure to stressors. In this regard, Long-Evans (LE) rats are widely used in stress research, but there is no specific study aiming at thoroughly characterizing HPA activity in LE versus other extensively used strains. In a first experiment, LE showed higher resting ACTH and corticosterone levels only at certain points of the circadian rhythm, but much greater ACTH responsiveness to stressors (novel environment and forced swim) than Sprague-Dawley (SD) rats. Accordingly, enhanced corticotropin-releasing hormone (CRH) expression in the paraventricular nucleus of the hypothalamus and reduced expression of glucocorticoid receptors were observed in the hippocampal formation. Additionally, they are hyperactive in novel environments, and prone to adopt passive-like behavior when compared to SD rats. Supporting that altered HPA function has a marked physiological impact, we observed in another set of animals much lower thymus weight in LE than SD rats. Finally, to demonstrate that LE rats are likely to have higher HPA responsiveness to stressors than most strains, we studied resting and stress levels of HPA hormones in LE versus Wistar and Fischer rats, the latter considered an example of high HPA responsiveness. Again, LE showed higher resting and stress levels of ACTH than both Wistar and Fischer rats. As ACTH responsiveness to stressors in LE rats is stronger than that previously reported when comparing other rat strains and they are commercially available, they could be an appropriate model for studying the behavioral and physiological implications of a hyper-active HPA axis under normal and pathological conditions.

Stress Responsiveness and Emotional Eating Depend on Youngsters' Chronic Stress Level and Overweight.

The persistent coexistence of stress and paediatric obesity involves interrelated psychophysiological mechanisms, which are believed to function as a vicious circle. Here, a key mechanistic role is assumed for stress responsiveness and eating behaviour. After a stress induction by the Trier Social Stress Test in youngsters (n = 137, 50.4% boys, 6-18 years), specifically those high in chronic stress level and overweight (partial η2 = 0.03-0.07) exhibited increased stress vulnerability (stronger relative salivary cortisol reactivity and weaker happiness recovery) and higher fat/sweet snack intake, compared to the normal-weight and low-stress reference group. Stress responsiveness seems to stimulate unhealthy and emotional eating, i.e., strong cortisol reactivity was linked to higher fat/sweet snack intake (ß = 0.22) and weak autonomic system recovery was linked to high total and fat/sweet snack intake (ß = 0.2-0.3). Additionally, stress responsiveness acted as a moderator. As a result, stress responsiveness and emotional eating might be targets to prevent stress-induced overweight.

The Yersinia pseudotuberculosis Cpx envelope stress system contributes to transcriptional activation of rovM.

The Gram-negative enteropathogen Yersinia pseudotuberculosis possesses a number of regulatory systems that detect cell envelope damage caused by noxious extracytoplasmic stresses. The CpxA sensor kinase and CpxR response regulator two-component regulatory system is one such pathway. Active Cpx signalling upregulates various factors designed to repair and restore cell envelope integrity. Concomitantly, this pathway also down-regulates key determinants of virulence. In Yersinia, cpxA deletion accumulates high levels of phosphorylated CpxR (CpxR~P). Accumulated CpxR~P directly repressed rovA expression and this limited expression of virulence-associated processes. A second transcriptional regulator, RovM, also negatively regulates rovA expression in response to nutrient stress. Hence, this study aimed to determine if CpxR~P can influence rovA expression through control of RovM levels. We determined that the active CpxR~P isoform bound to the promoter of rovM and directly induced its expression, which naturally associated with a concurrent reduction in rovA expression. Site-directed mutagenesis of the CpxR~P binding sequence in the rovM promoter region desensitised rovM expression to CpxR~P. These data suggest that accumulated CpxR~P inversely manipulates the levels of two global transcriptional regulators, RovA and RovM, and this would be expected to have considerable influence on Yersinia pathophysiology and metabolism.

Low vagal tone in two rat models of psychopathology involving high or low corticosterone stress responses.

The two stress-responsive physiological systems, autonomic nervous system (ANS) and hypothalamus-pituitary-adrenal (HPA) axis exert complementary and interrelated actions in the organism. Individuals that suffer stress-related psychopathologies frequently present simultaneous alterations -i.e., either low or high- responsiveness- in both systems. However, there is scarce evidence establishing whether a priori alterations in these systems -i.e., independent of previous stress exposure- may predispose to the development of psychopathologies possibly due to the lack of animal models simultaneously involving aberrant HPA and SNS responses. In this study, we describe two animal models selectively bred according to their differential (either high, 'High', or low, 'Low') glucocorticoid responsiveness to stress, in comparison to a third line of rats that displays intermediate ('Inter') glucocorticoid responses. The two extreme lines may be considered distinct models of psychopathology; the High line representing a model of constitutive mood alterations while the Low line a model of vulnerability to develop stress-induced psychopathologies. We recorded the electrocardiogram in rats from the three lines and quantified heart rate variability and vagal tone indexes during rest and stress challenges. Rats from both High and Low lines displayed higher heart rate and lower basal vagal tone than the Inter group, both at resting and following stress exposure. Specific pharmacological manipulations probing the relative contribution of sympathetic and parasympathetic components on HR modulation confirmed a relative lower vagal tone in High and Low lines and discarded differences in the sympathetic regulation of heart rate between the lines. Therefore, the two genetically-selected High and Low glucocorticoid rat lines emerge as two valuable preclinical models of psychopathology involving two key risk factors for psychiatric and cardiovascular disorders, namely dysregulations in the HPA axis and cardiac vagal functioning.

Age-Related Decrease in Stress Responsiveness and Proactive Coping in Male Mice.

Coping is a strategic approach to dealing with stressful situations. Those who use proactive coping strategies tend to accept changes and act before changes are expected. In contrast, those who use reactive coping are less flexible and more likely to act in response to changes. However, little research has assessed how coping style changes with age. This study investigated age-related changes in coping strategies and stress responsiveness and the influence of age on the processing of conditioned fear memory in 2-, 12- and 23-month-old male mice. Coping strategy was measured by comparing the escape latency in an active avoidance test and by comparing responses to a shock prod. The results showed that proactivity in coping response gradually decreased with age. Stress responsiveness, measured by stress-induced concentration of corticosterone, was also highest in 2-month-old mice and decreased with age. Consolidation of fear memory was highest in 12-month-old mice and was negatively correlated with the degree of stress responsiveness and proactivity in coping. Fear extinction did not differ among age groups and was not correlated with stress responsiveness or the proactivity of coping. However, the maintenance of extinct fear memory, which was best in 2-month-old mice and worst in 12-month-old mice, was negatively correlated with stress responsiveness but not with coping style. Age-dependent changes in the expression of glucocorticoid receptor (GR) and its regulatory co-chaperones, which are accepted mechanisms for stress hormone stimulation, were measured in the hippocampus. The expression of GR was increased at 12 months compared to other age groups. There were no differences in Hsp70 and BAG1 expression by age. These results can be summarized as follows: (1) stress responsiveness and proactivity in coping decreased with age class; (2) consolidation of fear memory was negatively correlated with both stress responsiveness and proactivity; however, maintenance of extinct fear memory was negatively correlated with stress responsiveness only; and (3) consolidation and maintenance of extinct fear memory appeared to be more influenced by factors other than stress reactivity and proactivity in coping, such as the amount of hippocampal glucocorticoid expression.

Anxious women do not show the expected decrease in cardiovascular stress responsiveness as pregnancy advances.

Altered stress responsiveness is a risk factor for mental and physical illness. In non-pregnant populations, it is well-known that anxiety can alter the physiological regulation of stress reactivity. Characterization of corresponding risks for pregnant women and their offspring requires greater understanding of how stress reactivity and recovery are influenced by pregnancy and women's anxiety feelings. In the current study, women were presented repeatedly with mental arithmetic stress tasks in the first and third pregnancy trimester and reported their trait anxiety using the state trait anxiety inventory. Cardiovascular stress reactivity in late pregnancy was lower than reactivity in the first pregnancy trimester (heart rate (HR): t(197)=4.98, p<.001; high frequency heart rate variability (HF HRV): t(196)=-2.09, p=.04). Less attenuation of stress reactivity occurred in more anxious women (HR: b=0.15, SE=0.06, p=.008; HF HRV: b=-10.97, SE=4.79, p=.02). The study design did not allow the influence of habituation to repeated stress task exposure to be assessed separately from the influence of pregnancy progression. Although this is a limitation, the clear differences between anxious and non-anxious pregnant women are important, regardless of the extent to which differing habituation between the groups is responsible. Less dampened stress reactivity through pregnancy may pose long-term risks for anxious women and their offspring. Follow-up studies are required to determine these risks.