Enhanced Stress Sensitivity Research Articles

T5. STRESS SENSITIZATION AS THE UNDERLYING MECHANISM LINKING CHILDHOOD TRAUMA AND PSYCHOTIC-LIKE SYMPTOMS IN NONCLINICAL YOUNG ADULTS

BackgroundThe traumagenic neurodevelopment model of psychosis poses that prolonged or severe stress exposure in critical developmental periods (i.e., childhood) disrupts psychobiological stress regulation mechanisms, increasing liability for the onset and persistence of psychotic symptoms after re-exposure to stressful events (Read et al., 2014). This disruption seems to result in a process of behavioral and biological sensitization by which the individual manifests an enhanced stress sensitivity to subsequent minor adversities in adulthood (Belda et al., 2015), which may cause an increased risk for psychosis. The behavioral manifestation of stress sensitization has been examined in samples at clinical risk for psychosis, but it has been scarcely studied in nonclinical populations. The first goal of the present study was to investigate whether the association between childhood trauma (CT) and perceived stress was moderated by the impact of recent life events in a nonclinical sample. The second goal was to test whether the association between CT and suspiciousness was mediated by perceived stress, and whether this mediation was moderated by the impact of life events. Following stress sensitization hypotheses, it was expected that the association between CT and suspiciousness would be mediated by higher levels of perceived stress. In turn, the impact of negative recent life events was expected to moderate the effect of CT on suspiciousness via increased levels of perceived stress.MethodsThe sample consisted of 168 Spanish nonclinical youngsters (mean age=28.01), belonging to the ongoing Barcelona Longitudinal Investigation of Schizotypy Study (BLISS). From a large pool of unselected college students, a selected subsample oversampled for schizotypy scores continues regular follow-up assessments. They were assessed for life events, perceived stress and suspiciousness at the concurrent assessment, whereas CT was assessed 7 years earlier at baseline. Linear regression and simple slope analyses were performed to test whether recent life events moderated the association between CT and suspiciousness. Moderated mediation analyses were conducted to examine the indirect effect of CT on suspiciousness via perceived stress moderated by the impact of recent life events.ResultsRecent life events significantly moderated the association between CT and perceived stress. Simple slope analyses indicated that this association was significant when subjects experienced negative or neutral life events, but not positive life events. Moderated mediation analyses revealed an indirect effect of CT on suspiciousness through perceived stress, which was moderated by the impact of recent life events. Thus, these mediational effects were significant for those subjects with a greater subjective appraisal of a negative or neutral impact of life events, but not for those experiencing a positive impact. The magnitude of the conditional indirect effect (as indicated by the Index of Moderated Mediation) was significantly different across levels of impact of recent life events (i.e., negative, neutral, positive).DiscussionThese findings provide further supporting evidence to the stress sensitization hypothesis for psychosis by showing its manifestation across both the clinical and nonclinical ranges of the hypothesized psychosis continuum. CT and perceived stress were associated when the impact of recent life events was negative or neutral, but not positive, suggesting that positive life events may play a protective role in the perception of stress and the role that stress shows in the mechanistic pathway to suspiciousness.

Febrile seizures and increased stress sensitivity in children: How it relates to seizure characteristics

BackgroundStudies suggest that the relationship between seizures and stress starts early in life. However, evidence of long-term altered stress reactivity following early-life seizures is lacking. Our objectives were to assess alterations in stress hormone reactivity in children with past febrile seizures (FS) and investigate how these alterations relate to clinical characteristics. MethodThis case–control study compared a convenience sample of children with simple FS (n = 24), complex FS (n = 18), and matched healthy controls (n = 42). Stress was induced by electrode placement for an electroencephalography (EEG) exam. Salivary cortisol to stress, using three samples collected before and after the stressor, was compared between groups and sex. The relationship between stress reactivity and clinical characteristics (i.e., FS duration, age at first FS, time since the last FS) was investigated. ResultsCortisol reactivity to stress was significantly different depending on study groups, F(1, 78) = 6.415, p = 0.003, η2p = 0.141, but not sex nor was there a significant interaction between group and sex (p ≥ 0.581). Participants with simple FS showed higher cortisol reactivity to stress (M = 14.936, Standard deviation (SD) = 26.852) compared with those with complex FS (M = −4.663, SD = 18.649, p = 0.015) and controls (M = −3.817, SD = 18.907, p = 0.003). There was no significant difference between participants with complex FS and controls (p > 0.999). Stress reactivity was not linked to clinical characteristics. ConclusionsChildren with past simple FS showed greater changes in salivary cortisol following stress, suggesting enhanced stress sensitivity. As similar results were not found in a population with complex FS, our study shows that stress alterations are not caused by seizure severity. Future studies are needed to investigate whether stress sensitivity may be premorbid to simple FS and may contribute to simple FS incidence.

The role of estradiol on social stress induced depressive‐like behavior and neuroinflammation in females

It has long been established that repeated exposure to social stress can lead to the development of psychosocial disorders, such as depression. Strikingly, women are more sensitive to stress‐related disorders, such as depression compared to men. This enhanced stress sensitivity in females begins at the onset of puberty and ends during menopause, suggesting that ovarian hormones could be a large contributing factor to this phenomenon. However, the mechanism by which ovarian hormones could be driving this enhanced stress sensitivity is unknown. Using a modified social defeat paradigm which consists of a rat bearing witness to an aggressive social defeat encounter, we have previously shown that witness stress produces depressive‐like anhedonia and enhanced pressor and tachycardic responses selectively in intact cycling females while females that are ovariectomized (OVX) are resistant, making this an ideal model to study mechanisms of stress susceptibility in females. We recently demonstrated that neuroinflammation is crucial in the development of depressive‐like anhedonia in socially stressed males. The purpose of this study was to determine the effects of estradiol on social stress‐induced neuroinflammation within the central amygdala (CeA) and locus coeruleus (LC) of witness stressed females. Study 1 determined the differential neuroinflammatory consequences of witness stress in intact cycling vs. OVX females. Much like our behavioral data suggests, intact cycling females show enhanced neuroinflammation in the CeA compared to OVX females. Interestingly, neuroinflammation was not elevated in the LC in response to witness stress, but rather OVX females demonstrated stress‐induced reductions of IL‐1β within the LC vs. controls. In order to determine the discrete role of estradiol in these neuroinflammatory responses to stress, study 2 determined cytokine levels in OVX females that received estradiol or placebo replacement. While estradiol replacement did not result in the emergence of stress‐induced depressive‐like anhedonia, it did promote anxiety‐like behavior as evidenced by increased burying during witness stress exposure. Based on this enhanced anxiety‐like response, we predict concomitant increases in neuroinflammation within the CeA, a brain region known to contribute to behavioral stress responses. Therefore, the current study suggests that ovarian hormones, potentially estrogen, may mediate enhanced stress sensitivity in females by promoting stress‐induced inflammation in critical brain regions involved in the behavioral stress response, providing novel therapeutic targets to study female stress resiliency and susceptibility.Support or Funding InformationASPIRE18080‐16‐41861, 15SDG22430017, and P20GM103641

Genetic Deletion of Neuronal PPARγ Enhances the Emotional Response to Acute Stress and Exacerbates Anxiety: An Effect Reversed by Rescue of Amygdala PPARγ Function.

Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) is a classical target for antidiabetic therapies with thiazolidinedione compounds. PPARγ agonists such as rosiglitazone and pioglitazone are in clinical use for the treatment of insulin resistance. PPARγ has recently attracted attention for its involvement in the regulation of CNS immune response and functions. Here, we demonstrate that neuronal PPARγ activation prevented the negative emotional effects of stress and exerted anxiolytic actions without influencing hypothalamic-pituitary-adrenal axis function. Conversely, pharmacological blockade or genetic deletion of PPARγ enhanced anxiogenic responses and increased vulnerability to stress. These effects appear to be controlled by PPARγ neuronal-mediated mechanisms in the amygdala.

β-endorphin regulates alcohol consumption induced by exercise restriction in female mice

Animal models have long been used to study the mechanisms underlying the complex association between alcohol and stress. Female mice prevented from running on a home-cage activity wheel increase voluntary ethanol consumption. β-endorphin is an endogenous opioid involved in negatively regulating the stress response and has also been implicated in the risk for excessive drinking. The present study investigates the role of β-endorphin in moderating free-choice consumption of ethanol in response to a blocked activity wheel. Female, transgenic mice with varying levels of the opioid peptide were given daily 2-h access to 20% ethanol with rotations on a running wheel blocked on alternate days. Subjects with low β-endorphin exhibited enhanced stress sensitivity by self-administering larger quantities of ethanol on days when wheel running was prevented. β-endorphin levels did not influence voluntary activity on the running wheel. There were genotypic differences in plasma corticosterone levels as well as corticotropin-releasing hormone mRNA content in multiple brain regions associated with the stress response in these free drinking and running subjects. Susceptibility to stress is enhanced in female mice with low levels of β-endorphin, and better understanding of the role for this opioid in mitigating the response to stressors may aid in the development of interventions and treatments for excessive use of alcohol in women.

Stress sensitivity and stress sensitization in psychopathology: an introduction to the special section.

The goal of this special section is to examine the mechanisms of enhanced sensitivity and sensitization to stress as they influence the etiology and pathophysiology of psychopathology. The 12 articles in the section focus on some of the most crucial and unanswered questions regarding the underlying mechanisms and functional consequences of stress sensitivity and stress sensitization in psychopathology. They address the constructs of stress sensitivity and stress sensitization using state-of-the-art, and often novel, methodologies. The special section also focuses on an important terminological distinction between two related but distinct stress mechanisms that are often conflated. Individuals who are sensitive to stress possess this characteristic as a putative trait that develops through genetically mediated transactional relations between temperamental characteristics and the early contextual environment. In contrast, individuals who are sensitized to stress become so over time through repeated exposure to external, as well as endogenous, stressors. Enhanced stress sensitivity and sensitization have been included in conceptual models of psychopathology. Yet, the specific mechanisms by which these stress processes impact the onset and course of psychiatric disorders are not fully understood. These articles focus on several mechanistic accounts of stress sensitivity and sensitization.

Food restriction does not relieve PTSD-like anxiety

We used the inescapable foot shock paradigm (IFS) in rats as an animal model for post-traumatic stress disorder (PTSD). Previously we showed that exercise reversed the enhanced stress sensitivity induced by IFS. From literature it is known that food restriction has antidepressant and anxiolytic effects. Since both treatments influence energy expenditure, we questioned whether food restriction reduces anxiety in the IFS model via a comparable, NPY dependent mechanism as enrichment.Anxiety of IFS-exposed animals was measured as change in locomotion and freezing after sudden silence in an open field test, before and after two weeks of food restriction. In addition a forced swim test (FST) was performed. Next, using qPCR, the expression of neuropeptide Y (NPY) and the neuropeptide Y1 receptor (Y1 receptor) was measured in the amygdala.Food restriction increased locomotion and decreased freezing behavior both in control and IFS animals. These effects were small. IFS-induced anxiety was not abolished after two weeks of food restriction. IFS did not influence immobility or the duration of swimming in the FST of animals fed ad libitum. However, food restriction increased swimming and decreased the duration of immobility in IFS-exposed animals. Y1 receptor expression in the basolateral amygdala decreased after both IFS and food restriction. Although food restriction seems to induce a general anxiolytic effect, it does not operate via enhanced Y1 receptor expression and has no effect on the more pathogenic anxiety induced by IFS.

Commentary on Degenhardt et al. (2013): Specific effect of adolescent cannabis use on anxiety – tentative explanations

Commentary on Degenhardt <i>et al</i>. (2013): Specific effect of adolescent cannabis use on anxiety – tentative explanations

Subinhibitory concentrations of antibiotics affect stress and virulence gene expression inListeria monocytogenesand cause enhanced stress sensitivity but do not affect Caco-2 cell invasion

Antibiotics can act as signal molecules and affect bacterial gene expression, physiology and virulence. The purpose of this study was to determine whether subinhibitory antibiotic concentrations alter gene expression and physiology of Listeria monocytogenes. Using an agar-based screening assay with promoter fusions, 14 of 16 antibiotics induced or repressed expression of one or more stress and/or virulence genes. Despite ampicillin-induced up-regulation of PinlA-lacZ expression, Caco-2 cell invasion was not affected. Subinhibitory concentrations of ampicillin and tetracycline caused up- and down-regulation of stress response genes, respectively, but both antibiotics caused increased sensitivity to acid stress. Six combinations of gene-antibiotic were quantified in broth cultures and five of the six resulted in the same expression pattern as the agar-based assay. Antibiotics affect virulence and/or stress gene expression; however, altered expression could not predict changes in phenotypic behaviour. Subinhibitory concentrations of antibiotics led to increased acid sensitivity, and we speculate that this is attributed to changes in cell envelope or reduced σ(B) -dependent gene expression. Although subinhibitory concentrations of antibiotics affect gene expression in L. monocytogenes, the changes did not increase virulence but did enhance the acid sensitivity.

A “Twist box” Code of p53 Inactivation: Twist box:p53 Interaction Promotes p53 Degradation

Twist proteins have been shown to contribute to cancer development and progression by impinging on different regulatory pathways, but their mechanism of action is poorly defined. By investigating the role of Twist in sarcomas, we found that Twist1 acts as a mechanism alternative to TP53 mutation and MDM2 overexpression to inactivate p53 in mesenchymal tumors. We provide evidence that Twist1 binds p53 C terminus through the Twist box. This interaction hinders key posttranslational modifications of p53 and facilitates itsMDM2-mediated degradation. Our study suggests the existence of a Twist box code of p53 inactivation and provides the proof of principle that targeting the Twist box:p53 interaction might offer additional avenues for cancer treatment.

Re-exposure and environmental enrichment reveal NPY-Y1 as a possible target for post-traumatic stress disorder

Exposure-based cognitive behavioral therapy in post-traumatic stress disorder (PTSD) patients relieves symptoms caused by fear association as well as symptoms that are not the result of associative learning. We used the inescapable foot shock model (IFS), an animal model for PTSD, to study the possible involvement of glutamate receptors, the corticotropin-releasing factor (CRF) system, and the neuropeptide Y (NPY) system in the reduction of stress sensitization following repeated re-exposure to the conditioning context. Starting one week after the IFS procedure, the rats were repeatedly re-exposed to the shock environment. Stress sensitivity was measured in a modified open field test (sudden silence was used as a stressor). Selected mRNAs (GluN1, -2A-C, GluA1-4, GluK1-5, CRF, CRF-R1, NPY, NPY-Y1) were quantified in the amygdala.Repeated re-exposure (RE) to the IFS context reduced both trauma-associated anxiety (to the IFS context) and the enhanced stress sensitivity (in the open field). Changes in glutamate receptor subunits (GluN1, GluN2A-B, GluA1, GluA4, GluK3, GluK4) were detected in the amygdala that were normalized by RE. However, infusion of the AMPA/kainate antagonist NBQX in the BLA (basolateral amygdala) did not improve the anxious behavior. RE normalized IFS-induced increases in CRF-R1 mRNA and increased NPY-Y1 mRNA expression in the amygdala. Previously, and repeated here, we showed that environmental enrichment (EE) enhances recovery from IFS. EE led to similar changes in CRF-R1 and NPY-Y1 expression as RE did. Importantly, administration of [Leu31, Pro34]-NPY (Y1 agonist) in the BLA normalized the enhanced sensitivity to stress after IFS.Our data suggest that the NPY-Y1 receptor in the amygdala may serve as a therapeutic target for the treatment of PTSD.

Appraisals of Stressful Life Events as a Genetically-Linked Mechanism in the Stress–Depression Relationship

Variation in the promoter region of the serotonin transporter gene (5-HTTLPR) has been linked to various cognitive-affective indices of stress sensitivity hypothesized to underlie vulnerability to depression. The current study examined the association of 5-HTTLPR with appraisals of naturally occurring acute life stressors in a community sample of 384 youth at elevated risk for depression due to oversampling for maternal depression. Interview measures administered at youth age 20 were used to assess subjective and objective (assigned by an independent rating team) appraisals of the negative impact of recent acute stressful life events. The presence of at least one S allele was associated with elevated subjective appraisals of the negative impact of acute stressors (P = 0.03). Consistent with an endophenotype perspective, support was found for a 5-HTTLPR-stress appraisals-depression mediation model both concurrently and longitudinally. Results indicate that enhanced stress sensitivity may act as an intermediate phenotype through which 5-HTTLPR affects risk for depression.

LRRK2 Mutant iPSC-Derived DA Neurons Demonstrate Increased Susceptibility to Oxidative Stress

Studies of Parkinson's disease (PD) have been hindered by lack of access to affected human dopaminergic (DA) neurons. Here, we report generation of induced pluripotent stem cells that carry the p.G2019S mutation (G2019S-iPSCs) in the Leucine-Rich Repeat Kinase-2 (LRRK2) gene, the most common PD-related mutation, and their differentiation into DA neurons. The high penetrance of the LRRK2 mutation and its clinical resemblance to sporadic PD suggest that these cells could provide a valuable platform for disease analysis and drug development. We found that DA neurons derived from G2019S-iPSCs showed increased expression of key oxidative stress-response genes and α-synuclein protein. The mutant neurons were also more sensitive to caspase-3 activation and cell death caused by exposure to stress agents, such as hydrogen peroxide, MG-132, and 6-hydroxydopamine, than control DA neurons. This enhanced stress sensitivity is consistent with existing understanding of early PD phenotypes and represents a potential therapeutic target.

Arabidopsis PPR40 connects abiotic stress responses to mitochondrial electron transport.

Oxidative respiration produces adenosine triphosphate through the mitochondrial electron transport system controlling the energy supply of plant cells. Here we describe a mitochondrial pentatricopeptide repeat (PPR) domain protein, PPR40, which provides a signaling link between mitochondrial electron transport and regulation of stress and hormonal responses in Arabidopsis (Arabidopsis thaliana). Insertion mutations inactivating PPR40 result in semidwarf growth habit and enhanced sensitivity to salt, abscisic acid, and oxidative stress. Genetic complementation by overexpression of PPR40 complementary DNA restores the ppr40 mutant phenotype to wild type. The PPR40 protein is localized in the mitochondria and found in association with Complex III of the electron transport system. In the ppr40-1 mutant the electron transport through Complex III is strongly reduced, whereas Complex IV is functional, indicating that PPR40 is important for the ubiqinol-cytochrome c oxidoreductase activity of Complex III. Enhanced stress sensitivity of the ppr40-1 mutant is accompanied by accumulation of reactive oxygen species, enhanced lipid peroxidation, higher superoxide dismutase activity, and altered activation of several stress-responsive genes including the alternative oxidase AOX1d. These results suggest a close link between regulation of oxidative respiration and environmental adaptation in Arabidopsis.

A new view on hypocortisolism

Low cortisol levels have been observed in patients with different stress-related disorders such as chronic fatigue syndrome, fibromyalgia, and post-traumatic stress disorder. Data suggest that these disorders are characterized by a symptom triad of enhanced stress sensitivity, pain, and fatigue. This overview will present data on the development, mechanisms and consequences of hypocortisolism on different bodily systems. We propose that the phenomenon of hypocortisolism may occur after a prolonged period of hyperactivity of the hypothalamic-pituitary-adrenal axis due to chronic stress as illustrated in an animal model. Further evidence suggests that despite symptoms such as pain, fatigue and high stress sensitivity, hypocortisolism may also have beneficial effects on the organism. This assumption will be underlined by some studies suggesting protective effects of hypocortisolism for the individual.

Enhanced effect of chronic stress on pregnancy outcome in Uje:WIST rats by prenatal treatment with lithium.

Female Uje:WIST rats were exposed to lithium (20 mmol LiCl/l drinking water, lithium levels about 1 mmol/l serum) for at least three weeks before mating and continuously up to the end of gestation. Female F1-offspring were raised without further treatment and mated at an age of 90-120 days with untreated males. The effect of chronic restraint stress during gestation on pregnancy outcome was estimated. Moderate changes (higher frequency of prolonged gestation, decreased body mass of the newborn pups) resembled those which were induced by considerably longer stress exposure (extended to the premating period) of prenatally untreated female Uje:WIST rats. An enhanced stress sensitivity following prenatal lithium treatment is discussed.

Substance P in Human Essential Hypertension

Summary: Substance P (SP) plays an important role in central nervous and peripheral blood pressure regulation. Its effects include modulating influence on the adrenergic system and inhibition of stress-induced plasma noradrenaline increase in animal studies. In patients with essential hypertension (n = 45, WHO stages 1 and 2) the SP-like immunoreactivity (SPLIR) was found significantly (p < 0.01) lower (1.36 ± 0.23 pg/100 μl) than in 24 normotensive subjects (4.54 ± 0.72 pg/100 μl). Furthermore, the influence of a mental stress test on SPLIR was investigated in patients with essential hypertension (n = 11, WHO stage 1) and compared with nine normotensive subjects. Whereas in normotensive subjects plasma SP increased under a standardized mental arithmetic test (4.03 ± 0.48 to 4.74 ± 0.56 pg/100 μl), in hypertensive patients a decrease of SP from lower baseline levels (2.85 ± 0.54 to 2.57 ± 0.54 pg/100 μl) was demonstrated. The significantly different changes of plasma SP in normotensive and hypertensive subjects under mental stress conditions had the opposite direction in comparison with the adrenergic reaction [higher and prolonged increase of plasma noradrenaline (NA) in the hypertensive group]. Under antihypertensive drug treatment with prazosin (4.5 mg/day, n = 10) or with captopril (450 mg/day, n = 10) an increase of plasma SP was registered. The results support the participation of SP in the pathogenesis of human hypertension and in therapeutic mechanisms. Lower plasma levels and decreased responsiveness of SP possibly represent the enhanced stress sensitivity in primary hypertension.

Substance P in Human Essential Hypertension

Substance P (SP) plays an important role in central nervous and peripheral blood pressure regulation. Its effects include modulating influence on the adrenergic system and inhibition of stress-induced plasma noradrenaline increase in animal studies. In patients with essential hypertension (n = 45, WHO stages 1 and 2) the SP-like immunoreactivity (SPLIR) was found significantly (p less than 0.01) lower (1.36 +/- 0.23 pg/100 microliters) than in 24 normotensive subjects (4.54 +/- 0.72 pg/100 microliters). Furthermore, the influence of a mental stress test on SPLIR was investigated in patients with essential hypertension (n = 11, WHO stage 1) and compared with nine normotensive subjects. Whereas in normotensive subjects plasma SP increased under a standardized mental arithmetic test (4.03 +/- 0.48 to 4.74 +/- 0.56 pg/100 microliters), in hypertensive patients a decrease of SP from lower baseline levels (2.85 +/- 0.54 to 2.57 +/- 0.54 pg/100 microliters) was demonstrated. The significantly different changes of plasma SP in normotensive and hypertensive subjects under mental stress conditions had the opposite direction in comparison with the adrenergic reaction [higher and prolonged increase of plasma noradrenaline (NA) in the hypertensive group]. Under antihypertensive drug treatment with prazosin (4.5 mg/day, n = 10) or with captopril (450 mg/day, n = 10) an increase of plasma SP was registered. The results support the participation of SP in the pathogenesis of human hypertension and in therapeutic mechanisms. Lower plasma levels and decreased responsiveness of SP possibly represent the enhanced stress sensitivity in primary hypertension.