Chronic social stress during adolescence in mice alters fat distribution in late life: prevention by antidepressant treatment

Obesity and visceral fat accumulation are key features of the metabolic syndrome that represents one of the main health problems in western societies due to its neurovascular and cardiovascular complications. Epidemiological studies have identified chronic stress exposure as an important risk factor for the development of obesity and metabolic syndrome, but also psychiatric diseases, especially affective disorders. However, it is still unclear if chronic stress has merely transient or potentially lasting effects on body composition. Here, we investigated the effects of chronic social stress during the adolescent period on body fat composition in mice one year after the cessation of the stressor. We found that stress exposure during the adolescent period decreases subcutaneous fat content, without change in visceral fat, and consequently increases the visceral fat/subcutaneous fat ratio in adulthood. Further, we demonstrated that treatment with a selective serotonin reuptake inhibitor (paroxetine) during stress exposure prevented later effects on body fat distribution. These results from a recently validated chronic stress paradigm in mice provide evidence that stressful experiences during adolescence can alter body fat distribution in adulthood, thereby possibly contributing to an increased risk for metabolic diseases. Antidepressant treatment disrupted this effect underlining the link between the stress hormone system, metabolic homeostasis and affective disorders.     

Chronic stress-induced alterations in mouse colonic 5-HT and defecation responses are strain dependent

Mood disorders and chronic stress are frequently associated with gastrointestinal (GI) symptoms including diarrhoea or constipation. Locally produced serotonin [5-hydroxytryptamine (5-HT)] regulates GI motility and is a key factor in the pathophysiology of stress-associated GI disorders. We aimed to establish whether chronic stress can differentially affect faecal output and colon 5-HT concentration in two inbred mouse strains: BALB/c and C57BL/6 which differ in their ability to cope with stress. Adult male BALB/c and C57BL/6 mice were restrained for 2?h daily for 10 days. Defecation was monitored during each stress session. Twenty-four hours after the last session of stress, plasma corticosterone concentration was higher than control in both strains, indicative of a physiological effect of chronic stress; however, stress-induced diarrhoea was more persistent in C57BL/6 mice. Basal concentration of colon 5-HT was higher in C57BL/6 mice, and stress elicited an increase in colon 5-HT only in this strain. Finally, na?ve BALB/c mice had a higher sensitivity (incidence of diarrhoea) to 5-HT (0.33?mg/kg, i.p.) than C57BL/6 mice. Our results suggest that differential defecation responses to stress may be associated with colon 5-HT concentration, which may in turn reflect the individual sensitivity to 5-HT. In addition, C57BL/6 mice emerge as a relevant model for studying GI alterations induced by chronic stress.     

Effects of chronic social stress during lactation on maternal behavior and growth in rats

Maternal mood disorders such as depression and chronic anxiety can negatively affect the lives of not only mothers, but also of partners, offspring, and future generations. Chronic exposure to psychosocial stress is common in postpartum mothers, and one of the strongest predictors of postpartum depression is social conflict. The objective of the current study was to evaluate the effects of chronic social stress (CSS) during lactation on the maternal behavior (which consists of maternal care and aggression toward a novel conspecific) of lactating rats, as well as on the growth of the dams and their offspring. It was hypothesized that chronic daily exposure to a novel male intruder would alter the display of maternal behavior and impair growth in both the dam and offspring during lactation due to the potentially disruptive effects on maternal behavior and/or lactation. The data indicate that CSS during lactation attenuates maternal care and the growth of both dams and pups, and increases self-grooming and maternal aggression toward a novel male intruder. These results support the use of CSS as a relevant model for disorders that impair maternal behavior and attenuate growth of the offspring, such as postpartum depression and anxiety.     

Chronic psychosocial stress increases the risk for inflammation-related colon carcinogenesis in male mice

Patients with inflammatory bowel diseases (IBDs) have a higher risk of developing colorectal cancer (CRC) than the general population. Furthermore, chronic psychosocial stress increases the likelihood of developing IBD and multiple types of malignant neoplasms, including CRC. Here, for the first time, we investigate the effects of chronic psychosocial stress in male mice on an artificially induced CRC, by employing the chronic subordinate colony (CSC) housing paradigm in combination with the reliable azoxymethane (AOM)/dextran sodium sulfate (DSS) CRC model. Colonoscopy revealed that CSC mice showed accelerated macroscopic suspect lesions. In addition, more CSC mice developed low-grade dysplasia (LGD) and/or high-grade dysplasia (HGD) in the colonic tissue compared to the single-housed control mice (SHC). CSC mice showed an increased number of Ki67+ and a decreased number of terminal deoxynucleotidyl transferase dUTP nick end labeling epithelial cells in colonic tissue. Colonic liver receptor homolog-1 (LRH-1), cyclooxygenase II (COXII), tumor necrosis factor, forkhead box P3 (FoxP3) mRNA as well as colonic ?-catenin, COXII, and LRH-1 protein expression were also increased in CSC compared with SHC mice. Although the number of CD4+ Th cells was increased, a tendency toward a decreased colonic interferon-γ (IFN-γ) mRNA expression was observed. Furthermore, despite an increased percentage of CD3+ cells and CD3+/FoxP3+ double-positive cells within mesenteric lymph node cells of CSC mice, IFN-γ secretion from these cells was unaffected. Altogether, our results suggest that chronic psychosocial stress increases the risk for AOM/DSS-induced and, thus, inflammation-related CRC. Finally, assessment of additional time points may test whether the shift from tumor-protective Th1 cell to regulatory T-cell immunity represents a consequence of increased carcinogenesis or a causal factor involved in its development.     

Effects of acute psychosocial stress exposure on endocrine and affective reactivity in college students differing in the 5-HTTLPR genotype and trait neuroticism

Enhanced stress vulnerability has been implicated in the pathogenesis of affective disorders. Although both genetic (5-HTTLPR) and cognitive (neuroticism) factors are known to increase stress vulnerability, no experimental study has investigated the interaction between these two factors on psychobiological reactivity following acute stress exposure. This study used a balanced experimental design to examine the interaction between the 5-HTTLPR genotype and trait neuroticism in neuroendocrine and affective stress responses. From a large group of 771 students, 48 carriers of the short/short (S/S) allele and 48 carriers of the long/long (L/L) allele with the lowest and the highest neuroticism scores (77 females, 19 males; mean age?±?SD: 20.6?±?2 years) were selected and exposed to an acute psychosocial stressor. Mood was assessed before and after the stressor, and salivary cortisol concentrations were measured before and at 20, 30, and 60?min after stressor onset. Acute stress increased salivary cortisol concentration regardless of either 5-HTTLPR genotype or neuroticism, but it caused a less profound negative mood change in L/L compared to S/S-allele carriers with the lowest neuroticism scores. The 5-HTTLPR genotype influences affective reactivity to acute stress conditional upon neuroticism, improving resilience to acute stress in L/L-allele carriers if they do not already possess high cognitive-affective (neuroticism) vulnerability.     

Effects of acute and chronic stress and of genotype on oxotremorine-induced locomotor depression of mice

The locomotor behavior of unstressed and stressed mice of two inbred strains, DBA/2 and C57/BL6, was investigated. Animals were tested in a toggle-floor box apparatus, 30 min after saline or oxotremorine treatment (ip). A dose of oxotremorine that did not depress the activity of na?ve mice (0.01 mg/kg) was chosen. Stressed mice were injected 24 h after either a single 2-h stress session (acute stress) or the last of 14 daily stress sessions of tube restraining (chronic stress). Acute stress did not modify the depressant effect of oxotremorine on locomotor behavior in either strain. On the contrary, chronic stress induced a clear sensitization of DBA but not C57 mice to the depressant effect of oxotremorine. These findings show that chronic stress may result in modifications of the cholinergic function, and its behavioral correlates, and that these changes are modulated by the genetic makeup.     

Pain‐induced aggression and changes in social behavior in mice

The effects of neuropathic, formalin, and acetic acid‐induced visceral pain were investigated on the social and aggressive behaviors in the Swiss male mice. Neuropathic pain was induced by tibial nerve transection (TNT). Also, somatic and visceral pain was conducted by intraplantar injection of diluted formalin (1%, 20 μl) and intraperitoneal administration of acetic acid (0.6%, 200 μl), respectively. Fourteen and twenty one days after the TNT surgery, and also, 1 and 7 days following formalin and acetic acid administration, the three‐chambered test was used to determine sociability and preference for social novelty and resident/intruder test was used for the evaluation of the aggressive behaviors. In the sociability phase of the three‐chambered test, all the three models of pain did not change the animal's sociability. However, in the social novelty preference phase, the animals in pain showed deficits in social novelty preference by a significant increase in the time spent with the familiar mice compared to the control groups. Also, animals in pain significantly showed more aggressive behaviors like biting and clinching and have much less attack latency in comparison to the control groups. Pain‐induced changes in the social novelty preference and aggressive behaviors continued in the neuropathic group until the end of the experiment. However, 7 days following the induction of both formalin and visceral pain, animals' social memory, and aggression almost returned to the standard value. These results suggest that long‐lasting pain could lead to social memory impairment and increase aggressive behaviors in mice.     

Permanent and transient effects of repeated preweaning stress on social and sexual behaviors of rats

We have reported that exposure of preweaning male and female rats to a model of unpredictable mild physical stressors (Neo-A) can decrease the behavioral and hormonal responses to acute and chronic stress as adults. In this paper we have analyzed the effect of Neo-A on development of social behaviors, including aggressiveness, social dominance, and sexual behavior in adulthood. The subjects were divided into two groups: Neo-A (daily exposed to unpredictable mild stresses- from day 2 up to day 15 of suckling; n = 30 litters) and controls (C) (undisturbed rats, except for testing, during the same period of life; n = 26 litters). When day 6 pups were submitted to a social clustering test the Neo-A group showed a higher rate of litter-mate clustering than C. The 35 days Neo-A males and Neo-A females submitted to a social behavior test after 24 h of social isolation also showed higher scores of time spent in active social interaction than controls, as well as a higher ratio of animals showing aggressive playing. A second social behavior test performed after 48 h of social isolation at days 75-80 of age revealed that only Neo-A females displayed increased social behavior and aggressive behaviors, whereas controls did not. A water competition test performed at 24 and 48 h after water deprivation showed that Neo-A adult males spent more time in possession of the drinking device and drank more frequently than C. When adult proestrous females were exposed to a sexual behavior test, the Neo-A group showed shorter latency and higher scores of lordosis quotient. These results support the view that exposure to this model of repeated mild stress early in life stimulates the development of social behavior, dominance and sexual behavior.     

Long-term effects of footshock and social defeat on anxiety-like behaviours in rats: Relationships to pre-stressor plasma corticosterone concentration

We compared the consequences of two stressors, 'unnatural' inescapable footshocks (IFSs) and 'natural' social defeat (SD), on behaviours typically sensitive to stress [sucrose preference, open field (OF), elevated plus maze (EPM) and acoustic startle responses (ASRs)] and the association with pre-stressor plasma corticosterone concentration. After initial blood sampling, rats (n?=?20 per group) were exposed to either 10 IFSs (1?mA intensity, 5?s duration each) or to 1?h SD (defeat by an aggressive resident male rat and further exposure but separated in a small cage) or to control procedures (handling). Rats were tested once for ASR (day 19), while the other behavioural tests were applied once weekly for 3 weeks. Both stress groups showed short-lasting lowered sucrose preference, and in the EPM they showed shorter total distance moved, shorter distance moved on open arms and less time on open arms compared to controls. In the OF test, IFS rats showed shorter total distance moved up to 2 weeks after stress. The SD group showed shorter total distance moved in the OF, which was only significant 2 weeks after stress. Low pre-stressor plasma corticosterone concentration was only associated with defecation (IFS rats) and latency to enter open arms in the EPM (all low corticosterone subgroups, n?=?10 per subgroup). SD rats with high initial plasma corticosterone concentration showed enhanced ASR compared to the other subgroups with high initial plasma corticosterone concentration (n?=?9 per subgroup). The results indicate that footshock and SD, while generally leading to an increase in anxiety behaviours, represent qualitatively different stressors.     

Immediate recall influences the effects of pre-encoding stress on emotional episodic long-term memory consolidation in healthy young men

The stress-associated activation of the hypothalamus-pituitary-adrenal axis influences memory. Several studies have supported the notion that post-learning stress enhances memory consolidation, while pre-retrieval stress impairs retrieval. Findings regarding the effects of pre-encoding stress, in contrast, have been rather inconsistent. In the current two studies, the impact of an immediate retrieval task on these effects was explored. In the first study, 24 healthy young male participants were exposed to a psychosocial laboratory stressor (Trier Social Stress Test) or a control condition before viewing positive, negative, and neutral photographs, which were accompanied by a brief narrative. Immediate as well as delayed (24?h later) free recall was assessed. Stress was expected to enhance emotional long-term memory without affecting immediate recall performance. Stress caused a significant increase in salivary cortisol concentrations but had no significant effects on immediate or delayed retrieval performance, even though a trend toward poorer memory of the stress group was apparent. Based on these findings, the second experiment tested the hypothesis that the beneficial effects of stress on emotional long-term memory performance might be abolished by an immediate recall test. In the second study (n?=?32), the same design was used, except for the omission of the immediate retrieval test. This time stressed participants recalled significantly more negative photographs compared to the control group. The present study indicates that an immediate retrieval attempt of material studied after stress exposure can prevent or even reverse the beneficial effects of pre-encoding stress on emotional long-term memory consolidation.     

The chronic psychosocial stress paradigm in male tree shrews: evaluation of a novel animal model for depressive disorders

To improve our knowledge of the causal mechanisms of stress-related disorders such as depression, we need animal models that mirror the situation in patients. One promising model is the chronic psychosocial stress paradigm in male tree shrews, which is based on the territorial behaviour of these animals that can be used to establish naturally occurring challenging situations under experimental control in the laboratory. Co-existence of two males in visual and olfactory contact leads to a stable dominant-subordinate relationship, with subordinates showing distinct stress-induced behavioural and neuroendocrine alterations that are comparable to the symptoms observed during episodes of depression in patients such as constantly elevated circulating glucocorticoid hormones due to a chronic hyperactivity of the hypothalamic-pituitary-adrenal axis. To elucidate whether the chronic psychosocial stress model in tree shrews besides its "face validity" for depression also has "predictive validity", we treated subordinate tree shrews with the tricyclic antidepressant clomipramine and found a time-dependent restoration of both endocrine and behavioural parameters. In contrast, the anxiolytic diazepam was ineffective. Although the chronic psychosocial stress model in tree shrews requires further validation, it has sufficient face, predictive, and construct validity to become an interesting non-rodent model for research on the etiology and pathophysiology of depression.     

Sleep deprivation impairs object recognition in mice

Many studies in animals and humans suggest that sleep facilitates learning, memory consolidation, and retrieval. Moreover, sleep deprivation (SD) incurred after learning, impaired memory in humans, mice, rats, and hamsters. We investigated the importance of sleep and its timing in an object recognition task in OF1 mice subjected to 6h SD either immediately after the acquisition phase (0-6 SD) or 6h later (7-12 SD), and in corresponding undisturbed controls. Motor activity was continuously recorded with infrared sensors. All groups explored two familiar, previously encountered objects to a similar extent, both at the end of the acquisition phase and 24h later during the test phase, indicating intact familiarity detection. During the test phase 0-6 SD mice failed to discriminate between the single novel and the two familiar objects. In contrast, the 7-12 SD group and the two control groups explored the novel object significantly longer than the two familiar objects. Plasma corticosterone levels determined after SD did not differ from time-matched undisturbed controls, but were significantly below the level measured after learning alone. ACTH did not differ between the groups. Therefore, it is unlikely that stress contributed to the memory impairment. We conclude that the loss of sleep and the activities the mice engaged in during the SD, impaired recognition memory retrieval, when they occurred immediately after acquisition. The delayed SD enabled memory consolidation during the 6h when the mice were allowed to sleep, and had no detrimental effect on memory. Neither SD schedule impaired object familiarity processing, suggesting that only specific cognitive abilities were sensitive to the intervention. Sleep may either actively promote memory formation, or alternatively, sleep may provide optimal conditions of non-interference for consolidation.     

Chronic illness and aggressive behaviour: A population-based study of 4-year-olds

The objective of this study was to examine the hypothesis that aggressive behaviour is explained by various medical conditions. The current study investigated this hypothesis in a population-based study of families with a 4-year-old child (n?=?1915). Maternal reports of child health and development were assessed and a paediatrician examined a subsample (n?=?263) with a chronic illness. Twice as many toddlers with a chronic physical disorder displayed aggressive behaviour when compared with toddlers without such disorders. All seven medical diagnostic categories included children with aggressive behaviour, but the highly prevalent condition of asthma contributed to more than a third of the cases with co-occurrence of chronic illness and aggressive behaviour. Neurological, sensory and skin/joint disorders accounted for another third. Subsequent analyses showed that poor language was an additional risk factor while attending day-care centres in groups with 5?–?15 children was a protective factor against aggressive behaviour.     

Juvenile stress potentiates aversive 22-kHz ultrasonic vocalizations and freezing during auditory fear conditioning in adult male rats

Traumatic experiences that occur during adolescence can render individuals vulnerable to mood and anxiety disorders. A model in juvenile rats (age: 27-29 days) was developed previously to study the long-term effects of adolescent stress exposure on behaviour and physiology. This paradigm, termed juvenile stress, involves subjecting juvenile rats to different stressors on consecutive days over a 3-day period. Here, we investigated the effects of the juvenile stress paradigm on freezing behaviour and aversive 22-kHz ultrasonic vocalizations (USVs) during auditory fear conditioning in adult male rats (age: 68-90 days). We found that rats previously subjected to juvenile stress increased aversive 22-kHz USVs (total calls and time spent calling) compared with controls during fear-conditioning training. The acoustic USV parameters between control and juvenile stress rats were largely equivalent, including duration, peak frequency and amplitude. While rats did not differ in freezing behaviour during fear conditioning, juvenile stress rats exhibited greater cue-conditioned freezing upon testing 24 h later. Our results show that juvenile stress elicited different long-term changes in freezing and aversive USVs during fear conditioning. Furthermore, they highlight the importance of assessing USVs to detect experience-dependent differences between control and stress-exposed animals which are not detectable by measuring visible behaviour.     

Post-traumatic Stress Disorder among child perpetrators and victims of violence from the Northern Uganda civil war: Findings from the WAYS study

War experiences are known risk factors for post-traumatic stress disorder (PTSD) and other poor psychosocial outcomes. This study aimed to assess the extent to which perpetrating violence (operationalised as intentional and unintentional killing or mutilation) and being a victim of violence (operationalised as being a victim of violence, e. g., witnessing violence, injuries, torture) predict PTSD and other psychosocial outcomes independently in war-affected youth of Northern Uganda. Data on war experiences, PTSD, psychosocial problems, and socio-demographic characteristics were collected from the youth formerly abducted by the Ugandan Lord’s Resistance Army (LRA) at baseline (mean age = 22.39 years; SD = 10.47) and at follow-up (mean age = 23.52 years; SD = 9.28) using self-report questionnaires. On average, the participants spent 3.13 years in captivity (SD = 2.99) and were abducted at 14.14 years of age (SD = 4.21). Regression models were fitted to predict PTSD and psychosocial outcomes from perpetrating violence controlling for being a victim of violence and demographic characteristics. Thirty-seven percent (n = 168) reported killing or being responsible for killing while in rebel captivity. After adjusting for being a victim of violence, perpetrating violence remained a statistically significant predictor of PTSD and poor psychosocial outcomes such as depression, anxiety, somatic complaints, psychotic symptoms, and conduct problems. Among war-affected youth returning from LRA captivity, perpetrating violence may just be as toxic a risk factor for PTSD and other psychosocial outcomes as being a victim of violence. Mental health workers should consider both the effects of being a victim of violence and perpetrating violence in treatment planning.     

The generality of cognitive bias in acute stress disorder

Cognitive bias was investigated in acutely traumatised civilians with either acute stress disorder (ASD; n = 26) or no ASD (n = 24). Participants completed the Acute Stress Disorder Interview, the Beck Depression Inventory, the Beck Anxiety Inventory (BAI), the Impact of Event Scale (IES), and an Event Probability Questionnaire and an Event Cost Questionnaire that comprised items pertaining to (a) external harm, (b) somatic sensations and (c) social events. ASD participants exaggerated both the probability of negative external harm, somatic and social events occurring, and the adverse cost of those events more than non-ASD participants. Elevated probability and cost estimates were predicted by BAI and IES-Avoidance scores, respectively. These findings are discussed in the context of different patterns observed in other anxiety disorders, and interpreted in terms of network theories of posttraumatic stress.     

5-羟色胺基因缺陷增强急性应激后高唤醒状态

剧烈的应激刺激会引起持续的高唤醒状态, 是多种应激障碍的核心症状, 并推进其他症状的发生发展。本研究关注5-羟色胺在应激诱发高唤醒的发生、发展中的作用, 通过测量听觉惊吓反射水平反映高唤醒状态, 考察色氨酸羟化酶-2基因缺陷小鼠在天敌或电击应激前后高唤醒的变化。研究发现, 雄性基因缺陷小鼠在应激后出现持续一周以上的高唤醒表现, 而野生型小鼠高唤醒状态很快恢复。结果提示, 基因缺陷引起的5-羟色胺降低可能是强应激诱发的持续高唤醒的易感因素。     

Chronic stress modulates the use of spatial and stimulus-response learning strategies in mice and man

Acute stress modulates multiple memory systems in favor of caudate nucleus-dependent stimulus-response and at the expense of hippocampus-dependent spatial learning and memory. We examined in mice and humans whether chronic stress has similar consequences. Male C57BL/6J mice that had been repeatedly exposed to rats ("rat stress") used in a circular hole board task significantly more often a stimulus-response strategy (33%) than control mice (0%). While velocity was increased, differences in latency to exit hole, distance moved or number of holes visited were not observed. Increased velocity and performance during retention trials one day later indicates altered emotionality and motivation to explore in rat stressed mice. Forty healthy young men and women were split into "high chronic stress" and "low chronic stress" groups based on their answers in a chronic stress questionnaire ("Trier Inventory of Chronic Stress"-TICS) and trained in a 2D task. A test trial immediately after training revealed that participants of the "high chronic stress" group used the S-R strategy significantly more often (94%) than participants of the "low chronic stress" group (52%). Verbal self-reports confirmed the strategy derived from participants' choice in the test trial. Learning performance was unaffected by the chronic stress level. We conclude that one consequence of chronic stress is the shift to more rigid stimulus-response learning, that is accompanied by changes in motivational factors in mice.     

Chronic stress and sex differences on the recall of fear conditioning and extinction

Chronic stress effects and sex differences were examined on conditioned fear extinction. Male and female Sprague–Dawley rats were chronically stressed by restraint (6 h/d/21 d), conditioned to tone and footshock, followed by extinction after 1 h and 24 h delays. Chronic stress impaired the recall of fear extinction in males, as evidenced by high freezing to tone after the 24 h delay despite exposure to the previous 1 h delay extinction trials, and this effect was not due to ceiling effects from overtraining during conditioning. In contrast, chronic stress attenuated the recall of fear conditioning acquisition in females, regardless of exposure to the 1 h extinction exposure. Since freezing to tone was reinstated following unsignalled footshocks, the deficit in the stressed rats reflected impaired recall rather than impaired consolidation. Sex differences in fear conditioning and extinction were observed in nonstressed controls as well, with control females resisting extinction to tone. Analysis of contextual freezing showed that all groups (control, stress, male, female) increased freezing immediately after the first tone extinction trial, demonstrating contextual discrimination. These findings show that chronic stress and sex interact to influence fear conditioning, with chronic stress impairing the recall of delayed fear extinction in males to implicate the medial prefrontal cortex, disrupting the recall of the fear conditioning acquisition in females to implicate the amygdala, and nonstressed controls exhibiting sex differences in fear conditioning and extinction, which may involve the amygdala and/or corticosterone levels.     

Psychological stress reactivates dextran sulfate sodium-induced chronic colitis in mice

Inflammatory bowel disease (IBD) is a chronic condition with alternating active and quiescent phases of inflammation. Stress has been suggested as a factor triggering a relapse of IBD. We investigated the role of repetitive psychological stress [water avoidance stress (WAS)] in reactivating colonic inflammation in a murine model of dextran sulfate sodium (DSS)-induced chronic colitis. Colitis was induced in C57BL/6 female mice by exposure to 3% DSS (5 days). During chronic inflammation(day 34), mice underwent repetitive WAS (1 h/day/7 days) and were given a sub-threshold concentration of DSS (1%, 5 days)or normal water to drink. At euthanasia (day 40), inflammatory parameters were assessed (colon inflammatory score, levels of inflammatory markers and histology). Mice with chronic colitis exposed to WAS had higher macroscopic and microscopic colonic inflammatory scores and levels of inflammatory markers (mainly IL-1beta, IL12p40 and CCL5) than non-stressed mice. Inflammatory responses were further enhanced by the presence of a sub-threshold concentration of DSS (1%). In mice without chronic inflammation, neither WAS nor 1% DSS, individually or in combination, elicited any inflammation. Hence stress, per se, reactivates a quiescent chronic inflammation, but does not initiate inflammation in healthy mice. Stress should be regarded as an environmental factor triggering IBD relapses in humans.