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.     

Chronic restraint stress impairs T-cell immunity and promotes tumor progression in mice

Long-term exposure to stressful situations can affect the immune system. The T-cell response is an important component of anti-tumoral immunity. Hence, impairment of the immune function induced by a chronic stressor has been postulated to alter the immunosurveillance of tumors, thus leading to a worse neoplastic prognosis. Here, we show that chronic restraint stress affects T-cell mediated immunity in mice. This was evidenced by a decrease of mitogen-induced T-cell proliferation, a reduction in CD4(+)T lymphocyte number and a decrease of tumor necrosis factor-alpha (TNF-alpha) and Interferon-gamma (IFN-gamma) production in stressed mice. Additionally, mice subjected to chronic restraint stress displayed an enhancement of tumor growth in a syngeneic lymphoma model, i.e. an increase of tumor proliferation and a reduction of animal survival. Finally, stressed mice had a reduced specific cytotoxic response against these tumor cells. These results suggest that chronic exposure to stress promotes cancer establishment and subsequent progression, probably by depressing T-cell mediated immunity. The T-cell immunity impairment as well as the tumor progression enhancement emphasize the importance of the therapeutic management of stress to improve the prognosis of cancer patients.     

Chronic propranolol induces deficits in retention but not acquisition performance in the water maze in mice

Agents that alter adrenergic receptors, such as "beta-blockers," also alter memory storage. However, reports suggest that beta-adrenergic receptor antagonists, such as propranolol, have conflicting behavioral effects with acute vs chronic dosing. This study was designed to evaluate the effects of chronic propranolol on retention for a spatial learning task. Adult male ICR mice were given daily injections of propranolol (2, 4, 8, or 12 mg/kg ip) or 0. 9% NaCl for 15 days prior to, and during, trials in a Morris water maze. Mice received five massed acquisition (escape) trials in each of three daily sessions, followed by a single 60-s probe trial on the fourth day. The location of the submerged platform was constant for each animal over acquisition trials, but varied across animals; starting position varied across trials. A 5 (dose) x 3 (trial blocks) mixed factorial ANOVA for escape time yielded a significant trial blocks effect only (p <.001), showing performance improving over sessions. Time spent in the target quadrant on the probe trial was shorter under all doses of propranolol when compared to vehicle group (all p <.001), indicating poorer retention of prior platform location. This effect, however, was not dose-related. Swim speed was not significantly affected by propranolol. These data demonstrate that chronic dosing with propranolol can impair retention of spatial learning, which cannot be attributed to reduced arousal or motor function.     

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.     

Acute exercise: buffering psychosocial stress responses in women.

We evaluated the experimental hypothesis that an acute bout of aerobic exercise (AE) serves as a buffer to psychosocial stress responses in low to moderate physically fit women. Forty-eight (24 White, 24 Black) 25- to 40-year-old women participated in two counterbalanced experimental conditions: an attention control and a 40-min bout of AE at 70% heart rate (HR) reserve. The attention control and AE treatments were followed by (a) 30 min of quiet rest, (b) exposure to mental and interpersonal threat, and (c) 5 min of recovery. Blood pressure (BP) and HR were monitored at baseline, during the stressors, and throughout recovery. Self-reported distress was assessed before each stressor and upon completion of the recovery period. The results provided clear evidence that exercise dampens BP reactivity to psychosocial stress. Additionally, compared with the attention placebo control, AE reduced both the frequency and intensity of anxiety-related thoughts that occur in anticipation of interpersonal threat and challenge.     

Chronic psychosocial factors and acute physiological responses to laboratory-induced stress in healthy populations: a quantitative review of 30 years of investigations

This meta-analysis included 729 studies from 161 articles investigating how acute stress responsivity (including stress reactivity and recovery of hypothalamic-pituitary-adrenal [HPA] axis, autonomic, and cardiovascular systems) changes with various chronic psychosocial exposures (job stress; general life stress; depression or hopelessness; anxiety, neuroticism, or negative affect; hostility, aggression, or Type-A behavior; fatigue, burnout, or exhaustion; positive psychological states or traits) in healthy populations. In either the overall meta-analysis or the methodologically strong subanalysis, positive psychological states or traits were associated with reduced HPA reactivity. Hostility, aggression, or Type-A behavior was associated with increased cardiovascular (heart rate or blood pressure) reactivity, whereas anxiety, neuroticism, or negative affect was associated with decreased cardiovascular reactivity. General life stress and anxiety, neuroticism, or negative affect were associated with poorer cardiovascular recovery. However, regarding the sympathetic nervous system and parasympathetic nervous system, there were no associations between the chronic psychosocial factors and stress reactivity or recovery. The results largely reflect an integrated stress response pattern of hypo- or hyperactivity depending on the specific nature of the psychosocial background.     

Food deprivation induces conspecific pup-killing in mice

Periods of 24 to 48 hours of food deprivation reliably induced pup-killing in 30–50% of non-killer male mice. The behavior was prevented by previous experience with young and did not perseverate to non-deprived states. Castrated males and intact females also exhibited pup-killing following food deprivation, suggesting that the behavior is neither sexdependent nor related to the presence of testosterone. The findings are discussed in terms of their relationship to predatory behaviors and population dynamics.     

Severity of psychosocial stress and outcome of alcoholism treatment

We examined the relation between stressful life events and drinking outcome among 129 male alcoholics who had completed an alcohol treatment program. Life events were assessed for the year prior to treatment and for the 3 months after treatment and were rated on the Psychiatric Epidemiology Research Interview and the Contextual Rating System. Approximately 40% of the pretreatment stressors were found to be directly or indirectly related to alcohol use. When stressors related to drinking were excluded from consideration, we found that men who returned to drinking after treatment experienced more severe or highly threatening stress before their relapse than men who remained abstinent during the follow-up period. These data suggest that although less severe stress may not increase risk for relapse, acute severe stressors and highly threatening chronic difficulties may be associated with elevated relapse risk.     

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.     

Gender and ethnic differences in psychosocial stress and generalized distress among Hispanics

This study examined the relationship between gender, ethnicity, psychosocial stress and generalized distress in 593 Hispanic immigrants, Mexican Americans, and Anglo Americans using the Hispanic Stress Inventory (HSI) and the Center for Epidemiologic Studies Depression Scale (CES-D). Findings revealed that immigrant females had higher scores on the Cultural/Family Conflict sub-scale of the HSI and on the CES-D than immigrant males. Also, higher levels of generalized distress and psychosocial stress associated with the immigration process were found among immigrants from Central America when compared with Mexican immigrants. Central Americans' stress appraisal ratings on specific HSI items related to pre-migration trauma were significantly higher than the ratings of Mexican immigrants. Our findings indicate that research and clinical service delivery models must be sensitive to the vast heterogeneity within the Hispanic population with respect to differences in the experiences of psychosocial stress as related to gender and ethnicity.This project was partially supported by Grant USPHS MH24854 to the third author from the National Institute of Mental Health, Division of Biometry and Applied Science, Minority Research Resources Branch.     

Chronic stress,acute stress,and depressive symptoms

Although life events continue to be the major focus of stress research, recent studies suggest that chronic stress should be a more central focus. An evaluation of this issue is presented using data from a large community survey of married men (n = 819) and women (n = 936). Results show that chronic stresses are more strongly related to depressive symptoms than acute stresses in all but one life domain. The interaction patterns exhibited by chronic and acute stresses are predominantly associated with lower levels of depression than those predicted by a main effects model. This pattern suggests that chronic stresses may reduce the emotional effects of acute stresses. Although the processes through which this effect occurs are not clear, it is suggested that anticipation and reappraisal reduce the stressfulness of an event by making its meaning more benign. Implications for future research on chronic and acute stress effects are discussed.     

Systemic 5-bromo-2-deoxyuridine induces conditioned flavor aversion and c-Fos in the visceral neuraxis

5-bromo-2-deoxyuridine (BrdU) is often used in studies of adult neurogenesis and olfactory learning, but it can also have toxic effects on highly proliferative tissue. We found that pairing Kool-Aid flavors with acute systemic injections of BrdU induced strong conditioned flavor aversions. Intermittent injections during Kool-Aid-glucose conditioning interfered with learning of a conditioned flavor-nutrient preference. Acute injection of BrdU also elevated plasma corticosterone levels and induced c-Fos in the visceral neuraxis. Thus, acute or intermittent systemic injections of BrdU (50-200 mg/kg) have aversive effects that may interfere with learning.     

Chronic stress and depressive disorders in older adults

Current and lifetime rates of Diagnostic and Statistical Manual (rev. 3rd ed.) disorders were compared in 86 older adults caring for a spouse with a progressive dementia and 86 sociodemographically matched control subjects. Dementia caregivers were significantly more dysphoric than non-care givers. The frequencies of depressive disorders did not differ between groups in the years before care giving, and there were no group differences in first-degree relatives' incidence of psychiatric disorder. During the years they had been providing care, 30% of care givers experienced a depressive disorder (major depression, dysthymia, or depression not otherwise specified) versus 1% of their matched controls in the same time period. Only two care givers who met criteria during care giving had met criteria for a depressive disorder before care giving, and family history was not even weakly related to the identification of at-risk care givers. In contrast to these group differences in depressive disorders, there were no significant differences in other Axis I disorders either before or during care giving. Thus, the chronic strains of care giving appear to be linked to the onset of depressive disorders in older adults with no prior evidence of vulnerability.     

Neural bases of moderation of cortisol stress responses by psychosocial resources

Psychosocial resources have been tied to lower psychological and biological responses to stress. The present research replicated this relationship and extended it by examining how differences in dispositional reactivity of certain neural structures may underlie this relationship. Two hypotheses were examined: (a) psychosocial resources are tied to decreased sensitivity to threat and/or (b) psychosocial resources are associated with enhanced prefrontal inhibition of threat responses during threat regulation. Results indicated that participants with greater psychosocial resources exhibited significantly less cortisol reactivity following a stress task, as predicted. Analyses using functional magnetic resonance imaging revealed that psychosocial resources were associated with greater right ventrolateral prefrontal cortex and less amygdala activity during a threat regulation task but were not associated with less amygdala activity during a threat sensitivity task. Mediational analyses suggest that the relation of psychosocial resources to low cortisol reactivity was mediated by lower amygdala activity during threat regulation. Results suggest that psychosocial resources are associated with lower cortisol responses to stress by means of enhanced inhibition of threat responses during threat regulation, rather than by decreased sensitivity to threat.     

Chronic self-perceived stress and set-shifting performance in undergraduate students

Given recent findings on the potential for detrimental effects of chronic stress on the prefrontal cortex, additional research on the relationship between chronic stress and performance on executive functioning tasks (dependent on prefrontal functioning) is needed. Eighty-one undergraduate students completed a self-report measure of stress over the previous month (perceived stress scale--PSS) and the comprehensive trail-making test (CTMT, Trials 3 and 5). Results revealed a statistically significant positive correlation between PSS score and time needed to complete Trial 5 of the CTMT, which places demands on the set-shifting component of executive functioning. This finding adds to a growing body of work that suggests a relationship between chronic stress and executive functioning, and extends these findings to include set-shifting performance.     

Go no-go performance under psychosocial stress: beneficial effects of implementation intentions

Acute stress has been found to have negative and implementation intentions (IIs) to have positive effects on cognitive performance. This study was the first to examine the effects of IIs on executive action control under acute psychosocial stress. Forty-two male subjects aged 21-39 years were randomly assigned to the Trier Social Stress Test (TSST) versus a rest condition. In addition, the instruction to the executive task (a go no-go task) was manipulated (IIs versus standard instruction). After the stress test, a dual-task procedure including a go no-go task was conducted. The TSST resulted in increases in cortisol response, heart rate and state anxiety compared to the rest condition. Acute stress significantly impaired go no-go performance, but only in the group without IIs. We conclude that under acute stress conditions executive functioning is reduced, but the use of IIs can be an effective strategy to overcome this negative effect.     

Moderate psychosocial stress appears not to impair recall of words learned 4 weeks prior to stress exposure

Recent studies in humans have reported that recall of previously learned material is especially sensitive to the disruptive effects of pharmacologically induced cortisol elevations. Whether similar effects occur after exposure to psychosocial stress remains to be shown. Moreover it is unknown whether stress before or after the initial learning interacts with the later effects of repeated stress on delayed recall (e.g. state-dependent learning). Forty subjects participated in the present experiment. They learned a word list either one hour before or 10 min after exposure to a psychosocial laboratory stressor. Delayed recall was tested 4 weeks later, again either before or after stress. Salivary cortisol levels increased significantly in response to both stress exposures. Stress had no effects on the initial learning and also did not impair delayed recall. Moreover there was no evidence for state-dependent learning. The current data seem to be in conflict with previous studies demonstrating that delayed recall is especially sensitive to elevated cortisol levels. Several reasons for these discrepancies are discussed. Among them is the small sample size, the moderate cortisol increase in response to the second stress exposure but also the long recall delay, which might lead to memory traces less susceptible to stress.     

Automatic emotional information processing and the cortisol response to acute psychosocial stress

Attentional shifting may represent a means of regulating the stress response. Previously, automatic processing of emotional information was predictive of subsequent cortisol levels during a repeated loss stressor (Ellenbogen, Schwartzman, Stewart, & Walker, 2006). The stress induction did not, however, elicit a substantive cortisol increase. Thus, we sought to replicate this finding using the Trier Social Stress Test (TSST), a validated psychosocial stress induction. Seventy-nine students performed a modified spatial cuing task with supraliminal and masked pictorial stimuli during the TSST (n = 36) and a control condition (n = 43). The TSST elicited a greater cortisol response than did the control condition [F(1,76) = 4.6, p < .05]. Attentional shifting during trials with masked angry faces predicted cortisol change during the TSST (β = .76; t = 2.1, p < .05), but not during the control condition. These data suggest that early automatic emotional information processing is important in the regulation of the cortisol stress response, although the direction of effect is not known.     

Posttraumatic stress disorder and psychosocial functioning within two samples of MVA survivors

To examine criterion F variables of PTSD, the psychosocial functioning of two samples of motor vehicle accident (MVA) survivors was investigated. Within each sample, comparisons between MVA survivors with and without PTSD were conducted on four psychosocial functioning indices at three time points. In addition, the relationships between specific PTSD symptom clusters and psychosocial functioning indices were examined. The study revealed that, in general, MVA survivors with PTSD evidenced poorer psychosocial functioning than did survivors without PTSD. The emotional numbing symptoms of PTSD emerged as the most consistent predictors of the psychosocial functioning indices. The implications of these findings to the comprehensive treatment of PTSD are discussed.     

Strain-dependent modulation of memory by stress in mice

The effects of immobilization stress were investigated in Swiss Webster (Swiss), DBA/2 (DBA), and C57BL/6 (C57) mice, tested in a passive avoidance situation. Retention performance was impaired in Swiss and DBA mice, and improved in C57 mice, immobilized immediately, but not 2 hr, after training. These effects lasted for less than 7 days in DBA and Swiss mice, while they were still present, in the C57 strain, 14 days after training. The naloxone antagonism of the effects observed was also demonstrated. The results are discussed in terms of the possible role of endogenous opioids, stress hormones, and genetic makeup in the stress-induced modulation of memory processes in the mouse.