According to cognitive activation theory, long-lasting work demands without rest or lack of copin... more According to cognitive activation theory, long-lasting work demands without rest or lack of coping may lead to sustained activation and pathology. Cortisol is one of the most important stress hormones in humans and increased basal levels of cortisol are considered a valid marker for sustained activation. In order to investigate this association further, we investigate the relationships between salivary cortisol profiles, job stress, work load (effort/reward, demand/control) and health (subjective health complaints and healthrelated quality of life) in a population of health care workers. Forty-four women filled in a questionnaire and collected five saliva samples on two consecutive working days (1: wakeup time, 2: wake-up time+30 min, 3: wake-up time+45 min, 4: 1500 h and 5: 2200 h). There was no relationship between psychosocial factors at work and cortisol levels in the morning (cortisol level at wake-up time and awakening cortisol response (ACR)). Only the confounding variable tobacco reached a significant level in the hierarchical regressions analyses. Our significant findings are limited to the afternoon decline and the evening values. The decrease during the day relates to decision authority, physical functioning, general health, and vitality in the single, unadjusted regression analyses. The decrease also relates to coffee intake, which we included originally as a confounding variable. In the final hierarchical regression of the evening values, only decision authority and coffee were significantly related to cortisol levels in the evening.
The Cognitive Activation Theory of Stress (CATS) offers formal and systematic definitions of the ... more The Cognitive Activation Theory of Stress (CATS) offers formal and systematic definitions of the terms and concepts used in stress research. The stress response depends on acquired expectancies to the outcome of the stimulus and the available responses. The stress response itself is an alarm, an increase in arousal necessary for performance and adequate reactions to challenges. The response is healthy and necessary for survival. Only when sustained over time may potential health risks occur. The basic rules for when stress occurs are the same across cultures and species, from fish to Olympic performance in humans. The important dimensions for health are positive expectancies of outcome (coping), control, and safety, for all individuals in all species. Q 2005 Published by Elsevier Ltd. Psychoneuroendocrinology (2005) 30, 933-938 www.elsevier.com/locate/psyneuen 0306-4530/$ -see front matter Q
Within the Cognitive Activation Theory of Stress (CATS), the stress response occurs whenever ther... more Within the Cognitive Activation Theory of Stress (CATS), the stress response occurs whenever there is a discrepancy between what the organism is expecting, and what really exists. It affects the biochemistry of the brain, mobilizes resources, affects performance, and endocrine, vegetative, and immune systems. Initial positive feedback and feed-forward mechanisms are gradually changed by homeostatic mechanisms. Slower reactive hormones such as cortisol seem to dampen the initial response. The time course may depend on psychological mechanisms. Subjects with efficient coping show the fast-and short-lasting catecholamine response, while subjects with high defense mechanisms (related to stimulus expectancies) may show more signs of prolonged activation. Non-coping individuals show a sustained general activation which may develop into somatic disease or illness. 0
Sexual abuse contributes to the development of multiple forms of psychopathology, including anxie... more Sexual abuse contributes to the development of multiple forms of psychopathology, including anxiety and depression, but the extent to which genetics contributes to these disorders among sexual abuse victims remains unclear. In this translational study, we first examined gene expression in the brains of rodents exposed to different early-life conditions (long, brief or no maternal separation). Hypothesizing that genes revealing changes in expression may have relevance for psychiatric symptoms later in life, we examined possible association of those genes with symptoms of anxiety and depression in a human sample of sexual abuse victims. Changes in rodent brain gene expression were evaluated by means of correspondence and significance analyses of microarrays by comparing brains of rodents exposed to different early-life conditions. Tag single-nucleotide polymorphisms (SNPs) of resulting candidate genes were genotyped and tested for their association with symptoms of anxiety and depression (Hospital Anxiety and Depression Scale) in a sample of 361 sexual abuse victims, using multinomial logistic regression. False discovery rate was applied to account for multiple testing in the genetic association study, with q-value of 0.05 accepted as significant. We identified four genes showing differential expression among animals subjected to different early-life conditions as well as having potential relevance to neural development or disorders: Notch1, Gabrr1, Plk5 and Zfp644. In the human sample, significant associations were observed for two NOTCH1 tag SNPs: rs11145770 (OR = 2.21, q = 0.043) and rs3013302 (OR = 2.15, q = 0.043). Our overall findings provide preliminary evidence that NOTCH1 may be implicated in the susceptibility to anxiety and depression among sexual abuse victims. The study also underscores the potential importance of animal models for future studies on the health consequences of early-life stress and the mechanisms underlying increased risk for psychiatric disorders.
h i g h l i g h t s CMS increases phosphorylation of eIF4E and eEF2 specifically in the prefronta... more h i g h l i g h t s CMS increases phosphorylation of eIF4E and eEF2 specifically in the prefrontal cortex. Sleep deprivation elevates eEF2 phosphorylation in all three brain regions. Prior CMS modulates the sleep deprivation effect on translation in the hippocampus. Sleep in healthy animals predicts changes in eIF4E and eEF2 phosphorylation in the PFC. Prior exposure to CMS abolishes relationship between sleep and translational activity.
Chronic stress is linked to development of depression and may trigger neurobiological changes und... more Chronic stress is linked to development of depression and may trigger neurobiological changes underlying the disease. Downregulation of the secretory peptide brain-derived neurotrophic factor (BDNF) and the transcriptional regulator calcium/cyclic-AMP responsive binding protein (CREB) have been implicated in stress and depression-related pathology in animal studies. When animals are exposed to the chronic mild stress (CMS) protocol, multiple depression-like symptoms are observed. Here we investigated the effect of CMS on BDNF protein expression and CREB activation in the dentate gyrus and hippocampus proper. Rats exposed for 5 weeks to repeated, unpredictable, mild stressors showed reduced BDNF expression and inhibited phosphorylation of CREB (Ser-133) in the dentate gyrus (-25.0%+/-3.5% and -29.7+/-7.3%, respectively), whereas no significant effects were observed in the hippocampus proper. CMS-treated rats consumed less sucrose compared to control rats, indicating a state of anhedonia. Moreover, phospho-CREB levels in the dentate gyrus were positively correlated with the animals' sucrose intake at the end of the CMS protocol. These results couple chronic mild stress to a downregulation of CREB activity and BDNF protein expression specifically within the dentate gyrus and support the possibility that the BDNF-CREB system plays an important role in the response to environmental challenges.
Gastric ulceration in rats is exacerbated by allowing a so-called recovery period after exposure ... more Gastric ulceration in rats is exacerbated by allowing a so-called recovery period after exposure to an ulcerogenic stressor. One hypothesis, which has support from pharmacological studies, argues that this effect is brought about by a rebound of parasympathetic activation. We tested this parasympathetic rebound hypothesis by presenting animals with a fear-inducing (sympathetic-activating) conditioned stimulus (CS) after 2 hr of water-restraint stress. Contrary to the hypothesis, presentation of such a CS increased severity of ulceration compared with those animals that did not receive the CS after restraint stress and control animals. These ulceration data favor instead a sustained activation hypothesis for ulceration, whereby presentation of the CS effectively prolonged the length of time during which animals were under stress, thus enhancing the degree of ulceration. Measurement of plasma corticosterone however indicated a negative correlation between adrenocortical activity and degree of gastric ulceration, contrary to that expected by a sustained activation hypothesis. It is suggested that this inconsistency may be because of the activating of a pituitary-endorphinogenic mediated stress analgesia.
Electric shocks are stressful and if signalled can result in Pavlovian conditioning of the stress... more Electric shocks are stressful and if signalled can result in Pavlovian conditioning of the stress response. Stress arising from such shocks or conditioned psychological ''threat'' influences vulnerability to gastrointestinal disorders. Reviewed are our studies with rats showing that unconditioned stress experiences sensitize the glandular portion of the stomach to later restraint-in-water induced erosions, as an animal model of ulcer disease. These stress effects are not attributable to corticoids but may be opioid/endorphin dependent. The unconditioned stress-induced sensitization is reduced by allowing the rat either control over or prediction of the shocks even though the direct experience with shocks is identical. Elicitation of the conditioned stress response by a signal during the ulcer induction or even shortly afterwards increases gastric vulnerability to erosions. We are now finding parallel unconditioned stress effects on colonic erosions and increases in intestinal permeability induced by dextran sulphate sodium, as an animal model of inflammatory bowel disease. We conclude that psychological context of past trauma and/or current threat increases vulnerability to gastrointestinal disorders. D
The aims of this preliminary study were to foster the development of an animal model of inflammat... more The aims of this preliminary study were to foster the development of an animal model of inflammatory bowel disease (IBD). We hereby studied the effects of dextran sulphate sodium (DSS) in drinking water on (a) intestinal permeability and (b) faecal levels of granulocyte marker protein (GMP) in rats. Methods were adopted to keep stress at a minimum. The animals had free access to DSS for 36 or 96 hrs. Controls received only water. Oral administration of 51 Cr-labelled ethylenediaminetetraacetic acid ( 51 CrEDTA) is used for clinical evaluation of intestinal permeability in IBD. 51 CrEDTA was administered by training the animals to drink a given quantity of fluid within 5 minutes in a specific environment. On the test day, they voluntarily consumed 1 ml water containing 2 µCi 51 CrEDTA. Urine samples were taken from filter paper in their home-cages for 6 hrs and radioactivity measured in a gamma counter. Faecal samples were collected after 36 and 96 hrs on DSS or water for GMP analysis. RESULTS: GMP was elevated in the DSSinduced animals after both 36 hrs (p<.05) and 96 hrs (p<.01), the elevation being greater after 96 hrs. Consumption of DSS increased the urinary excretion of 51 CrEDTA after 36 hrs, but not after 96 hrs. Only DSS consumption for 96 hrs resulted in visible colonic erosions in either the proximal, mid or distal part of the colon. CONCLUSION: DSS has an acute effect upon urinary excretion of 51 CrEDTA, and 96 hrs of access to DSS is sufficient to induce elevated GMP levels and colonic erosions in adult rats.
Deutsch, D, (19%), Motlwrs &lt;)nd tht-ir children hear a mLisicji illusion in slrikingly sim... more Deutsch, D, (19%), Motlwrs &lt;)nd tht-ir children hear a mLisicji illusion in slrikingly similar UMys. journal of the Aioustie:il Societii of .&#x27;\iiiei-iea, 99, 2482. IX&#x27;iitsch, D., Kuyper, VV.L.,&amp; i-islier, V. (l&#x27;-i87). The tntone paradox: Its pte^ii&#x27;iicc .iiid fiii-ni of dts-ti&#x27;JbuHon in a gener.il ...
Rats were stressed with (a) signaled footshocks, (b) unsignaled footshocks, or (c) handled withou... more Rats were stressed with (a) signaled footshocks, (b) unsignaled footshocks, or (c) handled without footshocks as a prepubertal juvenile (28-36 days old), as an adult (96 days old), or both. This yielded nine treatment groups (3 x 3). Two days after the adult treatment, all animals were challenged by restraint and partial immersion in water (19 °C) to assess their relative susceptibility to gastric erosions ("ulcers"). We found that any prior exposure to footshock stress increased the amount of ulcers; juvenile and adult experiences each produced equal increases but the combination of the two was less ulcerogenic than either alone. The predictability of the footshocks did nbt modulate ulccrogenicity. Adult corticosterone responses to (a) adult stress and (b) ulcer induction were not related to the observed ulcer severity; however, juvenile footshock stress appeared to reduce the corticoid response to the ulcerogenic challenge but not to the adult footshock stress.
Traumas have both immediate consequences and proactive consequences. Examples include learned hel... more Traumas have both immediate consequences and proactive consequences. Examples include learned helplessness, HPA-axis responsivity, gastrointestinal vulnerability to ulcer, and other correlates of anxiety disorders. Both immediate and proactive consequences may be modulated by behavioral and cognitive evolutionary evolved adaption processes, among which are forms of learning that enable &amp;amp;amp;amp;#39;coping&amp;amp;amp;amp;#39;. Examples of associative and non-associative forms of coping and effects on learned helplessness, HPA-axis responsivity, and gastrointestinal vulnerability are presented. The importance of attention to behavioral contingencies in situations in which potentially traumatic events occur is emphasized as critical to understanding that it is not the physical event(s) per se that determine the immediate and long term consequences.
The pioneering work of Brady&#x27; and Weiss&#x27; firmly established that the incidence ... more The pioneering work of Brady&#x27; and Weiss&#x27; firmly established that the incidence and seventy of gastrointestinal symptomatology in monkeys and rats are subject to psychological influences, even though their initial results were contradictory regarding the effects of ...
MURISON, R. AND J. B. OVERMIER. Some psychosomatic causal factors of restraint-in-water stress ul... more MURISON, R. AND J. B. OVERMIER. Some psychosomatic causal factors of restraint-in-water stress ulcers. PHYSIOL BEHAV 53(3) 577-581, 1993.--Rats were stressed by 75 min restraint in a tUbe suspended vertically while dry (19°C) or partially immersed in tanks of water at different temperatures (19, 27, 35°C), either in a conscious state or while under pentobarbital anesthesia. Restraint was followed by 75 min rest in the home cage and then sacrificed under halothane anesthesia. Assessment of the degree of gastric erosion indicated that restraint alone, whether the animal was rendered unconscious or not, was not sufficient to induce ulceration. However, in conscious animals, the addition of partial immersion did induce ulceration that was inversely related to the temperature of the water bath. This effect was not merely the result of brain stem and spinal reflex processes, because unconscious animals exposed to the most severe conditions (19°C) showed no ulceration.
We investigated the effect of prior acute stress on colonic permeability induced by a chemical ir... more We investigated the effect of prior acute stress on colonic permeability induced by a chemical irritant known to induce symptoms similar to inflammatory bowel disease in rodents. Adult male rats (n = 12) were stressed by a single session of ten unpredictable, uncontrollable foot shocks, and half were home cage controls (n = 12). Twenty-nine days later, half of each treatment group was exposed to 4% DSS (dextran sulphate sodium) solution in their drinking water for 48 hours while half received pure water over two periods separated by 17 days. After food deprivation overnight and light isoflurane anaesthesia the following morning, the animals were given a colonic infusion of 2000 nCi (nanocurie) 51CrEDTA (51Cr-labelled ethylenediaminetetraacetic acid) and then placed individually in metabolic cages for a six hours continuous urine collection. Radioactivity in urine was measured by a gamma counter and percentage recovery of 51CrEDTA calculated as an indicator of colonic mucosal permeability. Results concluded that pre-shocked animals exposed to DSS showed significantly higher mucosal permeability than the pre-shocked animals given water, and the non-shocked animals given either DSS or water. Pre-shock in combination with two exposures to a chemical irritant separated by 17 days had a pronounced effect on colonic permeability, indicating that stress should be considered a possible initiating or contributory factor to increased intestinal permeability related to a mucosal challenge.
The aim of the paper was to study the relationship between heart rate variability (HRV) and corti... more The aim of the paper was to study the relationship between heart rate variability (HRV) and cortisol release during cognitive challenging tasks. Forty-nine male naval cadets from the Royal Norwegian Naval Academy were administered computerised versions of attentional and working memory tests. The results from this study support the hypothesis of a negative correlation between HRV and cortisol secretion during cognitive tasks. Confirmation of the hypothesis with the low HRV group scoring higher on cortisol only during performance of cognitive tasks and recovery was also found. Furthermore, a replication of the previous findings of a negative association between cortisol levels and performance were supported when using uncorrected comparisons. None of the correlations survived Bonferonin corrections. The findings are discussed in relation to factors increasing HRV, thus improving tolerance to cognitive stress in onboard environments.
This paper reviews the history of the transition from the belief that gastrointestinal ulcers are... more This paper reviews the history of the transition from the belief that gastrointestinal ulcers are caused primarily by psychological factors to the current state of belief that they are caused primarily by infection and argues that neither is fully accurate. We argue that psychological factors play a significant role as predisposing to vulnerability, modulating of precipitation, and sustaining of gastric ulceration. We review data that challenge the assumption of a simple infectious disease model and adduce recent preclinical data that confirm the predisposing, modulatory, and sustaining roles for psychological factors. We note that others, too, are now challenging the adequacy of the contemporary simple bacterial infection model. We hope to replace the competition between psychology and medicine with cooperation in understanding and treating patients suffering gastric ulceration and ulcer.
Background and Objective: Early life adverse events may influence susceptibility/resistance to ch... more Background and Objective: Early life adverse events may influence susceptibility/resistance to chronic inflammatory diseases later in life by permanently dysregulating brain-controlled immune-regulatory systems. We have investigated the impact of infant-mother separation during early postnatal life on the severity of experimental periodontitis, as well as systemic stress and immune responses, in adulthood.
Material and Methods: Pups of periodontitis resistant Lewis rats were separated from their mothers for 3 h daily during postnatal days 2-14 (termed maternal deprivation; MD), separated for 15 min daily during the same time period (termed handling; HD), or left undisturbed. As adults, their behaviour was tested in a novel stressful situation, and ligature-induced periodontitis applied for 21 days. Two h before sacrifice all rats were exposed to a gram-negative bacterial lipopolysaccharide (LPS) challenge to induce a robust immune and stress response.
Results: Compared to undisturbed controls, MD rats developed significantly more periodontal bone loss as adults, whereas HD rats showed a tendency to less disease. MD and HD rats exhibited depression-like behaviour in a novel open field test, while MD rats showed higher glucocorticoid receptor (Gr) expression in the hippocampus, and HD rats had altered methylation of genes involved in the expression of hippocampal Gr. LPS provoked a significantly lower increase in circulating levels of the cytokine TGF-1β in MD and HD rats, but there were no significant differences in levels of the stress hormone corticosterone.
Conclusion: Stressful environmental exposures in very early life may alter immune responses in a manner that influences susceptibility/resistance to periodontitis.
Prolonged maternal separation in rats has several effects on health and behavior. Here we investi... more Prolonged maternal separation in rats has several effects on health and behavior. Here we investigated how maternal separation might interact with social stress in adulthood on behavior and gastrointenstinal permeability. The effects of either daily 180 min long term pup-dam separation (LMS) during the stress hyporesponsive period or daily 10 min brief maternal separation (BMS) on behavior, corticosterone and intestinal permeability were investigated, compared to a non-handling (NH) condition in male offspring. The animals from each separation condition were then randomly assigned to adult stress and control conditions, where the stress condition was exposure to 14 days of social instability (CSI). Sucrose preference, elevated plus maze behavior and corticosterone were measured. Colitis was experimentally induced by dextran sulfate sodium for 7 days, followed by measurement of intestinal permeability using the 51 CrEDTA method. Granulocyte marker protein was measured in feces and colons were examined histologically for inflammation. Prior to the social stress, the LMS offspring showed elevated corticosterone levels, lower elevated plus maze activity and less fluid consumption. After social stress, corticosterone levels were suppressed in LMS animals and again they showed less fluid consumption. LMS animals had significantly higher intestinal permeability, but only when also exposed to the social stress in adulthood. The current results support a two-hit model, whereby early life events interact with adult life events in altering animals' vulnerability.
The aims of this preliminary study were to foster the development of an animal model of inflammat... more The aims of this preliminary study were to foster the development of an animal model of inflammatory bowel disease (IBD). We hereby studied the effects of dextran sulphate sodium (DSS) in drinking water on (a) intestinal permeability and (b) faecal levels of granulocyte marker protein (GMP) in rats. Methods were adopted to keep stress at a minimum. The animals had free access to DSS for 36 or 96 hrs. Controls received only water. Oral administration of 51 Cr-labelled ethylenediaminetetraacetic acid ( 51 CrEDTA) is used for clinical evaluation of intestinal permeability in IBD. 51 CrEDTA was administered by training the animals to drink a given quantity of fluid within 5 minutes in a specific environment. On the test day, they voluntarily consumed 1 ml water containing 2 µCi 51 CrEDTA. Urine samples were taken from filter paper in their home-cages for 6 hrs and radioactivity measured in a gamma counter. Faecal samples were collected after 36 and 96 hrs on DSS or water for GMP analysis. RESULTS: GMP was elevated in the DSSinduced animals after both 36 hrs (p<.05) and 96 hrs (p<.01), the elevation being greater after 96 hrs. Consumption of DSS increased the urinary excretion of 51 CrEDTA after 36 hrs, but not after 96 hrs. Only DSS consumption for 96 hrs resulted in visible colonic erosions in either the proximal, mid or distal part of the colon. CONCLUSION: DSS has an acute effect upon urinary excretion of 51 CrEDTA, and 96 hrs of access to DSS is sufficient to induce elevated GMP levels and colonic erosions in adult rats.
According to cognitive activation theory, long-lasting work demands without rest or lack of copin... more According to cognitive activation theory, long-lasting work demands without rest or lack of coping may lead to sustained activation and pathology. Cortisol is one of the most important stress hormones in humans and increased basal levels of cortisol are considered a valid marker for sustained activation. In order to investigate this association further, we investigate the relationships between salivary cortisol profiles, job stress, work load (effort/reward, demand/control) and health (subjective health complaints and healthrelated quality of life) in a population of health care workers. Forty-four women filled in a questionnaire and collected five saliva samples on two consecutive working days (1: wakeup time, 2: wake-up time+30 min, 3: wake-up time+45 min, 4: 1500 h and 5: 2200 h). There was no relationship between psychosocial factors at work and cortisol levels in the morning (cortisol level at wake-up time and awakening cortisol response (ACR)). Only the confounding variable tobacco reached a significant level in the hierarchical regressions analyses. Our significant findings are limited to the afternoon decline and the evening values. The decrease during the day relates to decision authority, physical functioning, general health, and vitality in the single, unadjusted regression analyses. The decrease also relates to coffee intake, which we included originally as a confounding variable. In the final hierarchical regression of the evening values, only decision authority and coffee were significantly related to cortisol levels in the evening.
The Cognitive Activation Theory of Stress (CATS) offers formal and systematic definitions of the ... more The Cognitive Activation Theory of Stress (CATS) offers formal and systematic definitions of the terms and concepts used in stress research. The stress response depends on acquired expectancies to the outcome of the stimulus and the available responses. The stress response itself is an alarm, an increase in arousal necessary for performance and adequate reactions to challenges. The response is healthy and necessary for survival. Only when sustained over time may potential health risks occur. The basic rules for when stress occurs are the same across cultures and species, from fish to Olympic performance in humans. The important dimensions for health are positive expectancies of outcome (coping), control, and safety, for all individuals in all species. Q 2005 Published by Elsevier Ltd. Psychoneuroendocrinology (2005) 30, 933-938 www.elsevier.com/locate/psyneuen 0306-4530/$ -see front matter Q
Within the Cognitive Activation Theory of Stress (CATS), the stress response occurs whenever ther... more Within the Cognitive Activation Theory of Stress (CATS), the stress response occurs whenever there is a discrepancy between what the organism is expecting, and what really exists. It affects the biochemistry of the brain, mobilizes resources, affects performance, and endocrine, vegetative, and immune systems. Initial positive feedback and feed-forward mechanisms are gradually changed by homeostatic mechanisms. Slower reactive hormones such as cortisol seem to dampen the initial response. The time course may depend on psychological mechanisms. Subjects with efficient coping show the fast-and short-lasting catecholamine response, while subjects with high defense mechanisms (related to stimulus expectancies) may show more signs of prolonged activation. Non-coping individuals show a sustained general activation which may develop into somatic disease or illness. 0
Sexual abuse contributes to the development of multiple forms of psychopathology, including anxie... more Sexual abuse contributes to the development of multiple forms of psychopathology, including anxiety and depression, but the extent to which genetics contributes to these disorders among sexual abuse victims remains unclear. In this translational study, we first examined gene expression in the brains of rodents exposed to different early-life conditions (long, brief or no maternal separation). Hypothesizing that genes revealing changes in expression may have relevance for psychiatric symptoms later in life, we examined possible association of those genes with symptoms of anxiety and depression in a human sample of sexual abuse victims. Changes in rodent brain gene expression were evaluated by means of correspondence and significance analyses of microarrays by comparing brains of rodents exposed to different early-life conditions. Tag single-nucleotide polymorphisms (SNPs) of resulting candidate genes were genotyped and tested for their association with symptoms of anxiety and depression (Hospital Anxiety and Depression Scale) in a sample of 361 sexual abuse victims, using multinomial logistic regression. False discovery rate was applied to account for multiple testing in the genetic association study, with q-value of 0.05 accepted as significant. We identified four genes showing differential expression among animals subjected to different early-life conditions as well as having potential relevance to neural development or disorders: Notch1, Gabrr1, Plk5 and Zfp644. In the human sample, significant associations were observed for two NOTCH1 tag SNPs: rs11145770 (OR = 2.21, q = 0.043) and rs3013302 (OR = 2.15, q = 0.043). Our overall findings provide preliminary evidence that NOTCH1 may be implicated in the susceptibility to anxiety and depression among sexual abuse victims. The study also underscores the potential importance of animal models for future studies on the health consequences of early-life stress and the mechanisms underlying increased risk for psychiatric disorders.
h i g h l i g h t s CMS increases phosphorylation of eIF4E and eEF2 specifically in the prefronta... more h i g h l i g h t s CMS increases phosphorylation of eIF4E and eEF2 specifically in the prefrontal cortex. Sleep deprivation elevates eEF2 phosphorylation in all three brain regions. Prior CMS modulates the sleep deprivation effect on translation in the hippocampus. Sleep in healthy animals predicts changes in eIF4E and eEF2 phosphorylation in the PFC. Prior exposure to CMS abolishes relationship between sleep and translational activity.
Chronic stress is linked to development of depression and may trigger neurobiological changes und... more Chronic stress is linked to development of depression and may trigger neurobiological changes underlying the disease. Downregulation of the secretory peptide brain-derived neurotrophic factor (BDNF) and the transcriptional regulator calcium/cyclic-AMP responsive binding protein (CREB) have been implicated in stress and depression-related pathology in animal studies. When animals are exposed to the chronic mild stress (CMS) protocol, multiple depression-like symptoms are observed. Here we investigated the effect of CMS on BDNF protein expression and CREB activation in the dentate gyrus and hippocampus proper. Rats exposed for 5 weeks to repeated, unpredictable, mild stressors showed reduced BDNF expression and inhibited phosphorylation of CREB (Ser-133) in the dentate gyrus (-25.0%+/-3.5% and -29.7+/-7.3%, respectively), whereas no significant effects were observed in the hippocampus proper. CMS-treated rats consumed less sucrose compared to control rats, indicating a state of anhedonia. Moreover, phospho-CREB levels in the dentate gyrus were positively correlated with the animals&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; sucrose intake at the end of the CMS protocol. These results couple chronic mild stress to a downregulation of CREB activity and BDNF protein expression specifically within the dentate gyrus and support the possibility that the BDNF-CREB system plays an important role in the response to environmental challenges.
Gastric ulceration in rats is exacerbated by allowing a so-called recovery period after exposure ... more Gastric ulceration in rats is exacerbated by allowing a so-called recovery period after exposure to an ulcerogenic stressor. One hypothesis, which has support from pharmacological studies, argues that this effect is brought about by a rebound of parasympathetic activation. We tested this parasympathetic rebound hypothesis by presenting animals with a fear-inducing (sympathetic-activating) conditioned stimulus (CS) after 2 hr of water-restraint stress. Contrary to the hypothesis, presentation of such a CS increased severity of ulceration compared with those animals that did not receive the CS after restraint stress and control animals. These ulceration data favor instead a sustained activation hypothesis for ulceration, whereby presentation of the CS effectively prolonged the length of time during which animals were under stress, thus enhancing the degree of ulceration. Measurement of plasma corticosterone however indicated a negative correlation between adrenocortical activity and degree of gastric ulceration, contrary to that expected by a sustained activation hypothesis. It is suggested that this inconsistency may be because of the activating of a pituitary-endorphinogenic mediated stress analgesia.
Electric shocks are stressful and if signalled can result in Pavlovian conditioning of the stress... more Electric shocks are stressful and if signalled can result in Pavlovian conditioning of the stress response. Stress arising from such shocks or conditioned psychological ''threat'' influences vulnerability to gastrointestinal disorders. Reviewed are our studies with rats showing that unconditioned stress experiences sensitize the glandular portion of the stomach to later restraint-in-water induced erosions, as an animal model of ulcer disease. These stress effects are not attributable to corticoids but may be opioid/endorphin dependent. The unconditioned stress-induced sensitization is reduced by allowing the rat either control over or prediction of the shocks even though the direct experience with shocks is identical. Elicitation of the conditioned stress response by a signal during the ulcer induction or even shortly afterwards increases gastric vulnerability to erosions. We are now finding parallel unconditioned stress effects on colonic erosions and increases in intestinal permeability induced by dextran sulphate sodium, as an animal model of inflammatory bowel disease. We conclude that psychological context of past trauma and/or current threat increases vulnerability to gastrointestinal disorders. D
The aims of this preliminary study were to foster the development of an animal model of inflammat... more The aims of this preliminary study were to foster the development of an animal model of inflammatory bowel disease (IBD). We hereby studied the effects of dextran sulphate sodium (DSS) in drinking water on (a) intestinal permeability and (b) faecal levels of granulocyte marker protein (GMP) in rats. Methods were adopted to keep stress at a minimum. The animals had free access to DSS for 36 or 96 hrs. Controls received only water. Oral administration of 51 Cr-labelled ethylenediaminetetraacetic acid ( 51 CrEDTA) is used for clinical evaluation of intestinal permeability in IBD. 51 CrEDTA was administered by training the animals to drink a given quantity of fluid within 5 minutes in a specific environment. On the test day, they voluntarily consumed 1 ml water containing 2 µCi 51 CrEDTA. Urine samples were taken from filter paper in their home-cages for 6 hrs and radioactivity measured in a gamma counter. Faecal samples were collected after 36 and 96 hrs on DSS or water for GMP analysis. RESULTS: GMP was elevated in the DSSinduced animals after both 36 hrs (p<.05) and 96 hrs (p<.01), the elevation being greater after 96 hrs. Consumption of DSS increased the urinary excretion of 51 CrEDTA after 36 hrs, but not after 96 hrs. Only DSS consumption for 96 hrs resulted in visible colonic erosions in either the proximal, mid or distal part of the colon. CONCLUSION: DSS has an acute effect upon urinary excretion of 51 CrEDTA, and 96 hrs of access to DSS is sufficient to induce elevated GMP levels and colonic erosions in adult rats.
Deutsch, D, (19%), Motlwrs &lt;)nd tht-ir children hear a mLisicji illusion in slrikingly sim... more Deutsch, D, (19%), Motlwrs &lt;)nd tht-ir children hear a mLisicji illusion in slrikingly similar UMys. journal of the Aioustie:il Societii of .&#x27;\iiiei-iea, 99, 2482. IX&#x27;iitsch, D., Kuyper, VV.L.,&amp; i-islier, V. (l&#x27;-i87). The tntone paradox: Its pte^ii&#x27;iicc .iiid fiii-ni of dts-ti&#x27;JbuHon in a gener.il ...
Rats were stressed with (a) signaled footshocks, (b) unsignaled footshocks, or (c) handled withou... more Rats were stressed with (a) signaled footshocks, (b) unsignaled footshocks, or (c) handled without footshocks as a prepubertal juvenile (28-36 days old), as an adult (96 days old), or both. This yielded nine treatment groups (3 x 3). Two days after the adult treatment, all animals were challenged by restraint and partial immersion in water (19 °C) to assess their relative susceptibility to gastric erosions ("ulcers"). We found that any prior exposure to footshock stress increased the amount of ulcers; juvenile and adult experiences each produced equal increases but the combination of the two was less ulcerogenic than either alone. The predictability of the footshocks did nbt modulate ulccrogenicity. Adult corticosterone responses to (a) adult stress and (b) ulcer induction were not related to the observed ulcer severity; however, juvenile footshock stress appeared to reduce the corticoid response to the ulcerogenic challenge but not to the adult footshock stress.
Traumas have both immediate consequences and proactive consequences. Examples include learned hel... more Traumas have both immediate consequences and proactive consequences. Examples include learned helplessness, HPA-axis responsivity, gastrointestinal vulnerability to ulcer, and other correlates of anxiety disorders. Both immediate and proactive consequences may be modulated by behavioral and cognitive evolutionary evolved adaption processes, among which are forms of learning that enable &amp;amp;amp;amp;#39;coping&amp;amp;amp;amp;#39;. Examples of associative and non-associative forms of coping and effects on learned helplessness, HPA-axis responsivity, and gastrointestinal vulnerability are presented. The importance of attention to behavioral contingencies in situations in which potentially traumatic events occur is emphasized as critical to understanding that it is not the physical event(s) per se that determine the immediate and long term consequences.
The pioneering work of Brady&#x27; and Weiss&#x27; firmly established that the incidence ... more The pioneering work of Brady&#x27; and Weiss&#x27; firmly established that the incidence and seventy of gastrointestinal symptomatology in monkeys and rats are subject to psychological influences, even though their initial results were contradictory regarding the effects of ...
MURISON, R. AND J. B. OVERMIER. Some psychosomatic causal factors of restraint-in-water stress ul... more MURISON, R. AND J. B. OVERMIER. Some psychosomatic causal factors of restraint-in-water stress ulcers. PHYSIOL BEHAV 53(3) 577-581, 1993.--Rats were stressed by 75 min restraint in a tUbe suspended vertically while dry (19°C) or partially immersed in tanks of water at different temperatures (19, 27, 35°C), either in a conscious state or while under pentobarbital anesthesia. Restraint was followed by 75 min rest in the home cage and then sacrificed under halothane anesthesia. Assessment of the degree of gastric erosion indicated that restraint alone, whether the animal was rendered unconscious or not, was not sufficient to induce ulceration. However, in conscious animals, the addition of partial immersion did induce ulceration that was inversely related to the temperature of the water bath. This effect was not merely the result of brain stem and spinal reflex processes, because unconscious animals exposed to the most severe conditions (19°C) showed no ulceration.
We investigated the effect of prior acute stress on colonic permeability induced by a chemical ir... more We investigated the effect of prior acute stress on colonic permeability induced by a chemical irritant known to induce symptoms similar to inflammatory bowel disease in rodents. Adult male rats (n = 12) were stressed by a single session of ten unpredictable, uncontrollable foot shocks, and half were home cage controls (n = 12). Twenty-nine days later, half of each treatment group was exposed to 4% DSS (dextran sulphate sodium) solution in their drinking water for 48 hours while half received pure water over two periods separated by 17 days. After food deprivation overnight and light isoflurane anaesthesia the following morning, the animals were given a colonic infusion of 2000 nCi (nanocurie) 51CrEDTA (51Cr-labelled ethylenediaminetetraacetic acid) and then placed individually in metabolic cages for a six hours continuous urine collection. Radioactivity in urine was measured by a gamma counter and percentage recovery of 51CrEDTA calculated as an indicator of colonic mucosal permeability. Results concluded that pre-shocked animals exposed to DSS showed significantly higher mucosal permeability than the pre-shocked animals given water, and the non-shocked animals given either DSS or water. Pre-shock in combination with two exposures to a chemical irritant separated by 17 days had a pronounced effect on colonic permeability, indicating that stress should be considered a possible initiating or contributory factor to increased intestinal permeability related to a mucosal challenge.
The aim of the paper was to study the relationship between heart rate variability (HRV) and corti... more The aim of the paper was to study the relationship between heart rate variability (HRV) and cortisol release during cognitive challenging tasks. Forty-nine male naval cadets from the Royal Norwegian Naval Academy were administered computerised versions of attentional and working memory tests. The results from this study support the hypothesis of a negative correlation between HRV and cortisol secretion during cognitive tasks. Confirmation of the hypothesis with the low HRV group scoring higher on cortisol only during performance of cognitive tasks and recovery was also found. Furthermore, a replication of the previous findings of a negative association between cortisol levels and performance were supported when using uncorrected comparisons. None of the correlations survived Bonferonin corrections. The findings are discussed in relation to factors increasing HRV, thus improving tolerance to cognitive stress in onboard environments.
This paper reviews the history of the transition from the belief that gastrointestinal ulcers are... more This paper reviews the history of the transition from the belief that gastrointestinal ulcers are caused primarily by psychological factors to the current state of belief that they are caused primarily by infection and argues that neither is fully accurate. We argue that psychological factors play a significant role as predisposing to vulnerability, modulating of precipitation, and sustaining of gastric ulceration. We review data that challenge the assumption of a simple infectious disease model and adduce recent preclinical data that confirm the predisposing, modulatory, and sustaining roles for psychological factors. We note that others, too, are now challenging the adequacy of the contemporary simple bacterial infection model. We hope to replace the competition between psychology and medicine with cooperation in understanding and treating patients suffering gastric ulceration and ulcer.
Background and Objective: Early life adverse events may influence susceptibility/resistance to ch... more Background and Objective: Early life adverse events may influence susceptibility/resistance to chronic inflammatory diseases later in life by permanently dysregulating brain-controlled immune-regulatory systems. We have investigated the impact of infant-mother separation during early postnatal life on the severity of experimental periodontitis, as well as systemic stress and immune responses, in adulthood.
Material and Methods: Pups of periodontitis resistant Lewis rats were separated from their mothers for 3 h daily during postnatal days 2-14 (termed maternal deprivation; MD), separated for 15 min daily during the same time period (termed handling; HD), or left undisturbed. As adults, their behaviour was tested in a novel stressful situation, and ligature-induced periodontitis applied for 21 days. Two h before sacrifice all rats were exposed to a gram-negative bacterial lipopolysaccharide (LPS) challenge to induce a robust immune and stress response.
Results: Compared to undisturbed controls, MD rats developed significantly more periodontal bone loss as adults, whereas HD rats showed a tendency to less disease. MD and HD rats exhibited depression-like behaviour in a novel open field test, while MD rats showed higher glucocorticoid receptor (Gr) expression in the hippocampus, and HD rats had altered methylation of genes involved in the expression of hippocampal Gr. LPS provoked a significantly lower increase in circulating levels of the cytokine TGF-1β in MD and HD rats, but there were no significant differences in levels of the stress hormone corticosterone.
Conclusion: Stressful environmental exposures in very early life may alter immune responses in a manner that influences susceptibility/resistance to periodontitis.
Prolonged maternal separation in rats has several effects on health and behavior. Here we investi... more Prolonged maternal separation in rats has several effects on health and behavior. Here we investigated how maternal separation might interact with social stress in adulthood on behavior and gastrointenstinal permeability. The effects of either daily 180 min long term pup-dam separation (LMS) during the stress hyporesponsive period or daily 10 min brief maternal separation (BMS) on behavior, corticosterone and intestinal permeability were investigated, compared to a non-handling (NH) condition in male offspring. The animals from each separation condition were then randomly assigned to adult stress and control conditions, where the stress condition was exposure to 14 days of social instability (CSI). Sucrose preference, elevated plus maze behavior and corticosterone were measured. Colitis was experimentally induced by dextran sulfate sodium for 7 days, followed by measurement of intestinal permeability using the 51 CrEDTA method. Granulocyte marker protein was measured in feces and colons were examined histologically for inflammation. Prior to the social stress, the LMS offspring showed elevated corticosterone levels, lower elevated plus maze activity and less fluid consumption. After social stress, corticosterone levels were suppressed in LMS animals and again they showed less fluid consumption. LMS animals had significantly higher intestinal permeability, but only when also exposed to the social stress in adulthood. The current results support a two-hit model, whereby early life events interact with adult life events in altering animals' vulnerability.
The aims of this preliminary study were to foster the development of an animal model of inflammat... more The aims of this preliminary study were to foster the development of an animal model of inflammatory bowel disease (IBD). We hereby studied the effects of dextran sulphate sodium (DSS) in drinking water on (a) intestinal permeability and (b) faecal levels of granulocyte marker protein (GMP) in rats. Methods were adopted to keep stress at a minimum. The animals had free access to DSS for 36 or 96 hrs. Controls received only water. Oral administration of 51 Cr-labelled ethylenediaminetetraacetic acid ( 51 CrEDTA) is used for clinical evaluation of intestinal permeability in IBD. 51 CrEDTA was administered by training the animals to drink a given quantity of fluid within 5 minutes in a specific environment. On the test day, they voluntarily consumed 1 ml water containing 2 µCi 51 CrEDTA. Urine samples were taken from filter paper in their home-cages for 6 hrs and radioactivity measured in a gamma counter. Faecal samples were collected after 36 and 96 hrs on DSS or water for GMP analysis. RESULTS: GMP was elevated in the DSSinduced animals after both 36 hrs (p<.05) and 96 hrs (p<.01), the elevation being greater after 96 hrs. Consumption of DSS increased the urinary excretion of 51 CrEDTA after 36 hrs, but not after 96 hrs. Only DSS consumption for 96 hrs resulted in visible colonic erosions in either the proximal, mid or distal part of the colon. CONCLUSION: DSS has an acute effect upon urinary excretion of 51 CrEDTA, and 96 hrs of access to DSS is sufficient to induce elevated GMP levels and colonic erosions in adult rats.
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Papers by Robert Murison
Material and Methods: Pups of periodontitis resistant Lewis rats were separated from their mothers for 3 h daily during postnatal days 2-14 (termed maternal deprivation; MD), separated for 15 min daily during the same time period (termed handling; HD), or left undisturbed. As adults, their behaviour was tested in a novel stressful situation, and ligature-induced periodontitis applied for 21 days. Two h before sacrifice all rats were exposed to a gram-negative bacterial lipopolysaccharide (LPS) challenge to induce a robust immune and stress response.
Results: Compared to undisturbed controls, MD rats developed significantly more periodontal bone loss as adults, whereas HD rats showed a tendency to less disease. MD and HD rats exhibited depression-like behaviour in a novel open field test, while MD rats showed higher glucocorticoid receptor (Gr) expression in the hippocampus, and HD rats had altered methylation of genes involved in the expression of hippocampal Gr. LPS provoked a significantly lower increase in circulating levels of the cytokine TGF-1β in MD and HD rats, but there were no significant differences in levels of the stress hormone corticosterone.
Conclusion: Stressful environmental exposures in very early life may alter immune responses in a manner that influences susceptibility/resistance to periodontitis.
Material and Methods: Pups of periodontitis resistant Lewis rats were separated from their mothers for 3 h daily during postnatal days 2-14 (termed maternal deprivation; MD), separated for 15 min daily during the same time period (termed handling; HD), or left undisturbed. As adults, their behaviour was tested in a novel stressful situation, and ligature-induced periodontitis applied for 21 days. Two h before sacrifice all rats were exposed to a gram-negative bacterial lipopolysaccharide (LPS) challenge to induce a robust immune and stress response.
Results: Compared to undisturbed controls, MD rats developed significantly more periodontal bone loss as adults, whereas HD rats showed a tendency to less disease. MD and HD rats exhibited depression-like behaviour in a novel open field test, while MD rats showed higher glucocorticoid receptor (Gr) expression in the hippocampus, and HD rats had altered methylation of genes involved in the expression of hippocampal Gr. LPS provoked a significantly lower increase in circulating levels of the cytokine TGF-1β in MD and HD rats, but there were no significant differences in levels of the stress hormone corticosterone.
Conclusion: Stressful environmental exposures in very early life may alter immune responses in a manner that influences susceptibility/resistance to periodontitis.