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    Robert Murison

    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... 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 to an ulcerogenic stressor. One hypothesis, which has support from pharmacological studies, argues that this effect is brought about by a... 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.
    Deutsch, D, (19%), Motlwrs <)nd tht-ir children hear a mLisicji illusion in slrikingly similar UMys. journal of the Aioustie:il Societii of .'\iiiei-iea, 99, 2482. IX'iitsch, D., Kuyper, VV.L.,& i-islier,... more
    Deutsch, D, (19%), Motlwrs <)nd tht-ir children hear a mLisicji illusion in slrikingly similar UMys. journal of the Aioustie:il Societii of .'\iiiei-iea, 99, 2482. IX'iitsch, D., Kuyper, VV.L.,& i-islier, V. (l'-i87). The tntone paradox: Its pte^ii'iicc .iiid fiii-ni of dts-ti'JbuHon in a gener.il ...
    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... 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 'coping'. 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' and Weiss' firmly established that the incidence and seventy of gastrointestinal symptomatology in monkeys and rats are subject to psychological influences, even though their initial results... more
    The pioneering work of Brady' and Weiss' 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 ...
    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... 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 caused primarily by psychological factors to the current state of belief that they are caused primarily by infection and argues that neither... 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 chronic inflammatory diseases later in life by permanently dysregulating brain-controlled immune-regulatory systems. We have investigated the... 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.
    Research Interests:
    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),... more
    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.
    The purpose of this study was to investigate the relationship between the startle response and ethanol. Aspects of the startle response, including initial and average startle, habituation, and prepulse inhibition (PPI) were studied. The... more
    The purpose of this study was to investigate the relationship between the startle response and ethanol. Aspects of the startle response, including initial and average startle, habituation, and prepulse inhibition (PPI) were studied. The startle response was measured to detect potential predictors of voluntary ethanol consumption and to observe whether ethanol ingestion would affect startle in subsequent tests. Rats were tested three times in a standard startle chamber. After the initial startle test, rats categorized as showing high or low PPI were allocated in a balanced way to a free-choice ethanol-water regime or to the water-regime control group. At the end of the ethanol period (lasting for 16 days, including access to ethanol for 10 days), the rats were tested again in the startle chamber 24 h after ethanol removal. After 5 weeks of ethanol abstinence, rats were exposed to a final startle test. The response to the first 120-dB stimulus showed an inverted U-shaped, curvilinear relationship to later ethanol consumption. Startle habituation appeared to have predictive value regarding ethanol consumption, with rats showing the most efficient habituation drinking most. Data showed no relationship between PPI and ethanol intake. Rats given access to ethanol showed greater habituation in the post-ethanol test than did the water controls. After 5 weeks of abstinence, low ethanol-consuming rats showed lower startle responses to the first 120-dB stimulus than did high ethanol-consuming rats. The present data suggest a two-way relationship between startle response characteristics and alcohol.
    The aim of the study was to investigate the effect of emotional stress on apical root resorption (ARR) and tooth displacement during orthodontic tooth movement in rats. A further area of interest was to evaluate if the expression of... more
    The aim of the study was to investigate the effect of emotional stress on apical root resorption (ARR) and tooth displacement during orthodontic tooth movement in rats. A further area of interest was to evaluate if the expression of interleukin-1 alpha (IL-1alpha) as well as the density and distribution of peptidergic nerve fibres immunoreactive to calcitonin gene-related peptide (CGRP) in the periodontal ligament (PDL) are associated with possible stress-induced changes in root resorption and tooth movement. A total of 52 male Wistar rats, aged 6 weeks, were divided in three experimental and one control group (n = 4). Group 1 had orthodontic tooth movement and received foot shocks (OTMS; n = 16), group 2 had orthodontic tooth movement but received no foot shocks (OTMNS; n = 16), and group 3 had no orthodontic tooth movement and received foot shocks (NOTMS; n = 16). Each group was further divided into four subgroups (n = 4), corresponding to the period of the experiment, i.e. 3, 7, 13, and 21 days. At the end of each experimental period, the blood samples were taken, the animals were sacrificed, and the jaws excised, deminerialized, and processed for immunocytochemistry. One-way analysis of variance was used to detect inter-group differences for all investigated variables. CGRP immunopositive nerve fibres were evaluated qualitatively. All the experimental groups demonstrated higher corticosterone levels than the control group, suggesting a stress-induced experience by orthodontic treatment per se. The OTMS group had the least amount of cellular cementum throughout the experimental periods and showed significant reduction in tooth displacement, especially at 3 and 7 days. No obvious changes were observed in the dental tissue expression of IL-1alpha and CGRP immunoreactive nerve fibres between the stressed and non-stressed orthodontically treated groups.
    The circadian system develops and changes in a gradual and programmed process over the lifespan. Early in life, maternal care represents an important zeitgeber and thus contributes to the development of circadian rhythmicity. Exposure to... more
    The circadian system develops and changes in a gradual and programmed process over the lifespan. Early in life, maternal care represents an important zeitgeber and thus contributes to the development of circadian rhythmicity. Exposure to early life stress may affect circadian processes and induce a latent circadian disturbance evident after exposure to later life stress. Disturbance of the normal regulation of circadian rhythmicity is surmised to be an etiological factor in depression. We used postnatal maternal separation in rats to investigate how the early life environment might modify the circadian response to later life unpredictable and chronic stress. During postnatal days 2-14, male Wistar rats (n = 8 per group) were daily separated from their mothers for a period of either 180 min (long maternal separation; LMS) or 10 min (brief maternal separation; BMS). In adulthood, rats were exposed to chronic mild stress (CMS) for 4 weeks. Body temperature, locomotor activity and heart rate were measured and compared before and after CMS exposure. LMS offspring showed a delayed body temperature acrophase compared to BMS offspring. Otherwise, adult LMS and BMS offspring demonstrated similar diurnal rhythms of body temperature, locomotor activity and heart rate. Exposure to CMS provoked a stronger and longer lasting hypothermia in LMS rats than in BMS rats. The thermoregulatory response appears to be moderated by maternal care following reunion, an observation made in the LMS group only. The results show that early life stress (LMS) in an early developmental stage induced a thermoregulatory disturbance evident upon exposure to unpredictable adult life stressors.
    Many symptoms of human depressive disorders are also observed in animals after exposure to unpredictable stressors. The chronic mild stress (CMS) paradigm was developed in order to better model the human situation by using chronic mild... more
    Many symptoms of human depressive disorders are also observed in animals after exposure to unpredictable stressors. The chronic mild stress (CMS) paradigm was developed in order to better model the human situation by using chronic mild stressors over a longer period. It is claimed that the model induces anhedonia in the animals, a core symptom of depression in humans. Despite the fact that the CMS model has a high degree of face validity, there are a number of laboratories in which the establishment of the model is less reliably observed. We have examined behavior (sexual activity and open field activity) together with hedonic measures (sucrose and saccharine intake) after exposure to CMS. CMS decreased male sexual activity (e.g. reduced capability to ejaculate) and increased activity in an open field test. The hedonic measures showed diverging results after CMS in our laboratory. Sucrose consumption was reduced, while saccharine consumption did not show a comparable change. It is concluded that CMS induces comparable alterations to some depression-like symptoms in humans. Saccharine consumption is not a reliable indicator of the hedonic responsiveness to CMS.
    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... 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.
    Depression in humans is associated with sleep abnormalities of three types: altered rapid eye movement (REM) sleep, fragmented sleep, and reduced delta sleep. In an animal model of depression, chronic exposure to mild stressors (CMS, e.g.... more
    Depression in humans is associated with sleep abnormalities of three types: altered rapid eye movement (REM) sleep, fragmented sleep, and reduced delta sleep. In an animal model of depression, chronic exposure to mild stressors (CMS, e.g. periods of soiled cage, reversed light/dark cycle, grouped housing, food and/or water deprivation) causes behavioral and hormonal changes which, in humans, often are associated with depression. In the CMS model, a reduced sucrose intake has been defined as one of the core symptoms of depression, anhedonia, although this finding is not consistent among various laboratories. In the present study, we investigated if the CMS procedure, in our laboratory, would cause decreased sucrose intake and, also, give sleep changes similar to what is found in depressed patients.Exposure to CMS decreased sucrose intake in our rats. The largest effect was obtained after 2 weeks of the stress protocol. CMS rats spent more time in REM sleep and showed more fragmented sleep compared to their baseline recording, while there were no changes in the control rats. Increased sleep fragmentation in CMS rats was particularly evident by increased number of arousals, and increased REM sleep and slow-wave-sleep-1 (SWS-1) episodes. The duration of sleep stage episodes was decreased. The amount of slow-wave-sleep-2 (SWS-2) was not decreased, however SWS-2 in percent of total SWS was reduced. Correlation analysis showed that animals that had less consumption of sucrose spent more time in REM sleep and had increased number of REM sleep episodes. In this study, CMS appears to be a model of depression.
    One of the most established hypotheses of depression focuses on alteration of the serotonergic (5-HT) function. Recent evidence suggests that serotonergic involvement in depression may be modulated by the action of gamma-hydroxybutyric... more
    One of the most established hypotheses of depression focuses on alteration of the serotonergic (5-HT) function. Recent evidence suggests that serotonergic involvement in depression may be modulated by the action of gamma-hydroxybutyric acid (GABA). Furthermore, altered GABAergic function is also evident in depressed patients and in animal models of depression. Disturbed sleep is characteristic of patients with mood disorders. The most pronounced changes of the 5-HT firing activity occur during sleep. Hence, the present paper reports a study on simultaneously measurement of hippocampal levels of serotonin and GABA during waking and sleep in the chronic mild stress (CMS) animal model of depression. The neurotransmitter findings are accompanied by depression-like symptoms (e.g. sleep alterations and reduced sucrose intake, a putative indicator of anhedonia in rodents). Our results show that animals exposed to CMS had lower hippocampal GABA levels compared to controls. In addition, after CMS there was a lack of 5-HT stage-dependency. A subgroup (five out of eight animals) showed a consistent increase in 5-HT levels in slow wave sleep and REM sleep. We also observed that this increase occurred in those animals regarded as most anhedonic (lowest intake of sucrose solution). Moreover, REM sleep was positively correlated with anhedonia. No interaction between 5-HT and GABA was found in the hippocampus. The data suggest that both GABAergic and serotonergic systems may be simultaneously but independently involved in depression. The alteration in 5-HT function may represent a link between depression-like behaviour and sleep abnormalities found in depressed patients.
    Social defeat, resulting from the fight for a territory is based on the resident–intruder paradigm. A male rat intruder is placed in the territory of an older, bigger and more aggressive male resident and is defeated. In the present... more
    Social defeat, resulting from the fight for a territory is based on the resident–intruder paradigm. A male rat intruder is placed in the territory of an older, bigger and more aggressive male resident and is defeated. In the present study, a double exposure to social defeat increased sleep fragmentation due to an increased amount of waking and slow-wave-sleep-1 (SWS-1) episodes. Also, social defeats increased the amount of slow-wave-sleep-2 (SWS-2). In repeated exposures to an open field, socially defeated rats showed low central activity and persistent defecation indicating high emotionality. The strongest effects of social defeat on sleep and open field behaviour were seen sub-chronically after stress. Social defeat did not induce changes in rapid eye movement (REM) sleep (e.g. total amount, latency), sleep latency, sexual activity, body weight or adrenal weight. A negative correlation between habituation in open field central activity and total sleep fragmentation indicates a commonality of effects of social defeat on both behaviour and sleep.
    Since the publication of our initial review of restraint stress in 1986, much work has continued with this technique, either as a tool for the investigation of other pharmacological, physiological, or pathologic phenomena or with... more
    Since the publication of our initial review of restraint stress in 1986, much work has continued with this technique, either as a tool for the investigation of other pharmacological, physiological, or pathologic phenomena or with restraint stress itself serving as the object of the study. As we noted in 1986, the major use of restraint has been for the induction of stress responses in animals and, more specifically, for the investigation of drug effects, particularly as they affect typical stress-related pathology--gastrointestinal, neuroendocrine, and immunological agents have been extensively studied. In compiling this update on restraint stress and its effects, we noted an increasing emphasis on central nervous system mechanisms in peripheral disease, especially gastrointestinal disease. In particular, many CNS-active agents have been tested for their effects on gastric and duodenal lesion formation and gastric secretion, including antidepressants, antipsychotics, anxiolytics, noradrenergic, serotonergic, dopaminergic, and peptidergic compounds. Some of these agents are especially active in the gastrointestinal tract even when administered centrally, further solidifying the concept of a brain-gut axis. The present update includes studies of: methods and procedures, pre-restraint manipulations, post-restraint/healing effects, and drug effects. In addition, a current bibliography of reports that have employed restraint is included.

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