Robert Murison

Reduced fear expression after lesions of the ventral hippocampus

The hippocampus has a critical role in several fundamental memory operations, including the conditioning of fear to contextual information. We show that the hippocampus is necessary also for unconditioned fear, and that the involved circuitry is at the ventral pole of the hippocampus. Rats with selective hippocampal lesions failed to avoid open arms in an elevated plus-maze and had decreased neuroendocrine stress responses during confinement to a brightly lit chamber. These effects were reproduced by lesions of the ventral half of the hippocampus, but not by damage to the dorsal three-quarters of the hippocampus or the amygdala. Ventral lesions failed to impair contextual fear conditioning or spatial navigation, suggesting that the ventral hippocampus may specifically influence some types of defensive fear-related behavior.

Restraint stress in biomedical research: An update

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.

Effects of chronic mild stress on sexual behavior, locomotor activity and consumption of sucrose and saccharine solutions

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.

Intracerebroventricular neuropeptide Y suppresses open field and home cage activity in the rat

Effects of intracerebroventricular administration of neuropeptide Y on open field behaviour, behavioural habituation and corticosterone response to open field testing, and on home cage activity have been investigated in the rat. In the open field, NPY reduced activity in a dose-dependent manner. Behavioural habituation was not influenced. After 5 days of recovery, NPY-treated animals did not differ from non-treated in any of the measured parameters. Peripheral corticosterone levels were not significantly affected, although there was a strong tendency towards an increase. Injection of 2 nmol NPY did not produce any gross neurological deficits. At this dose, NPY greatly suppressed home cage activity. The effect lasted throughout the recording period of 22 h, abolishing the normal circadian variation in activity. After 5 days of recovery, the effect was no longer present. Our interpretation of these findings is, that NPY is a highly potent endogenous agent capable of producing certain important aspects of behavioural sedation in a reversible manner. Since NPY did not decrease the corticosterone response to a novel stimulus, its pattern of actions seems to differ from synthetic sedative drugs.

Chronic mild stress affects sucrose intake and sleep in rats.

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.

Association between childhood physical abuse and gastrointestinal disorders and migraine in adulthood.

Previous studies suggest that childhood physical abuse is a strong predictor of mental disorders during adulthood.1–5 An association between childhood abuse and increased use of medical services has also been documented,6 suggesting that childhood physical abuse is associated with poor health. In contrast, relatively little information is available on the link between childhood physical abuse and physical illness in adulthood. We examined the association between childhood physical abuse and the odds of gastrointestinal disorders and migraine headache among adults in the community. We hypothesized that childhood physical abuse would be associated with increased odds of gastrointestinal disorders and migraine headache during adulthood, and that this association would be independent of comorbid mental disorders.

Extracellular levels of serotonin and GABA in the hippocampus after chronic mild stress in rats. A microdialysis study in an animal 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 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.

The effect of sleep deprivation and recovery sleep on plasma corticosterone in the rat

The effect of 24-h sleep deprivation by forced locomotion on plasma corticosterone was investigated in the rat. Corticosterone was slightly elevated after 21.5 h sleep deprivation, but did not differ from controls after a 2.5-h recovery period. An acute 20-min forced locomotion period caused a marked rise in plasma corticosterone. It is concluded that stress is not a major factor contributing to the massive effects of sleep deprivation on sleep parameters.

The time dimension in stress responses: relevance for survival and health

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.

Coffee, stress and cortisol in nursing staff

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 health-related 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: wake-up 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.