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Biomedical subjects

J M Koolhaas

Publications and source records attributed to J M Koolhaas.

At least 19 recordsLinked to original sources
PubMed1999

A single social defeat transiently suppresses the anti-viral immune response in mice.

Most of the studies dealing with effects of stress on anti-viral immunity have been carried out with stressors that are of long duration and that bear little relationship to the nature of the species. In this paper, we investigated the effect of a stressor mimicking real-life situations more closely, being social defeat of male mice, on anti-viral immunity. A single social defeat was applied at 3 or 6 days after inoculation with pseudorabies virus, a herpes virus. It appeared that lymph node cellularity, virus specific IL-2 and IFN-gamma production and lymphocyte proliferation were suppressed at 1 day after defeat, but these parameters restored to control values quickly thereafter. We conclude that the stress of a single social defeat evokes a transient immune suppression, which might have consequences if a pathogenic or lethal virus is involved.

Animals↗
PubMed1999

Effects of mild stress on the immune response against pseudorabies virus in mice.

Stress is a recognised problem in intensive pig husbandry, which might lead to changes in immune reactivity. To study the effect of stress on the development of an anti-viral immune response, we used a murine model in which mice were immunized with an attenuated strain of pseudorabies virus (PRV). The effect of two stress treatments, both relevant to intensive pig husbandry, on the development of the specific immune response against PRV was investigated. The stress treatments consisted of restraint, social isolation, and transport and they differed in predictability. The specific immune response against PRV, which developed in the draining lymph nodes, was measured by a lymphocyte proliferation assay and cytokine production assays. Our results showed that the unpredictable stress treatment had no effect on the development of the immune response against PRV in mice, whereas the predictable stress treatment actually hastened the immune response.

Animals↗
PubMed1999

Housing familiar male wildtype rats together reduces the long-term adverse behavioural and physiological effects of social defeat.

Social stress in rats is known to induce long-lasting, adverse changes in behaviour and physiology, which seem to resemble certain human psychopathologies, such as depression and anxiety. The present experiment was designed to assess the influence of individual or group housing on the vulnerability of male Wildtype rats to long-term effects of inescapable social defeat. Group-housed rats were individually exposed to an aggressive, unfamiliar male conspecific, resulting in a social defeat. Defeated rats were then either individually housed or returned to their group. The changes in their behaviour and physiology were then studied for 3 weeks. Results showed that individually housed rats developed long-lasting, adverse behavioural and physiological changes after social defeat. Their body growth was significantly retarded (p < .05) between 7 and 14 days after defeat. When individually and group-housed rats were exposed to a mild stressor (sudden silence) 2 days after defeat, both groups became highly immobile. However, when exposure was repeated at day 21, individually housed rats were still highly immobile compared to group-housed rats which regained their normal mobility after only 7 days. In an open field test, also regularly repeated, individually housed rats took significantly longer to leave their home base and were also significantly less mobile than group-housed rats over the entire 3-week test period as well as at specific timepoints. When the rats were placed in an elevated plus-maze 14 days after defeat, those that were individually housed were significantly more anxious than those that were group-housed. When tested at 21 days after defeat in a combined dexamethasone (DEX)/corticotrophin-releasing factor (CRF) test, results showed that the hypothalamic-pituitary-adrenocortical (HPA) activity in individually housed rats was higher. This was evidenced in the latter animals by the fact that DEX was significantly less able to suppress the secretion of ACTH and corticosterone, and by a significantly higher release of ACTH after administration of CRF. Although the weights of the spleen and testes of the two groups did not differ, the adrenals of individually housed rats were larger and the thymus and seminal vesicles were smaller. We conclude that when rats are isolated after defeat, they show long-lasting, adverse behavioural and physiological changes that resemble symptoms of stress-related disorders. In contrast, when familiar rats are housed together these effects of a social defeat are greatly reduced. These findings show that housing conditions importantly influence the probability of long-term adverse behavioural and physiological effects of social defeat in male Wildtype rats.

Adrenal Cortex↗
PubMed1999

Selective antiaggressive effects of alnespirone in resident-intruder test are mediated via 5-hydroxytryptamine1A receptors: A comparative pharmacological study with 8-hydroxy-2-dipropylaminotetralin, ipsapirone, buspirone, eltoprazine, and WAY-100635.

The present study characterized the effects of the novel, selective, and potent 5-hydroxytryptamine1A (serotonin) (5-HT1A) receptor agonist, alnespirone [S-20499, (S)-N-4-[5-methoxychroman-3-yl)propylamino)butyl- 8-azaspiro-(4,5)-diacetamide, hydrochloride] on offensive and defensive resident-intruder aggression in wild-type rats and compared its actions with those of the prototypical full 5-HT1A agonist 8-hydroxy-2- dipropylaminotetralin (8-OH-DPAT), the partial 5-HT1A agonists ipsapirone and buspirone, and the mixed 5-HT1A/1B agonist eltoprazine. All five agonists exerted effective dose-dependent decreases of offensive aggressive behavior in resident rats; 8-OH-DPAT was the most potent (ID50 = 0.074 mg/kg), followed by eltoprazine (0.24), buspirone (0.72), ipsapirone (1.08), and alnespirone (1.24). However, in terms of selectivity of the antiaggressive effects as determined by the absence of decrements in social interest and general motor activity, alnespirone appeared to be superior. In the defensive aggression test, neither alnespirone nor any of the other four agonists changed defensive behaviors in the intruder rats. The involvement of 5-HT1A receptors in the antiaggressive actions of these drugs was confirmed by showing that the selective 5-HT1A receptor antagonist WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2- pyridinyl)cyclohexanecarboxamide trihydrochloride), which was inactive alone, fully prevented the antiaggressive effects of alnespirone, 8-OH-DPAT, and buspirone and partly reversed those of ipsapirone and eltoprazine. The data clearly indicate that alnespirone effectively suppresses offensive aggression with an advantageous profile of action compared with other full or partial 5-HT1A agonists. These selective antiaggressive actions of alnespirone are mediated by stimulating 5-HT1A receptors, presumably the somatodendritic autoreceptors at the raphe nuclei. Furthermore, the data provide evidence for a major involvement of these 5-HT1A receptors in the modulation of aggressive behavior by 8-OH-DPAT, ipsapirone, buspirone, and eltoprazine.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1999

Play is indispensable for an adequate development of coping with social challenges in the rat.

In this study, young rats were deprived of early social interactions during weeks 4 and 5 of life. Different behavioral tests were conducted in adulthood to study the behavioral responses of rats lacking early social experiences. Juvenile deprivation resulted in decreased social activity and an altered sexual pattern, but did not affect locomotor activity or the performance in the elevated plus maze. Furthermore, behavioral and neuroendocrine responses of juvenile isolated rats were dramatically altered when they were confronted with territorial aggression. Juvenile deprived rats did not readily display a submissive posture in response to the resident and showed no immobility behavior after being returned to the resident's territory, while their plasma corticosterone and adrenaline concentrations were significantly increased compared to nonisolated controls. In contrast, behavioral responses in the shock prod test were not affected by previous isolation. The results suggest that early social experiences are vital for interactions with conspecifics later in life, i.e., aggression, sexual, and social interactions.

Adaptation, Psychological↗
PubMed1998

Effects of strawbedding on physiological responses to stressors and behavior in growing pigs.

To study the effects of environmental enrichment on physiological responses to stressors and behavior in growing pigs, pigs were housed in either a poor environment (standard farrowing pens followed by standard rearing and fattening pens) or in an enriched environment (larger farrowing pens followed by larger rearing and fattening pens, provision of straw). Body temperature, heart rate and salivary cortisol were measured during baseline conditions and in response to relocation, isolation and restraint. Pigs housed in the poor environment performed more manipulative social behavior directed to penmates than pigs housed in the enriched environment. Physiological responses to the stressors were the same for enriched- and poor-housed pigs. Surprisingly, enriched-housed pigs had significantly higher baseline salivary cortisol concentrations, especially at 14 and 17 weeks of age. Moreover, enriched housed pigs had a lower baseline body temperature at 17 weeks of age. Thus, provision of straw has an effect on behavior, baseline HPA-axis activity and baseline body temperature in growing pigs.

Adrenal Glands↗
PubMed1998

Coping with stress in rats and mice: differential peptidergic modulation of the amygdala-lateral septum complex.

This chapter focuses on the parvicellular vasopressin (VP) system originating from the medial nucleus of the amygdala (MeA) and bed nucleus of the stria terminalis (BNST). The vasopressinergic fibers of these nuclei innervate a number of limbic brain areas including the septum-hippocampal complex. Interestingly, this VP system is sexually dimorphic and the VP synthesis in this system depends on circulating gonadal steroids. Studies in rats and mice show that the variation in the lateral septal VP network within the male gender is as large as the variation between the sexes as reported in the literature. Non-aggressive males are characterized by a far more extensive VP network and a higher VP content in the lateral septal area than aggressive males. A review of the literature on the function of lateral septal VP in the organization of behavior reveals not only a modulatory role of behavior in a social context, but also of fear- and anxiety-related behaviors. It is argued that these seemingly diverse functions might be explained by the concept of coping style. Extensive behavioral and physiological analyses in a variety of animal species show that males may be characterized by the way in which they cope with environmental challenges in general. Aggressive males tend to cope actively with their environment whereas non-aggressive males seem to accept the situation as it is more easily. In several tests, we determined the effects of chronic infusion of the V1 receptor antagonist locally into the lateral septal area in male rats. The main conclusion from these experiments is that LS VP does not modulate coping style in general. However, the experiments confirm the idea that LS VP has a certain degree of functional specificity in social behavior and social learning tasks. Together with the observation that the size and distribution of the vasopressinergic system may be highly variable between individual males in relation to their coping style, this suggests that the lateral septal vasopressinergic system is involved in the differential capacity of individuals to cope behaviorally with challenges of a social nature.

Adaptation, Psychological↗
PubMed1998

Behavioral and physiological consequences of repeated daily intracerebroventricular injection of corticotropin-releasing factor in the rat.

The present study was conducted to investigate the long-term consequences of repeated daily bolus injections of corticotropin-releasing factor (CRF) intracerebroventricularly (ICV) on ongoing locomotor activity and physiology in the home cage of individually housed rats. For this purpose ovine CRF (1 microgram/3 microliters) was injected once daily during the early resting phase into the lateral ventricle for a period of 10 days. Changes in daily rhythms in heart rate, body temperature and motor activity were recorded telemetrically before and during the treatment period. Daily central CRF injection delayed the body weight gain, increased adrenal weight, and decreased the weight of the thymus at the end of the experiment. The acute behavioral and physiological responses to CRF did not habituate with repetition of treatment. CRF treatment also failed to affect the long-term regulation of baseline heart rate, body temperature and motor activity during the light phase, as measured during the hour preceding the daily CRF injection. Mean heart rate during the dark phase was, however, significantly decreased in CRF-treated rats during the whole experimental 10-day period, without any sign of habituation. The failure of episodic CRF to affect long-term regulation of baseline body temperature during the light as well as the dark phase was noteworthy because an increased daytime body temperature lasting for several days is a characteristic marker of various behavioral stressors. Since a previous study showed that the temperature response during chronic CRF infusion was similar to the long-term effects of behavioral stress it is hypothesized that chronic but not episodic increases in central CRF levels are related to the induction and persistence of part of the stress-related behavioral and physiological disorders.

Animals↗
PubMed1998

Differential effects of CRH infusion into the central nucleus of the amygdala in the Roman high-avoidance and low-avoidance rats.

Roman-high (RHA/Verh) and low (RLA/Verh) avoidance rats are selected and bred for rapid learning versus non-acquisition of two-way, active avoidance behavior in a shuttle box. RHA/Verh rats generally show a more active coping style than do their RLA/Verh counterparts when exposed to various environmental challenges. The central nucleus of the amygdala (CeA) is known to be involved in the regulation of autonomic, neuroendocrine and behavioural responses to stress and stress-free conditions, and it is considered in relation to coping strategies. Corticotropin-releasing hormone (CRH) seems to be a key factor in the control of the CeA output. Neuroanatomical studies have revealed that the majority of CRH fibers from the CeA have direct connections with autonomic regulatory nuclei in the brainstem, e.g. lateral parabrachial nucleus (lPB), ventrolateral periaquaductal gray (vlPAG). The modulating effects of CRH (30 ng) on CeA activity were studied by infusion of CRH into the CeA in freely moving male RHA/Verh and RLA/Verh rats under stress-free conditions. Heart-rate and behavioural activities were repeatedly measured before, during and after local administration of CRH or vehicle, after which early gene product FOS immunocytochemistry and CRH-mRNA in situ hybridisation were carried out in selected brain areas. CRH infusion into the CeA caused a long lasting increase in heart-rate and behavioural activation in the RHA/Verh rats, leaving the RLA/Verh rats unaffected. As a result of CRH infusion, the number of FOS positive cells in the CeA and lPB of RLA/Verh rats was increased whereas an opposite response was found in the RHA/Verh rats. However, CRH into the CeA of the Roman rat lines induced no pronounced effects on FOS staining in the vlPAG and CRH mRNA levels in the CeA. These results indicate that the CRH system of the CeA, connected with the output brainstem areas, is differentially involved in cardiovascular and behavioural responses.

Adaptation, Psychological↗
PubMed1998

Vulnerability to arrhythmias during social stress in rats with different sympathovagal balance.

An increased activity of the sympathetic nervous system is an important factor in the genesis of ventricular arrhythmias. Changes in average R-R interval, R-R interval variability (indirect measure of sympathovagal balance), occurrence of arrhythmias, and plasma norepinephrine concentrations were measured during a social stress episode (defeat) in two strains of rats, Wistar and wild type, which were supposed to differ in their autonomic stress responsiveness. Electrocardiograms were telemetrically recorded, and blood samples were withdrawn through jugular vein catheters from healthy, freely moving animals. R-R interval variability was estimated by the following time-domain parameters: the standard deviation of the mean R-R interval, the coefficient of variance, and the root mean square of successive differences in R-R interval. Average R-R interval and R-R interval variability measures, as well as plasma norepinephrine concentrations, indicated a higher sympathetic tone, a larger sympathetic responsiveness, and a lower parasympathetic antagonism after sympathetic activation in wild-type animals, which also showed a much higher incidence of arrhythmias (ventricular premature beats), compared with Wistar rats. These two strains might represent a valuable experimental model for studying the mechanisms (cellular/electrophysiological) responsible for the susceptibility to arrhythmias in healthy individuals exposed to stressful situations.

Analysis of Variance↗
PubMed1997

Lateral septal vasopressin in rats: role in social and object recognition?

The capacity of male rats to remember familiar conspecifics is called social recognition. It is a form of short-term memory modulated by lateral septal (LS) vasopressin (VP). The specificity of this phenomenon was studied by examining whether recognition of previously investigated objects is also under control of lateral septal VP. For social recognition male Wistar rats were confronted with juveniles for 5 min. Re-exposure to the same juvenile took place after 30 or 120 min, or with a different juvenile after 30 min. This procedure was duplicated for object recognition using a plastic food cup or a 50 ml Erlenmeyer flask. After these initial tests osmotic minipumps and brain cannulae were implanted, infusing VP receptor antagonist into the LS (dPTyr(Et)AVP, 1 ng/0.5 microl/h, bilateral). Animals were re-tested for social and object recognition using 30 min re-test interval (same juvenile or object). We reproduced previous reports concerning social recognition; animals recognized juveniles after 30 min, not after 120 min and VP antagonist treatment blocked recognition. Testing for object recognition revealed a reduction in investigation time at the 30 min interval (same and different object), but not after 120 min. VP antagonist treatment was unable to block object recognition. The data suggest that, in contrast to social recognition, object recognition reflects a form of habituation, which is not under the control of lateral septal VP.

Animals↗
PubMed1997

Differential lateral septal vasopressin in wild-type rats: correlation with aggression.

The vasopressin (VP)-containing projections from the cells of the bed nucleus of the stria terminalis to the lateral septum (LS) are sexually dimorphic and dependent on gonadal steroids. Recently, the difference in VP distribution found among both sexes was also demonstrated in male mice genetically selected for different levels of intermale aggression. In the present study we examined whether this differential VP distribution in males also exists in an outbred strain of wild-type rats. After the animals were tested for their level of aggression, the VP content and the fiber density of the LS were measured using radioimmunoassay and immunocytochemistry, respectively. In addition, basal levels of plasma testosterone (T) were measured. Both biochemical data and immunocytochemical data revealed a negative correlation between VP and intermale aggression. Aggressive rats exhibited low levels of VP whereas intermediate and nonaggressive animals showed higher levels. Differences in adult levels of T were not found. The results are in accordance with the observations previously found in male mice, reconfirming the correlation between lateral septal VP and aggression.

Aggression↗
PubMed1997

The circadian rhythm of salivary cortisol in growing pigs: effects of age, gender, and stress.

This experiment was designed to examine circadian rhythmicity of cortisol in saliva of growing pigs, in relation to age, gender, and (time of) stressor application. Additionally, the acute cortisol response to a stressor was studied. Five groups, each consisting of 3 barrows and 3 gilts, were involved in the experiment. In a Control Group, saliva samples were taken at 1-h intervals at 12, 16, 20, and 24 weeks of age. Within 1 week, rhythmicity of cortisol was assessed during two 24-h spans (Monday and Friday). Rhythm characteristics were evaluated by cosinor analysis, describing the rhythm by several parameters. In 2 groups at 12 weeks and 2 other groups at 20 weeks of age, a stressor was applied (4 h of isolation) on Thursday morning or evening. Again, rhythmicity was assessed on Monday and Friday by sampling at 2-h intervals. Acute cortisol effects were studied by sampling at several time-points during isolation. Between 12 and 24 weeks of age, basal cortisol concentrations decreased and a rather stable and adult circadian rhythm was reached at 20 weeks of age. Average basal cortisol concentrations were higher in barrows than in gilts. Furthermore, after isolation, the amplitude of the rhythm was increased in barrows but was unchanged in gilts. The rhythm was more unstable and the maximum value tended to shift only after evening isolation. Stressor timing, but also age, was found to affect average cortisol concentrations. Moreover, stressor timing was important for the acute cortisol response: the increase was higher in the morning. The results of this study emphasize the importance of considering the circadian rhythmicity of cortisol, in relation to age, gender, and (time of) stressor application, when studying the cortisol response of animals to stressors.

Age Factors↗
PubMed1997

Nesting material as environmental enrichment has no adverse effects on behavior and physiology of laboratory mice.

Environmental enrichment may improve the quality of life of captive animals by altering the environment of animals so that they are able to perform more of the behavior that is within the range of the animal's species-specific repertoire. When enrichment is introduced into an animal's environment, it is important to evaluate the effect of the enrichment program and to assess whether the animal continues to use the enrichment in the long-term. Groups of mice were housed under either standard or enriched conditions for several weeks. Nesting material which was highly preferred in previous studies was used as enrichment. During the period of differential housing several behavioral parameters (behavioral tests and handling) and physiological parameters (urine and plasma corticosterone, food and water intake, body and adrenal weight) were monitored to determine the impact of environmental enrichment. Observations were made to determine whether or not the mice continued to use the enrichment. The results indicated that throughout the study all mice used the nesting material to build nests and that mice from enriched conditions weighed more than mice housed under standard conditions, although the latter consumed more food. No major differences for behavioral and physiological parameters were found between the groups of mice housed under different conditions. Therefore it is not likely that supply of nesting material will jeopardize the outcome of experiments.

Adrenal Glands↗
PubMed1997

The temporal dynamics of the stress response.

This paper summarises the available evidence that failure of defense mechanisms in (semi)-natural social groups of animals may lead to serious forms of stress pathology. Hence the study of social stress may provide animal models with a high face validity. However, most of the animal models of human stress-disorders have concentrated on the consequences of chronic exposure to stressors. The present paper considers recent data, indicating that a single experience with a major stressor in the form of social defeat may have long-term consequences ranging from hours to days and weeks. It seems that the experience of a major stressor sensitizes the animal to subsequent stressors. The consequences of these long-term temporal dynamics of the stress response to the development of stress-related disorders and stress-vulnerability are discussed.

Aggression↗
PubMed1997

Muscarinic acetylcholine receptor immunoreactivity in the amygdala--I. Cellular distribution correlated with fear-induced behavior.

This study examined the distribution of muscarinic acetylcholine receptor-immunoreactive neurons in the amygdaloid complex of the rat, with emphasis on the central nucleus. The monoclonal antibody M35 raised against purified muscarinic acetylcholine receptor protein was used to visualize muscarinic acetylcholine receptor-immunoreactive cells. Muscarinic acetylcholine receptor immuno-reactivity was high in the central nucleus and low to moderate in all other regions of the amygdaloid complex. Within the central nucleus, the muscarinic acetylcholine receptor-immunoreactive neurons were found predominantly in the lateral subdivision. This region contained medium-sized neurons (largest diameter ranging from 10 to 15 microns), with a round or slightly ovoid cell shape. At the subcellular level, however, the labeled neurons revealed relatively few muscarinic acetylcholine receptor-immunoreactive postsynaptic densities. Immunofluorescent double-labeling demonstrated that nearly all of the muscarinic acetylcholine receptor-immunoreactive neurons (98.6%) in the central nucleus expressed abundant amounts of nicotinic acetylcholine receptors, further substantiating the cholinoceptive character of these cells. In addition, the vast majority of these muscarinic acetylcholine receptor-immunoreactive neurons (94.3%) were GABAergic neurons. The muscarinic acetylcholine receptor-immunoreactive neurons expressed moderate levels of protein kinase gamma, one of the likely intracellular mediators between muscarinic acetylcholine receptors and their elicited physiological response. The number and staining intensity of muscarinic acetylcholine receptor-immunoreactive neurons in the central nucleus varied dramatically among rats. This individual variation correlated positively with the rat's expression of conditioned immobility and correlated negatively with active shock avoidance performance. These results suggest that the GABAergic/cholinoceptive neuronal elements in the central nucleus are involved in the expression of fear-induced behaviors. This interpretation is further elaborated in a forthcoming paper.

Amygdala↗
PubMed1997

Muscarinic acetylcholine receptor immunoreactivity in the amygdala--II. Fear-induced plasticity.

Changes in the distribution of muscarinic acetylcholine receptor-immunoreactive neurons were examined in the amygdaloid complex at different time-intervals following a single training session of active shock avoidance in a two-way shuttle-box. Muscarinic acetylcholine receptors were visualized using M35, a monoclonal antibody raised against purified muscarinic acetylcholine receptor protein. Both in naive animals and 2 h after active shock avoidance training, muscarinic acetylcholine receptor immunoreactivity was high in the central nucleus, and only low to moderate in other amygdaloid regions. Twenty-four hours after training, however, the muscarinic acetylcholine receptor immunoreactivity distribution pattern was reversed, showing a dramatic increase in the corticomedial nucleus, while in contrast, in other amygdaloid regions including the central nucleus, muscarinic acetylcholine receptor immunoreactivity was reduced to only a few scattered neurons. Additional studies with a modified experimental design indicated that fear conditioning mechanisms in association with the severity of the aversive stimuli, and not the learning of the avoidance response, may account for the changes in muscarinic acetylcholine receptor immunoreactivity in the amygdala. These results are consistent with the prominent role of the central nucleus in the conditioning and expression of the fear response. A closer examination revealed that 8 h after training the changes in both the central and corticomedial nuclei became significant. The differences still existed after 25 days, but three months after the training session the receptor distribution was returned to normal. The long-lasting, but reversible nature of these changes indicates that fear conditioning is accompanied by a dynamic plasticity of muscarinic acetylcholine receptor immunoreactivity in the amygdaloid complex.

Amygdala↗