Biomedical subjects

J M Koolhaas

Publications and source records attributed to J M Koolhaas.

At least 19 recordsLinked to original sources

PubMed2004

Bidirectional shift in the cornu ammonis 3 pyramidal dendritic organization following brief stress.

The negative impact of chronic stress at the structure of apical dendrite branches of cornu ammonis 3 (CA3) pyramidal neurons is well established. However, there is no information available on the CA3 dendritic organization related to short-lasting stress, which suffices to produce long-term habituation or sensitization of anxiety behaviors and neuroendocrine responses. Here, we tested the effects evoked by brief stress on the arrangements of CA3 pyramidal neuron dendrites, and the activity-dependent properties of the commissural-associational (C/A) excitatory postsynaptic potentials (EPSPs). Adult male rats were socially defeated followed by 3 weeks without further treatment or as comparison exposed to a regimen of a social defeat every second day for the same time period. We assessed CA3 pyramidal neurons with somatic whole-cell recording and neurobiotin application in acute hippocampal slices. The results from morphometric analysis of post hoc reconstructions demonstrated that CA3 dendrites from repeatedly stressed rats were reduced in surface area and length selectively at the apical cone (70% of control, approximately 280 microm from the soma). Brief stress, however, produced a similar decrease in apical dendritic length (77% of control, approximately 400 microm from the soma), accompanied by an increased length (167% of control) and branch complexity at the basal cone. The structural changes of the dendrites significantly influenced signal propagation by shortening the onset latency of EPSPs and increasing input resistance (r=0.45, P<0.01), of which the first was significantly changed in repeatedly stressed animals. Both brief and repeated stress long-lastingly impaired long-term potentiation of C/A synapses to a similar degree (P<0.05). These data indicate that the geometric plasticity of CA3 dendrites is dissociated from repetition of aversive experiences. A double social conflict suffices to drive a dynamic reorganization, by site-selective elimination and de novo growth of dendrite branches over the course of weeks after the actual experience.

Adrenal Glands↗

PubMed2004

Long-term effects of husbandry procedures on stress-related parameters in male mice of two strains.

In socially unstable groups of male laboratory mice, individuals may experience a chronic stress situation. Previous experiments have shown that the transfer of specific olfactory cues during cage cleaning, and the provision of nesting material decrease aggression and stress in group-housed male mice. In this study, the combined effect of these husbandry procedures were tested for their long-term effect on stress in groups of moderately aggressive (BALB/c) and severely aggressive (CD-1) male mice. The physiological and behavioural stress-related parameters used were body weight, food and water intake, spleen and thymus weight, adrenal tyrosine hydroxylase activity, urine corticosterone levels and behaviour in a cage emergence test. Long-term provision of nesting material and its transfer during cage cleaning was found to influence several stress-related physiological parameters. Mice housed in cages enriched with nesting material had lower urine corticosterone levels and heavier thymuses, and they consumed less food and water than standard-housed mice. Furthermore, marked differences were found between strains. CD-1 mice were less anxious in the cage emergence test, weighed more, ate and drank more, and had heavier thymuses but lighter spleens and lower corticosterone levels than BALB/c mice. We conclude that the long-term provision of nesting material, including the transfer of nesting material during cage cleaning, reduces stress and thereby enhances the welfare of laboratory mice.

Agonistic Behavior↗

PubMed2003

Fecal corticosteroids in a territorial bird selected for different personalities: daily rhythm and the response to social stress.

In this study we tested the hypothesis that in a passerine bird (great tit, Parus major) individuals differing for coping strategies differ in the magnitude of the adrenocortical response to social stress as well. Furthermore, we aimed at characterizing daily rhythms in corticosteroid release before and after social stress. We used 16 males from either of two lines bidirectionally selected for different coping strategies (fast and slow explorers). Social stress was induced by confrontation with an aggressive resident male. Corticosteroid metabolites were analyzed in feces collected at 90-min intervals from 900 to 1630 h on a baseline day, on the day of the social conflict, and on the following day. In both days and in both lines levels varied with time of day in a robust rhythm with a peak in the first sample of the morning and a trough at the end of the light phase. This rhythm correlates with activity (perch hopping). An overall increase in levels relative to baseline day was observed between 30 and 140 min after the challenge. Birds of the less aggressive and more cautious line (slow explorers) showed a trend for a higher response compared to birds of the more aggressive and bolder line (fast explorers), which showed almost no response. On the day after the challenge the birds of the slow line exhibited significantly reduced corticosteroid secretion, probably due to an increased negative feedback. The results provide evidence for a physiological basis of different coping strategies in birds, emerging in response to social stress and with a pattern similar to that in other vertebrates.

Adaptation, Psychological↗

PubMed2003

Genetic selection for coping style predicts stressor susceptibility.

Genetically selected aggressive (SAL) and nonaggressive (LAL) male wild house-mice which show distinctly different coping styles, also display a differential regulation of the hypothalamic-pituitary-adrenal axis after exposure to an acute stressor. To test the hypothesis that coping style predicts stressor susceptibility, the present study examined line differences in response to a chronic stressor. Chronic psychosocial stress was evoked using two paradigms. In the first paradigm, a SAL or LAL male was living in sensory contact (except tactile contact) with a dominant SAL male for 25 days (sensory contact stress). In the second paradigm, a SAL or LAL male was, in addition to the first paradigm, defeated by a SAL male for 21 consecutive days (defeat stress). The sensory contact stressor induced in LAL mice chronic body weight loss and increased plasma adrenocorticotropic hormone levels compared to SAL mice and increased corticosterone levels, thymus involution and lower hippocampal mineralocorticoid receptor (MR) : glucocorticoid receptor (GR) ratio compared to LAL controls. The defeat stressor increased corticosterone secretion and caused adrenal hypertrophy and thymus involution in both mouse lines. Defeated LAL mice showed long-lasting body weight loss and higher corticosterone concentrations than SAL mice and lower hippocampal MR : GR ratio and decreased immobility behaviour in the forced swimming test than LAL controls. Hypothalamic corticotropin-releasing hormone mRNA expression was higher in defeated SAL than in controls. The present data show that both stress paradigms induced line-dependent physiological and neuroendocrine changes, but that the sensory contact stressor produced chronic stress symptoms in LAL mice only. This latter stress paradigm therefore seems promising to analyse the role of genetic factors in the individual differences in stress-related psychopathology.

Adaptation, Psychological↗

PubMed2001

High-voltage-activated Ca2+ currents and the excitability of pyramidal neurons in the hippocampal CA3 subfield in rats depend on corticosterone and time of day.

This study tested the time-of-day dependence of the intrinsic postsynaptic properties of hippocampal CA3 pyramidal neurons. High-voltage-activated Ca2+ currents and the Ca(2+)- and voltage-dependent afterhyperpolarizations were examined in slices of rat brains obtained at four distinct time periods. Just after onset of the dark phase, the steady-state amplitude of the Ca2+ current (-1.24+/-0.11 nA) was significantly greater (P<0.03) than that of the light phase (-0.84+/-0.06 nA). Over the entire time range, the amplitude of the Ca2+ current correlated with plasma corticosterone levels in a U-shaped function. Furthermore, depolarization-induced excitability during the dark phase exhibited an increased spike after depolarization (3.1+/-0.1 mV) and a slower adaptation of the firing frequency (146+/-18%). These findings point to a dynamic time-of-day dependence of the CA3 neuronal properties and postsynaptic Ca2+ currents.

Action Potentials↗

PubMed2001

Temporal and spatial dynamics of corticosteroid receptor down-regulation in rat brain following social defeat.

The experiments explored the nature and time course of changes in glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) binding in homogenates of various brain regions and pituitary of male Wistar rats following social defeat stress. One week after defeat, the binding capacity of GRs was decreased in the hippocampus and the hypothalamus while no changes were observed in the parietal cortex and the pituitary. The number of MRs remained at the same level as in undefeated rats. Three weeks postdefeat, the initially down-regulated GR returned to baseline level in the hippocampus and the hypothalamus. However, GR binding was now decreased in the parietal cortex. Severe down-regulation of MRs was detected in the hippocampal and septal tissue. The results show that brief but intense stress like social defeat induces a long-lasting down-regulation of corticosteroid receptors and that the temporal dynamics of these changes are not only differential for GRs and MRs but also for brain sites.

Aggression↗

PubMed2001

Modulation of aggression in male mice: influence of group size and cage size.

Aggression in group-housed male mice is known to be influenced by both cage size and group size. However, the interdependency of these two parameters has not been studied yet. In this study, the level of aggression in groups of three, five, or eight male BALB/c mice housed in cages with a floor size of either 80 or 125 cm(2)/animal was estimated weekly after cage cleaning for a period of 14 weeks. Furthermore, urine corticosterone levels, food and water intake, body weight, and number of wounds were measured weekly. At the end of the experiment, tyrosine hydroxylase (TH) activity, testosterone levels, and weight of spleen, thymus, testes, and seminal vesicles were determined. Results indicate a moderate increase of intermale aggression in larger cages when compared to the smaller cages. Aggression in groups of eight animals was considerably higher than in groups of three animals. The increase of agonistic behavior was observed both in dominant and subordinate animals. Physiological parameters indicate differences in stress levels between dominant and subordinate animals. It is concluded that aggressive behavior in group-housed male BALB/c mice is best prevented by housing the animals in small groups of three to five animals, while decreasing floor size per animal may be used as a temporary solution to decrease high levels of aggression in an existing social group.

Aggression↗

PubMed2001

Long-term effects of social stress on antiviral immunity in pigs.

Mixing of unfamiliar pigs is common practice in intensive pig husbandry. Since pigs maintain a dominance hierarchy, mixing often leads to vigorous fighting. Apart from the negative impact that fighting has on welfare, there is evidence that the social stress associated with fighting suppresses immune function. In the present experiment, we investigated the impact of mixing on specific long-term immune responses and protection against challenge infection after vaccination with pseudorabies virus (PRV). Specific pathogen-free (SPF) pigs were mixed pairwise with an unfamiliar same-gender conspecific or left undisturbed with a same-gender littermate at 3 days after vaccination with PRV. Half of the pigs were females (gilts) and half were castrated males (barrows). Mixing increased agonistic behavior to the same degree in gilts and barrows. Cortisol concentrations in saliva and catecholamine excretion in urine were increased in mixed pigs, and these effects were independent of dominance status and gender. Subsequently, the effects of mixing, gender, dominance status and interactions between these factors on immune response parameters were studied. The main result was that mixed barrows showed suppressed immune responses after vaccination and increased clinical symptoms after challenge infection compared to control barrows. Mixed gilts however did not differ from control gilts. It also appeared that mixed dominants were more seriously affected than mixed subordinates were. We conclude that, in some pigs, social stress after mixing suppresses the immune response to a viral vaccine and consequently impairs protection against challenge infection.

Agonistic Behavior↗

PubMed2001

Effect of social defeat in a territorial bird (Parus major) selected for different coping styles.

We addressed the questions (i) whether a social defeat triggers similar autonomic and behavioral responses in birds as is known from mammals and (ii) whether individuals that differ in coping style differ in their reaction to a social defeat. Adult captive male great tits (Parus major) from either of two different selection lines for coping style were used to test the effect of social defeat by an aggressive resident male conspecific on subsequent social and nonsocial behaviour, body temperature, breath rate and body mass. These parameters were measured 1 day before (baseline), immediately after and at Days 1 to 3 and 6 after the social interaction took place (Day 0). Social defeat decreased social exploration and increased body temperature substantially for at least 1 day in all birds. Breath rate and body mass were not affected. Birds belonging to the more aggressive and bolder line showed impairment in activity immediately after the social defeat. This is to our knowledge the first report showing that psychosocial stress in birds can have a similar impact as in rodents, but with a shorter recovery time. This might be due to species-specific differences in sensitivity to social stress, or to differences in the way social stress was induced.

Adaptation, Psychological↗

PubMed2001

Behavioral and physiological responses to stress are affected by high-fat feeding in male rats.

Interactions between monoaminergic neurochemistry and macronutrient intake have been frequently shown. Because monoaminergic systems in the brain are also closely involved in behavioral and physiological stress responses it can be hypothesized that differences in the macronutrient composition of diets are reflected in these responses. The present studies, therefore, were designed to assess the consequences of a change in dietary macronutrient composition on a variety of physiological and behavioral responses (both acute and long-term) to a number of stressors. The effect of chronic high-fat (HF; 61% kcal from fat) feeding on the stress responses was compared with controls receiving regular high-carbohydrate (HC; 63% kcal from carbohydrates) laboratory chow. Rats were kept on this diet for at least 2 months before they were exposed to either psychological (social defeat) or physiological (lipopolysaccharide, LPS, administration) stress. At baseline, chronic HF feeding caused a slight, but significantly reduction in body temperature relative to that observed in HC-fed rats. Following social defeat or LPS injection, HF feeding caused a faster recovery of the body temperature increase relative to animals on the HC diet. Stress-induced suppression of home cage locomotor activity and body weight gain were also reduced by HF feeding. The serotonergic 5-HT(1a) receptor hyposensitivity that was observed in HC-fed rats 2 weeks after stress was absent in the HF regimen. Although the present results cannot be readily interpreted as showing purely beneficial effects of high-fat diets on stress responsivity, the findings in the present study do encourage further investigation of possible ameliorating effects of high-fat diets on aspects of the behavioral and physiological response stress.

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

PubMed2001

Adaptation to social isolation. Acute and long-term stress responses of growing gilts with different coping characteristics.

The present experiment studied the acute and long-term stress responses of reactive and proactive prepubertal gilts to social isolation. Gilts with either reactive or proactive features were identified according to behavioral resistance in a backtest at a young age (2-4 days), respectively being low (LR) and high resistant (HR) in this test. At 7 weeks of age, 12 gilts of each type were socially isolated. Initially, isolation was stressful for both types of gilts, as shown by increased cortisol concentrations and decreased body temperatures. Moreover, both types reacted with increases in exploration and vocalizations. Stress responses to isolation, however, differed in magnitude and/or duration between LR and HR gilts, which was in line with expected reaction patterns on the basis of preferred ways of coping. The cortisol response to isolation was higher in LR gilts, and they generally showed more explorative behavior. HR gilts seemed to be more engaged in walking/running behavior in the first hour after isolation, they generally vocalized more and their noradrenaline excretion in urine was higher at 3 weeks after the start of isolation. Several responses to isolation in the longer term pointed to a prolonged higher general state of stress of HR gilts. Body temperature in HR gilts, for instance, did not recover during 3 weeks of isolation, but values returned to "normal" within 1 day in LR gilts. At 1 week of isolation, relatively high parasympathetic responsivity to novelty was observed in HR gilts, probably due to stress-related high sympathetic reactivity. A shift in percentages of leucocyte subsets, typically occurring under conditions of stress, only developed in HR gilts during isolation. Finally, gastric ulceration was found in one HR gilt, but did not occur in LR gilts. To conclude, LR and HR gilts differed in their strategies to adapt to social isolation, and especially for HR gilts, this procedure seemed to become a chronic stressor.

Acute Disease↗

PubMed2001

S20098 affects the free-running rhythms of body temperature and activity and decreases light-induced phase delays of circadian rhythms of the rat.

Mammalian endogenous circadian rhythms are entrained to the environmental day-night cycle by light exposure. Melatonin is involved in this entrainment by signaling the day-night information to the endogenous circadian pacemaker. Furthermore, melatonin is known to affect the circadian rhythm of body temperature directly. A striking property of the endogenous melatonin signal is its synthesis pattern, characterized by long-term elevated melatonin levels throughout the night. In the present study, the influence of prolonged treatment with the melatonin agonist S20098 during the activity phase of free-running rats was examined. This was achieved by giving S20098 in the food. The free-running body temperature and activity rhythms were studied. The present study shows that enhancement of the melatonin signal, using S20098, affected the free-running rhythm by gradual phase advances of the start of the activity phase, consequently causing an increase in length of the activity phase. A well-known feature of circadian rhythms is its time-dependent sensitivity for light. Light pulse exposure of an animal housed under continuous dark conditions can cause a phase shift of the circadian pacemaker. Therefore, in a second experiment, the influence of melatonin receptor stimulation on the sensitivity of the pacemaker to light was examined by giving the melatonin agonist S20098 in the food during 1 day prior to exposure to a 60-min light pulse of 0, 1.5, 15, or 150 lux given at circadian time (CT) 14. S20098 pretreatment caused a diminished light pulse-induced phase shift when a light pulse of low light intensity (1.5 lux) was given. S20098 treatment via the food was sufficient to exert chronobiotic activity, and S20098 treatment resulting in prolonged overstimulation of melatonin receptors is able to attenuate the effect of light on the circadian timing system.

Acetamides↗

PubMed2001

Increased maternal corticosterone levels in rats: effects on brain 5-HT1A receptors and behavioral coping with stress in adult offspring.

This study examined the consequences of elevated corticosterone levels in lactating rats on their offspring's serotonergic 5-hydroxytryptamine (5-HT)1A receptor system and behavioral coping with stress. The mothers received normal drinking water or water with corticosterone, which, via the milk, enters the circulation and brains of the pups. In adulthood, the corticosterone-nursed offspring showed a consistently more passive way of coping with environmental challenges. However, they did not seem to be more anxious. Autoradiographic analysis of the 5-HT1A receptor system revealed a decrease in the adult 5-HT1A receptor binding in the hippocampal CA1 region. The results support the hypothesis that differences in behavioral coping with stress by adult rats are associated with differences in the serotonergic system. At the same time, it suggests that adult coping and its neuronal substrates are not solely determined by genes but depend on subtle developmental factors as well.

Adaptation, Psychological↗

PubMed2000

Effects of environmental enrichment on behavioral responses to novelty, learning, and memory, and the circadian rhythm in cortisol in growing pigs.

Previously we showed that pigs reared in an enriched environment had higher baseline salivary cortisol concentrations during the light period than pigs reared under barren conditions. In the present experiment, it was investigated whether these higher baseline salivary cortisol concentrations were a real difference in cortisol concentration or merely represented a phase difference in circadian rhythm. The effects of different cortisol concentrations on the behavioral responses to novelty and learning and long-term memory in a maze test were also studied in enriched and barren housed pigs. At 9 weeks of age enriched and barren housed pigs did not differ in baseline salivary cortisol concentrations nor in circadian rhythm, but at 22 weeks of age barren housed pigs had a blunted circadian rhythm in salivary cortisol as compared to enriched housed pigs. The differences in baseline salivary cortisol concentrations between enriched- and barren-housed pigs are age-dependent, and become visible after 15 weeks of age. Enriched- and barren-housed piglets did not differ in time spent on exploration in the novel environment test. Barren-housed pigs had an impaired long-term memory in the maze test compared to enriched-housed pigs; however, no differences in learning abilities between enriched- and barren-housed pigs were found. Because blunted circadian cortisol rhythms are often recorded during states of chronic stress in pigs and rats or during depression in humans, it is suggested that the blunted circadian rhythm in cortisol in barren-housed pigs similarily may reflect decreased welfare.

Aging↗

PubMed2000

Somatodendritic 5-HT(1A) autoreceptors mediate the anti-aggressive actions of 5-HT(1A) receptor agonists in rats: an ethopharmacological study with S-15535, alnespirone, and WAY-100635.

To elucidate the relative contribution of somatodendritic 5-HT(1A) autoreceptors and postsynaptic 5-HT(1A) receptors in the specific anti-aggressive properties of 5-HT(1A) receptor agonists, the influence of the novel benzodioxopiperazine compound S-15535, which behaves in vivo as a competitive antagonist at postsynaptic 5-HT(1A) receptors and as an agonist at 5-HT(1A) autoreceptors, upon offensive and defensive aggression was investigated in wild-type rats using a resident-intruder paradigm. S-15535 exerted a potent dose-dependent decrease in offensive, but not defensive, aggressive behavior (inhibitory dose (ID)(50) = 1.11 mg/kg). This anti-aggressive profile was roughly similar to that of the potent pre- and postsynaptic 5-HT(1A) full agonist alnespirone (ID(50) = 1. 24). The drug's profound anti-aggressive actions were not accompanied by sedative side effects or signs of the "5-HT(1A) receptor-mediated behavioral syndrome," which are characteristically induced by prototypical 5-HT(1A) receptor agonists like 8-OH-DPAT and buspirone. The selective pre- and postsynaptic 5-HT(1A) antagonist WAY-100635, which was inactive given alone, abolished the anti-aggressive effects of S-15535 and alnespirone, thereby confirming the involvement of 5-HT(1A) receptors. Furthermore, combined administration of S-15535 and alnespirone elicited an additive anti-aggressive effect, providing further support for somatodendritic 5-HT(1A) receptor involvement. Finally, the postsynaptic 5-HT(1A) antagonistic properties of S-15535 were confirmed by showing blockade of the alnespirone-induced hypothermia, a postsynaptic 5-HT(1A) mediated response in the rat. These data provide extensive evidence that the anti-aggressive effects of 5-HT(1A) receptor agonists are expressed via their action on somatodendritic 5-HT(1A) autoreceptors, thereby most likely attenuating intruder-activated serotonergic neurotransmission.

Aggression↗

PubMed1999

Interruptions of early cortical development affect limbic association areas and social behaviour in rats; possible relevance for neurodevelopmental disorders.

Deficits in social behaviour are found in several neuropsychiatric disorders with a presumed developmental origin. Adequate social behaviour may rely importantly on the associative integration of new stimuli with previously stored, related information. The limbic allocortex, in particular the entorhinal region, is thought to support this kind of processing. Therefore, in the present study, gestating dams were treated with methylazoxymethanol acetate (MAM) on one of gestational days nine to twelve, to interrupt neuronal proliferation in the entorhinal region of the developing foetuses. Effects of prenatal MAM administration on social behaviour were evaluated in adult animals. As the entorhinal cortex has been implicated by some studies in spatial memory, effects on this function were also investigated. Following the behavioural studies, brain morphology was screened for effects of MAM. Our results show moderate to severe social impairment in MAM-treated animals, depending on the exact timing of prenatal exposure. By contrast, spatial reference and working memory were not importantly affected in any group. Analysis of brain morphology in the MAM-treated offspring supported maldevelopment of the entorhinal cortex and revealed mild abnormalities also in some connected limbic and limbic affiliated structures, such as the perirhinal and ectorhinal cortex, the anterior cingulate cortex and the medial septum-diagonal band region. Findings are discussed with respect to entorhinal cortex function, and with regard to their relevance for psychiatric disorders with a putatively neurodevelopmental pathogenesis, such as schizophrenia.

Animals↗

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

Differential modulation of lateral septal vasopressin receptor blockade in spatial learning, social recognition, and anxiety-related behaviors in rats.

The role of lateral septal vasopressin (VP) in the modulation of spatial memory, social memory, and anxiety-related behavior was studied in adult, male Wistar rats. Animals were equipped with osmotic minipumps delivering the VP-antagonist d(CH2)5-D-Tyr(Et)VAVP (1 ng/0.5 microl per h) bilaterally into the lateral septum (LS). Subsequently, all rats were subjected to four behavioral tests. First, animals were tested in a spatial learning paradigm (Morris water maze; 12 trials), followed by the social recognition test. A possible role for VP in anxiety-related behavior was then studied in the shock-probe burying test and the elevated plus-maze, respectively. The results showed that VP receptor antagonism impaired social recognition and reduced open-arm activity in the plus-maze, while it had no effect on spatial learning (Morris maze) and shock-probe burying behavior. The results indicate a strong task-dependent specificity of lateral septal VP functioning.

Animals↗