Social stress models in rodents: Towards enhanced validity.

Understanding the role of the social environment in the development of stress related diseases requires a more fundamental understanding of stress. Stress includes not only the stimulus and the response but also the individual appraisal of the situation. The social environment is not only essential for survival it is at the same time an important source of stressors. This review discusses the social stress concept, how it has been studied in rodents in the course of time and some more recent insights into the appraisal process. In addition to the factors controllability and predictability, outcome expectancy and feedback of the victim's own actions during the social stress are suggested to be important factors in the development of stress related disease. It is hypothesized that individual differences in the way in which these factors are used in the appraisal of everyday life situations may explain individual vulnerability.

ANIMAL BEHAVIOR AND WELL-BEING SYMPOSIUM: Interaction between coping style/personality, stress, and welfare: Relevance for domestic farm animals.

This paper will argue that understanding animal welfare and the individual vulnerability to stress-related disease requires a fundamental understanding of functional individual variation as it occurs in nature as well as the underlying neurobiology and neuroendocrinology. Ecological studies in feral populations of mice, fish, and birds start to recognize the functional significance of phenotypes that individually differ in their behavioral and neuroendocrine response to environmental challenge. Recent studies indicate that the individual variation within a species may buffer the species for strong fluctuations in the natural habitat. Similarly, evolutionary ancient behavioral trait characteristics have now been identified in a range of domestic farm animals including cattle, pigs, and horses. Individual variation in behavior can be summarized in a 3-dimensional model with coping style, emotionality, and sociality as independent dimensions. These dimensions can be considered trait characteristics that are stable over time and across situations within the individual. This conceptual model has several consequences. First, the coping style dimension is strongly associated with differential stress vulnerability. Social stress studies show that proactive individuals are resilient under stable environmental conditions but vulnerable when outcome expectancies are violated. Reactive individuals are, in fact, rather flexible and seem to adapt more easily to a changing environment. A second consequence relates to genetics and breeding. Genetic selection for one trait usually implies selection for other traits as well. It is discussed that a more balanced breeding program that takes into account biologically functional temperamental traits will lead to more robust domestic farm animals. Finally, the relationship between temperamental traits, animal production, fitness, and welfare is discussed.

The neurobiology of offensive aggression: Revealing a modular view.

Experimental studies aimed at understanding the neurobiology of aggression started in the early 20th century, and by employing increasingly sophisticated tools of functional neuroanatomy (i.e., from electric/chemical lesion and stimulation techniques to neurochemical mapping and manipulations) have provided the important framework for the functional brain circuit organization of aggressive behaviors. Recently, newly emerging technologies for mapping,measuring and manipulating neural circuitry at the level of molecular and genetically defined neuronal subtypes promise to further delineate the precise neural microcircuits mediating the initiation and termination of aggressive behavior, and characterize its dynamic neuromolecular functioning. This paper will review some of the behavioral, neuroanatomical and neurochemical evidence in support of a modular view of the neurobiology of offensive aggressive behavior. Although aggressive behavior likely arises from a specific concerted activity within a distributed neural network across multiple brain regions, emerging opto- and pharmacogenetic neuronal manipulation studies make it clear that manipulation of molecularly-defined neurons within a single node of this global interconnected network seems to be both necessary and sufficient to evoke aggressive attacks. However, the evidence so far also indicates that in addition to behavior-specific neurons there are neuronal systems that should be considered as more general behavioral control modules. The answer to the question of behavioral specificity of brain structures at the level of individual neurons requires a change of the traditional experimental setup. Studies using c-fos expression mapping usually compare the activation patterns induced by for example aggression with a home cage control. However, to reveal the behavioral specificity of this neuronal activation pattern, a comparison with other social and non-social related behaviors such as mating, defensive burying or running might be more appropriate. In addition, the correlations between aggressive behavior and other behaviors in different environmental contexts might give an indication of these more general behavioral control functions. Elucidating how neural circuits that modulate social-aggressive behavior also mediate other complex emotional behaviors or states will lead to a better understanding of the molecular mechanisms by which social deficits are expressed in various neuropsychiatric disorders. This likely will lead to more efficacious pharmacological or circuit-based therapeutics to curb excessive/abnormal aggressive behavior and improve social function.

Adolescent social stress does not necessarily lead to a compromised adaptive capacity during adulthood: a study on the consequences of social stress in rats.

Childhood bullying or social stress in adolescent humans is generally considered to increase the risk of developing behavioral disorders like depression in adulthood. Juveniles are hypothesized to be particularly sensitive to stressors in their environment due to the relatively late maturation of brain areas that are targeted by stress such as the prefrontal cortex and hippocampus. In our study male adolescent rats were subjected to repeated social defeat on postnatal day (PND) 28, 31 and 34 (experiment 1) or to daily social defeats between PND 35 and 42 (experiment 2). Adolescent rats in experiment 1 were socially housed in pairs with a male of similar age during and after the social defeat. In experiment 2 adolescents were housed either alone or with an age-mate for 7 days (PND 35-42) next to either a highly aggressive or a non-aggressive adult male neighbor with whom a repeated physical interaction was allowed. In experiment 1 the adolescent defeats affected subsequent play behavior with the cage mate. Socially stressed rats more frequently initiated play behavior but also adopted more frequently submissive postures during the play fights. As adults, they seemed to cope behaviorally and physiologically better with a similar exposure to a residential aggressive male rat than unstressed controls. In experiment 2 acute effects of adolescent social stress were studied on neuroplasticity markers like hippocampal cell proliferation and neurogenesis as well as hippocampal brain-derived neurotrophic factor (BDNF) levels. The 2nd experiment also studied long-term effects of the adolescent stress in the response to an adult social defeat. A few acute but minor changes in brain plasticity markers and behavior were observed but these were transient and no behavioral or physiological effects persisted into adulthood. The results from both experiments support the theory developed in the so-called "match-mismatch hypothesis" which claims that the final consequence of childhood adversity depends on how well the early life environment matches the challenges in later life. Socially stressed adolescents are rather resilient to the lasting behavioral and physiological effects of the stress exposure if they are socially housed afterward and have the ability to recover.

Chronic sleep restriction causes a decrease in hippocampal volume in adolescent rats, which is not explained by changes in glucocorticoid levels or neurogenesis.

Sleep loss strongly affects brain function and may even predispose susceptible individuals to psychiatric disorders. Since a recurrent lack of sleep frequently occurs during adolescence, it has been implicated in the rise in depression incidence during this particular period of life. One mechanism through which sleep loss may contribute to depressive symptomatology is by affecting hippocampal function. In this study, we examined the effects of sleep loss on hippocampal integrity at young age by subjecting adolescent male rats to chronic sleep restriction (SR) for 1 month from postnatal day 30 to 61. They were placed in slowly rotating drums for 20 h per day and were allowed 4 h of rest per day at the beginning of the light phase. Anxiety was measured using an open field and elevated plus maze test, while saccharine preference was used as an indication of anhedonia. All tests were performed after 1 and 4 weeks of SR. We further studied effects of SR on hypothalamic-pituitary-adrenal (HPA) axis activity, and at the end of the experiment, brains were collected to measure hippocampal volume and neurogenesis. Behavior of the SR animals was not affected, except for a transient suppression of saccharine preference after 1 week of SR. Hippocampal volume was significantly reduced in SR rats compared to home cage and forced activity controls. This volume reduction was not paralleled by reduced levels of hippocampal neurogenesis and could neither be explained by elevated levels of glucocorticoids. Thus, our results indicate that insufficient sleep may be a causal factor in the reductions of hippocampal volume that have been reported in human sleep disorders and mood disorders. Since changes in HPA activity or neurogenesis are not causally implicated, sleep disturbance may affect hippocampal volume by other, possibly more direct mechanisms.

Physiological and hormonal responses to novelty exposure in rats are mainly related to ongoing behavioral activity.

Stress research has been dominated by a circular type of reasoning that occurrence of a stress response is bad. Consequently, the stimulus is often interpreted as stressful in terms of aversiveness involving uncontrollability and unpredictability, which may have maladaptive and pathological consequences. However, the hypothalamic-pituitary-adrenal (HPA) axis and sympathico-adrenomedullary (SAM) system are not only activated in response of the organism to challenges, but also prepare and support the body for behavior. Therefore, a considerable part of the physiological and hormonal responses to a certain situation can be a direct reflection of the metabolic requirements for the normal ongoing behavioral activity, rather than of the stressful nature. In order to clarify this, behavioral, physiological, hormonal and electroencephalographic (EEG) responses to novel cage exposure were studied in male Sprague-Dawley rats. Forced confrontation with a novel cage has been interpreted as a psychological and aversive stressor. However, this interpretation is simply based on the occurrence of a stress response. This study aimed at detailed analysis of the time course of the novelty-induced responses. Different parameters were measured simultaneously in freely moving rats, which allowed correlational comparisons. Hereto, radio telemetry using a small implantable transmitter combined with permanent catheters and an automated blood sampling system was used. A camera placed above the cage allowed behavioral observations. The results show that novelty exposure induced significant increases in locomotor activity, heart rate, blood pressure and plasma corticosterone together with a complete lack of sleep as compared to the undisturbed control situation. The latency to reach significance and the duration of responses varied across parameters but all had recovered within 30min after termination of novelty. The behavioral activity (locomotor activity and EEG wakefulness duration) response pattern was significantly correlated with that of heart rate, blood pressure and plasma corticosterone. Behavioral observations showed mainly explorative behavior in response to novelty. Therefore, the present results indicate that the novelty-induced physiological and hormonal responses are closely related to the ongoing, mainly explorative behavioral activity induced by novelty. An interpretation in terms of metabolic support of ongoing behavior seems to be more appropriate than the frequently used stress interpretation. The present study also emphasizes the added value of simultaneous assessment of behavioral, physiological and hormonal parameters under controlled, non-confounding conditions.

Stress revisited: a critical evaluation of the stress concept.

With the steadily increasing number of publications in the field of stress research it has become evident that the conventional usage of the stress concept bears considerable problems. The use of the term 'stress' to conditions ranging from even the mildest challenging stimulation to severely aversive conditions, is in our view inappropriate. Review of the literature reveals that the physiological 'stress' response to appetitive, rewarding stimuli that are often not considered to be stressors can be as large as the response to negative stimuli. Analysis of the physiological response during exercise supports the view that the magnitude of the neuroendocrine response reflects the metabolic and physiological demands required for behavioural activity. We propose that the term 'stress' should be restricted to conditions where an environmental demand exceeds the natural regulatory capacity of an organism, in particular situations that include unpredictability and uncontrollability. Physiologically, stress seems to be characterized by either the absence of an anticipatory response (unpredictable) or a reduced recovery (uncontrollable) of the neuroendocrine reaction. The consequences of this restricted definition for stress research and the interpretation of results in terms of the adaptive and/or maladaptive nature of the response are discussed.

Neuroendocrinology of coping styles: towards understanding the biology of individual variation.

Individual variation in behavior and physiology is a widespread and ecologically functional phenomenon in nature in virtually all vertebrate species. Due to domestication of laboratory animals, studies may suffer from a strong selection bias. This paper summarizes behavioral, neuroendocrine and neurobiological studies using the natural individual variation in rats and mice. Individual behavioral characteristics appear to be consistent over time and across situations. The individual variation has at least two dimensions in which the quality of the response to a challenging condition (coping style) is independent from the quantity of that response (stress reactivity). The neurobiology reveals important differences in the homeostatic control of the serotonergic neuron and the neuropeptides vasopressin and oxytocin in relation to coping style. It is argued that a careful exploitation of the broad natural and biologically functional individual variation in behavior and physiology may help in developing better animal models for understanding individual disease vulnerability.

Is hyper-aggressiveness associated with physiological hypoarousal? A comparative study on mouse lines selected for high and low aggressiveness.

Aggressiveness is often considered a life-long, persistent personality trait and is therefore expected to have a consistent neurobiological basis. Recent meta-analyses on physiological correlates of aggression and violence suggest that certain aggression-related psychopathologies are associated with low functioning of the hypothalamo-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS). We tested this hypothesis in mice selected for high and low aggressiveness by measuring baseline plasma corticosterone levels and, via radiotelemetry, heart rate and core body temperature. The radiotelemetric recordings were made for 48 h under baseline undisturbed conditions and for 90 min after a handling stressor. Consistent with the hypoarousal hypothesis of violence, we found lower resting heart rates in two out of the three highly aggressive selection lines. In contrast, body temperature during the active phase, as another ANS-regulated physiological parameter, was higher in two out of three highly aggressive lines. The handling-induced tachycardiac and hyperthermic responses were similar across the six mouse lines except for the most docile and obese line, which showed a blunted reactivity. Besides significant differences between strains, no differences in plasma corticosterone levels were found between the high- and low-aggressive phenotypes. These results are discussed in relation to the different types of aggression (normal versus pathological) exhibited by the three highly aggressive lines. We conclude that while high trait-like aggressiveness is generally associated with a higher active phase core body temperature, only animals that express pathological forms of aggression are characterized by a low resting heart rate.

Coping style and immunity in animals: making sense of individual variation.

Predicting the individual vulnerability to immune mediated disease is one of the main challenges of modern biomedical research. However, the question of individual behavioral and physiological characteristics that might predict this vulnerability has been subject of research and debate for a long time. This paper will argue that animal models aimed at individual vulnerability should consider the biological function of variation in nature. An increasing number of studies show the ecological significance of variation within a species. Based on behavioral studies in several vertebrate species two coping style can be distinguished. Variation in coping style appears to play a role in the population dynamics and the evolutionary fitness of the species. Coping styles are reflected in a stable differentiation in the behavioral and physiological stress responsiveness over time and across situations. Based on the observations that the individual level of offensive aggressive behavior (i.e., the tendency to defend the home territory) is strongly related to the way animals react to various other environmental challenges, it is argued that the individual's level of offensiveness is an important indicator and component of a more trait-like behavioral and physiological response pattern (coping style) to environmental demands. The coping style of aggressive animals is principally aimed at a (pro)active prevention or manipulation of a stressor whereas the non-aggressive individuals tend to passively accept or react to it. Proactive coping is associated with high sympathetic reactivity to stressors whereas the more passive or reactive coping style generally has a higher HPA axis reactivity. In view of the immune modulating nature of these major neuroendocrine stress systems, one might expect that coping styles will be reflected in a differential vulnerability to immune mediated disease as well. Indeed, several studies have demonstrated such a relationship, indicating that the functional variation in coping style and related neuroendocrine stress reactivity, as it occurs in nature, might be a good standard for studies aimed at understanding individual vulnerability. This is in agreement with more recent views that also in humans stress reactivity may be the best predictor for the individual vulnerability to immune mediated diseases. This asks for a more fundamental and translational approach of individual disease vulnerability based on a common biological basis of individual differentiation in behavior and physiology in humans and animals.

Differential effects of stress on adult hippocampal cell proliferation in low and high aggressive mice.

Male wild house mice selected for a long (LAL) or a short (SAL) latency to attack a male intruder generally show opposing behavioural coping responses to environmental challenges. LAL mice, unlike SAL mice, adapt to novel challenges with a highly reactive hypothalamic-pituitary-adrenal axis and show an enhanced expression of markers for hippocampal plasticity. The present study aimed to test the hypothesis that these features of the more reactive LAL mice are reflected in parameters of hippocampal cell proliferation. The data show that basal cell proliferation in the subgranular zone (SGZ) of the dentate gyrus, assessed by the endogenous proliferation marker Ki-67, is lower in LAL than in SAL mice. Furthermore, application of bromodeoxyuridine (BrdU) over 3 days showed an almost two-fold lower cell proliferation rate in the SGZ in LAL versus SAL mice. Exposure to forced swimming resulted, 24 h later, in a significant reduction in BrdU + cell numbers in LAL mice, whereas cell proliferation was unaffected by this stressor in SAL mice. Plasma corticosterone and dentate gyrus glucocorticoid receptor levels were higher in LAL than in SAL mice. However, no differences between the SAL and LAL lines were found for hippocampal NMDA receptor binding. In conclusion, the data suggest a relationship between coping responses and hippocampal cell proliferation, in which corticosterone may be one of the determinants of line differences in cell proliferation responses to environmental challenges.

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.

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.

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.

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.

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.

Enhanced sensitivity of postsynaptic serotonin-1A receptors in rats and mice with high trait aggression.

Individual differences in aggressive behaviour have been linked to variability in central serotonergic activity, both in humans and animals. A previous experiment in mice, selectively bred for high or low levels of aggression, showed an up-regulation of postsynaptic serotonin-1A (5-HT(1A)) receptors, both in receptor binding and in mRNA levels, in the aggressive line [Brain Res 736 (1996) 338]. The aim of this experiment was to study whether similar differences in 5-HT(1A) receptors exist in individuals from a random-bred rat strain, varying in aggressiveness. In addition, because little is known about the functional consequences of these receptor differences, a response mediated via postsynaptic 5-HT(1A) receptors (i.e., hypothermia) was studied both in the selection lines of mice and in the randomly bred rats. The difference in receptor binding, as demonstrated in mice previously, could not be shown in rats. However, both in rats and mice, the hypothermic response to the 5-HT(1A) agonist alnespirone was larger in aggressive individuals. So, in the rat strain as well as in the mouse lines, there is, to a greater or lesser extent, an enhanced sensitivity of postsynaptic 5-HT(1A) receptors in aggressive individuals. This could be a compensatory up-regulation induced by a lower basal 5-HT neurotransmission, which is in agreement with the serotonin deficiency hypothesis of aggression.

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.

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.

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.