Sleep restriction in rats leads to changes in operant behaviour indicative of reduced prefrontal cortex function.

Sleep deprivation has profound effects on cognitive performance, and some of these effects may be mediated by impaired prefrontal cortex function. In search of an animal model to investigate this relationship we studied the influence of restricted sleep on operant conditioning in rats, particularly the performance in a differential reinforcement of low rate responding (DRL) task, which is highly dependent upon an intact prefrontal cortex. Animals were trained to withhold a lever press until an imposed delay of 30 s after the last press had passed in order to achieve a food reward. Once the animals had mastered the task, they were sleep-restricted for 7 days with 20 h of sleep deprivation per day. At the end of each daily sleep deprivation session, performance on the DRL task was assessed. The results show that sleep-restricted animals were less able to time their responses correctly, started pressing the lever more randomly and showed signs of behavioural disinhibition, the latter possibly reflecting enhanced impulsivity. Our data support the hypothesis that a sleep debt has disruptive consequences for the functioning of the prefrontal cortex. This model offers possibilities for future studies investigating the underlying biochemical and molecular mechanisms of this relationship.

Deep sleep after social stress: NREM sleep slow-wave activity is enhanced in both winners and losers of a conflict.

Sleep is considered to be a recovery process of prior wakefulness. Not only duration of the waking period affects sleep architecture and sleep EEG, the quality of wakefulness is also highly important. Studies in rats have shown that social defeat stress, in which experimental animals are attacked and defeated by a dominant conspecific, is followed by an acute increase in NREM sleep EEG slow wave activity (SWA). However, it is not known whether this effect is specific for the stress of social defeat or a result of the conflict per se. In the present experiment, we examined how sleep is affected in both the winners and losers of a social conflict. Sleep-wake patterns and sleep EEG were recorded in male wild-type Groningen rats that were subjected to 1h of social conflict in the middle of the light phase. All animals were confronted with a conspecific of similar aggression level and the conflict took place in a neutral arena where both individuals had an equal chance to either win or lose the conflict. NREM sleep SWA was significantly increased after the social conflict compared to baseline values and a gentle stimulation control condition. REM sleep was significantly suppressed in the first hours after the conflict. Winners and losers did not differ significantly in NREM sleep time, NREM sleep SWA and REM sleep time immediately after the conflict. Losers tended to have slightly more NREM sleep later in the recovery period. This study shows that in rats a social conflict with an unpredictable outcome has quantitatively and qualitatively largely similar acute effects on subsequent sleep in winners and losers.

Chronic enhancement of brain oxytocin levels causes enduring anti-aggressive and pro-social explorative behavioral effects in male rats.

Oxytocin (OXT) has been implicated in the regulation of social behaviors, including intermale offensive aggression. Recently, we showed that acute enhancement of brain OXT levels markedly suppressed offensive aggression and increased social exploration in resident rats confronted with an intruder in their home territory. Moreover, a different responsivity to the exogenous OXTergic manipulation was observed among individuals based on their baseline aggression. In this study we aimed at evaluating the behavioral response to chronically enhancing or attenuating central OXT levels, and at scrutinizing whether the trait-aggression moderates the treatment-induced behavioral changes. To this end, resident male wild-type Groningen rats were continuously (via osmotic minipumps) intracerebroventricularly infused with synthetic OXT or a selective OXT receptor (OXTR) antagonist for 7days. Changes in behavior were assessed performing a resident-intruder test before and at the end of the treatment period, as well as after 7days of withdrawal. Chronic infusion of OXT was found to selectively suppress aggression and enhance social exploration. Chronic blockage of OXTRs instead increased introductory aggressive behavior (i.e. lateral threat), yet without affecting the total duration of the aggression. The magnitude of the anti-aggressive changes correlated positively with the level of baseline aggression. Interestingly, OXT-induced behavioral changes persisted 7days after cessation of the treatment. In conclusion, these findings provide further evidence that enhanced functional activity of the central OXTergic system decreases social offensive aggression while it increases social explorative behavior. The data also indicate that chronically enhancing brain OXT levels may cause enduring anti-aggressive and pro-social explorative behavioral effects.

Aggression and aspects of impulsivity in wild-type rats.

Aggression is closely related to impulsive behavior both in humans and in animals. To avoid potential negative consequences, aggressive behavior is kept in control by strong inhibitory mechanisms. Failure of these inhibitory mechanisms results in violent behavior. In the present experiments, we investigated whether aggressive behavior is related to impulsive behavior. Furthermore, we investigated if violent behavior can be distinguished from "normal" aggressive behavior in terms of impulsivity levels. We used rats of the wild-type Groningen strain, rats of this strain differ widely in their level of offensive aggression expressed toward an unfamiliar intruder male, ranging from no aggression at all to very high levels of intense and sometimes violent behavior. Violent behavior was displayed by some of the animals that were given repeated winning experience. We used behavioral performance in an unpredictable operant conditioning paradigm for food reinforcement (variable interval 15) and performance in a differential-reinforcement of low rate (DRL-60s) responding as determinants for impulsivity. We predicted that offensive aggression is correlated with behavioral flexibility measured by the VI-15 procedure and that aggressive behavior is characterized by low behavioral inhibition on the DRL task. In addition we expected that violent animals would be characterized by extremely low levels of behavioral inhibition on the DRL task. We showed that the level of offensive aggression indeed positively correlated with VI-15 performance. In addition, we showed that behavioral performance on the DRL procedure is similar in low and high aggressive rats. However, violent animals can be dissociated by a lower efficiency of lever pressing on a DRL-60s schedule of reinforcement.

Structural and electrical myocardial remodeling in a rodent model of depression.

OBJECTIVE: Despite a well-documented association between stress and depression with cardiac morbidity and mortality, there is no satisfactory explanation for the mechanisms linking affective and cardiac disorders. This study investigated cardiac electrophysiological properties in an animal model of depression. METHODS: Depression-relevant physiological and behavioral parameters were measured in adult male wild-type rats during and after a period of intermittent social defeat stress (n = 12) or empty cage exposure (control, n = 11). Nine days after the last defeat/empty cage exposure, high-definition epicardial mapping was performed under anesthesia. RESULTS: Stressed animals versus controls displayed a larger reduction in the circadian amplitude of heart rate (-32% [3%] versus -13 [2%]; p = .001) and body temperature (-33% [4%] versus -5% [2%]; p = .001) rhythms, had smaller body weight gain (+11% [1%] versus +17% [1%]; p < .001), and showed a larger reduction in sucrose solution intake (-19% [6%] versus -7% [4%]; p = .006). Epicardial mapping analysis revealed a decrease in the transversal conduction velocity of the wavefront (0.23 [0.0] versus 0.27 [0.1] m/s; p = .02) and a shortening of the effective refractory period (86.8 [2.1] versus 95.9 [3.0] milliseconds; p = .01) in stressed animals. Upon killing, moderate left ventricular fibrosis was observed in the stressed group. CONCLUSIONS: Intermittent social stress procedure is associated with depression-like symptoms and altered myocardial electrical stability in a potentially proarrhythmic manner. In particular, reduced myocardial refractoriness and impaired conduction, which are considered major determinants of arrhythmogenesis, represent possible mechanisms underlying cardiac vulnerability.

Correlated behavioral traits in rats of the Roman selection lines.

The current theories of animal personality are based on the observation that individual variation in behavior and physiology appears to be consistent across contexts. Rats of the Roman selection lines have been originally selected for differences in shuttle-box behavior. Besides differences in active avoidance, these animals differ more generally in coping style. Roman high avoidance (RHA) rats show high levels of active avoidance, whereas Roman low avoidance (RLA) rats tend to respond with a more passive (i.e. freezing) response. Based on the two tier model of coping styles, we hypothesized that RHA rats would show high levels of offensive behavior and are more impulsive compared to RLA rats. We characterized animals in a two-way active avoidance task on five consecutive days. Thereafter animals were tested for their level of offensive aggression and impulsive behavior. The level of offensive aggression was examined in a standard resident-intruder paradigm. Furthermore, we tested aspects of impulsivity in an unpredictable operant conditioning paradigm (variable interval-15 schedule) for food reinforcement and during extinction of lever press behavior. We show that RHA rats are indeed characterized by high levels of two-way active avoidance in a shuttle-box paradigm. Surprisingly, the level of offensive aggression was higher in RLA compared to RHA rats. Consistent with the coping style interpretation, the number of lever presses in the VI-15 schedule for food reinforcement was higher in RHA rats compared to RLA rats. During a session of frustrating non-reward, RHA rats were more persistent. Taken together, results of the two-way active avoidance task and VI-15 performance in rats of the Roman selection lines fit with the two tier model of coping styles. Unexpectedly, the level of offensive aggression does not match with this model.

The acute glucocorticoid stress response does not differentiate between rewarding and aversive social stimuli in rats.

The mere presence of elevated plasma levels of corticosterone is generally regarded as evidence of compromised well-being. However, environmental stimuli do not necessarily need to be of a noxious or adverse nature to elicit activation of the stress response systems. In the present study, the physiological and neuroendocrine responses to repeated social stimuli that can be regarded as emotional opposites, i.e. social defeat and sexual behavior, were compared. Similar corticosterone responses were observed in animals confronted for the first time with either a highly aggressive male intruder or a receptive female, but a decrease was noticed in defeated rats tested during a third interaction. Only if animals are being physically attacked does the corticosterone response remain similar to the one observed during sexual behavior. In addition, the number of activated cells in the parvocellular hypothalamic paraventricular nucleus, as visualized by c-Fos immunocytochemistry, shows no difference between rats 1h after the third exposure to defeat or sex. Finally, biotelemetric recordings of heart rate, body temperature and locomotor activity show a robust response to both social stimuli that is generally, however, higher in animals being confronted with a receptive female. The data clearly indicate that acute plasma corticosterone levels are not reflecting the emotional valence of a salient stimulus. The magnitude of the response seems to be a direct reflection of the behavioral activity and hence of the metabolic requirements of activated tissues. Next to its direct metabolic role, acute increases in plasma corticosterone will have neurobiological and behavioral effects that largely depend on the neural circuitry that is activated by the stimulus that triggered its release.

Sleep deprivation impairs contextual fear conditioning and attenuates subsequent behavioural, endocrine and neuronal responses.

Sleep deprivation (SD) affects hippocampus-dependent memory formation. Several studies in rodents have shown that brief SD immediately following a mild foot shock impairs consolidation of contextual fear memory as reflected in a reduced behavioural freezing response during re-exposure to the shock context later. In the first part of this study, we examined whether this reduced freezing response is accompanied by an attenuated fear-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis. Results show that 6h of SD immediately following the initial shock results in a diminished adrenal corticosterone (CORT) response upon re-exposure to the shock context the next day. In the second part, we established whether the attenuated freezing response in SD animals is associated with reduced activation of relevant brain areas known to be involved in the retrieval and expression of fear memory. Immunohistochemical analysis of brain slices showed that the normal increase in phosphorylation of the transcription factor 3',5'-cyclic AMP response-element binding protein (CREB) upon re-exposure to the shock context was reduced in SD animals in the CA1 region of the hippocampus and in the amygdala. In conclusion, brief SD impairs the consolidation of contextual fear memory. Upon re-exposure to the context, this is reflected in a diminished behavioural freezing response, an attenuated HPA axis response and a reduction of the normal increase of phosphorylated CREB expression in the hippocampus and amygdala.

Does the early social environment affect structure and consistency of personality in wild-type male's rat?

Animal personality has been extensively studied from a functional and evolutionary point of view. Less attention has been paid to the development of personality, its phenotypic plasticity, and the influence of manipulation of early environmental factors. Here we describe the effects of manipulating the sex ratio of the litter, at postnatal day (pnd) 3, in wild-type rats, on personality traits in adulthood. We measured the treatment effects on aggression, defensive burying, and open field behavior at pnd 90 and 120, as well as on their contextual generality, and stability over time (differential and structural consistency). Main effects of litter composition were found on open field behavior at pnd 120 but not on the other behaviors. Since correlations between behaviors changed over time irrespective of the specific treatment, whereas in previous studies on unmanipulated litters this was not the case we suggest that early handling may disrupt adult personality traits. Overall the data indicate that personality is less stable over time that often assumed, having both proximate and ultimate implications.

A time for learning and a time for sleep: the effect of sleep deprivation on contextual fear conditioning at different times of the day.

STUDY OBJECTIVES: Sleep deprivation negatively affects memory consolidation, especially in the case of hippocampus-dependent memories. Studies in rodents have shown that 5 hours of sleep deprivation immediately following footshock exposure selectively impairs the formation of a contextual fear memory. In these studies, both acquisition and subsequent sleep deprivation were performed in the animals' main resting phase. However, in everyday life, subjects most often learn during their active phase. DESIGN: Here we examined the effects of sleep deprivation on memory consolidation for contextual fear in rats when the task was performed at different times of the day, particularly, at the beginning of the resting phase or right before the onset of the active phase. MEASUREMENTS AND RESULTS: Results show that sleep deprivation immediately following training affects consolidation of contextual fear, independent of time of training. However, in the resting phase memory consolidation was impaired by 6 hours of posttraining sleep deprivation, whereas, in the active phase, the impairment was only seen after 12 hours of sleep deprivation. Since rats sleep at least twice as much during the resting phase compared with the active phase, these data suggest that the effect of sleep deprivation depends on the amount of sleep that was lost. Also, control experiments show that effects of sleep deprivation were not related to the amount of stimulation the animals received and were therefore not likely an indirect effect of the sleep-deprivation method. CONCLUSION: These results support the notion that sleep immediately following acquisition, independent of time of day, promotes memory consolidation and that sleep deprivation may disrupt this process depending on the amount of sleep that is lost.

Delineation of violence from functional aggression in mice: an ethological approach.

The present study aims at delineating violence from aggression, using genetically selected high (SAL, TA, NC900) and low (LAL, TNA NC100) aggressive mouse strains. Unlike aggression, violence lacks intrinsic control, environmental constraints as well as functional endpoints. Conventional measures namely latency, frequency and duration were used initially to accomplish the objective of delineation using the above strains. However, these quantitative measures fail to reveal further details beyond the magnitude of differential aggression, especially within the high aggressive mouse strains. Hence, it was necessary to analyze further, the behavioral sequences that make up the agonistic encounter. Novel measures such as threat/(attack + chase) (T/AC) and offense/withdrawal (O/W) ratios, context dependency and first-order Markov chain analysis were used for the above purpose. Our present analyses reveal clear qualitative behavioral differences between the three high aggressive selection strains based on the following facets namely structure and context in an agonistic interaction. Structure refers to a detailed study of the agonistic interaction components (ritualistic display, offense and sensitivity to the opponent submission cues) between any two subjects (inter-male interaction for the present study). Context refers to the capacity to identify an opponent by nature of its state (free moving/anesthetized), sex and the environment (home/neutral territory). NC900 displayed context dependency and structurally a rich repertoire of agonistic interaction components with an opponent. SAL failed to show discrimination and its inter-male agonistic behavior is restricted to a repetitive and an opponent-insensitive pattern of attack and chase. TA was comparable to SAL in terms of the structure but sensitive to context variables. Thus, SAL seems to display a violent form of aggressive behavior, while NC900 display 'functional' hyperaggression against a docile opponent in an inter-male agonistic interaction.

Violent phenotype in SAL mice is inflexible and fixed in adulthood.

Violence was shown to be qualitatively different from functional hyper-aggression in mice selected for high aggression namely Short Attack Latency (SAL), Turku Aggressive (TA) and North Carolina (NC900) strains. This study aimed at investigating whether this adulthood violent phenotype as seen previously in the SAL mice is fixed and hence behaviorally inflexible right from day 1 of the experiment or consequential, i.e., subject to gradual change from functional aggression to violence. The functionally hyper-aggressive strains namely TA and NC900 strains served as controls for the study. Methodologically, behavioral (in)flexibility was studied using the overall sequential structure of agonistic behavior. In particular, intra-individual variations in the overall agonistic behavior as well as offensive, pre- and post-offensive behavior transitions, directly related to the resident-intruder interactions were investigated. The SAL mice showed the least intra-individual variation in their overall sequential agonistic structure as well as a fixed offense-oriented agonistic behavior of highest magnitude when compared with the other strains. Additionally, the pre- and post- offensive transitions were most salient in the functionally hyper-aggressive TA and NC900 strains, whereas virtually absent in the SAL mice. Thus, the violent behavior of the adult SAL mice is behaviorally inflexible or fixed, whereas the functionally hyper-aggressive behavior of the adult TA and NC900 mice is behaviorally flexible and constantly adaptive to the opponent behavior, over 3 days of repeated resident-intruder interaction.

Development of violence in mice through repeated victory along with changes in prefrontal cortex neurochemistry.

Recent reviews on the validity of rodent aggression models for human violence have addressed the dimension of pathological, maladaptive, violent forms of aggression in male rodent aggressive behaviour. Among the neurobiological mechanisms proposed for the regulation of aggressive behaviour in its normal and pathological forms, serotonin plays a major role. However, the results on the detailed mechanism are still confusing and controversial, mainly because of difficulties in extrapolating from rodent to human psychopathological behaviour. Our aim was to investigate the involvement of serotonin in pathological aggression. We subjected mice genetically selected for high (SAL, TA, NC900 lines) and low (LAL, TNA, NC100) aggression levels to a repeated resident-intruder experience (RRI mice) or to handling as a control procedure (CTR mice). Pathological aggression parameters we recorded were aggression towards females and lack of communication between the resident and its opponent. In the same mice, we measured the monoamine levels in the prefrontal cortex, a brain region strongly involved in the regulation of motivated behaviour. Our results show that SAL mice augmented their proneness to attack and showed the most pathological phenotype, with disregard of the opponent's sex, high territorial behavioural patterns, and low sensitivity to signals of subordination. In contrast, TA and NC900 augmented their proneness to attack and low discrimination of the opponent's signals, without showing offence towards females. After repeated resident-intruder experience, serotonin levels in the prefrontal cortex were significantly lower in SAL than in LAL whereas dopamine turnover was significantly higher, compared to CTR mice. Serotonin turnover was significantly reduced in all RRI mice, with no strain differences. Noradrenaline was significantly lower in aggressive mice of the TA and NC900 lines compared to their low-aggressive counterparts, with no effect of the repeated resident-intruder experience. We conclude that social experience changes prefrontal cortex neurochemistry and elicits pathologically aggressive phenotypes.

Long-lasting suppression of hippocampal cell proliferation and impaired cognitive performance by methotrexate in the rat.

Methotrexate (MTX) is a cytostatic agent widely used in combination with other agents as adjuvant chemotherapy for breast cancer and is associated with cognitive impairment as a long-term side effect in some cancer patients. This paper aimed to identify a neurobiological mechanism possibly responsible for this cognitive impairment using an animal model. The first study explored the hypothesis that MTX reduces neuronal cell proliferation. A dose-dependent long-lasting decrease in hippocampal cell proliferation was shown with Ki-67 immunocytochemistry, following a single intravenous injection of MTX (37.5-300 mg/kg). Animals treated with MTX also showed a dose-dependent transient decrease in body weight gain. In the second study, the effect of MTX (250 mg/kg) on two spatial learning tasks was examined. Animals treated with MTX learned the Morris water maze task adequately; however, these animals showed a longer latency time to cross the platform location in the probe trial, reflecting an impairment of spatial memory function. In the novel object recognition task, animals treated with MTX failed to distinguish a novel object from a familiar one, indicating a decrease in the comparator function of the hippocampus. Our studies indicated that, in the rat, MTX has a dose-dependent negative effect on hippocampal cell proliferation, and on cognitive behavior. These findings suggest that adverse effects of certain cytotoxic agents on hippocampal cell proliferation may have a potential contributory role in cognitive impairment observed in humans after chemotherapy.

Differential role of the 5-HT1A receptor in aggressive and non-aggressive mice: an across-strain comparison.

Differential role of the 5-HT(1A) receptor in aggressive and non-aggressive mice: an across-strain comparison. PHYSIOL BEHAV 00(0) 000-000, 2006. According to the serotonin (5-HT)-deficiency hypothesis of aggression, highly aggressive individuals are characterized by low brain 5-HT neurotransmission. Key regulatory mechanisms acting on the serotonergic neuron involve the activation of the somatodendritic inhibitory 5-HT(1A) autoreceptor (short feedback loop) and/or the activation of postsynaptic 5-HT(1A) receptors expressed on neurons in cortico-limbic areas (long feedback loop). In this study, we examined whether low serotonin neurotransmission is associated with enhanced 5-HT(1A) (auto)receptor activity in highly aggressive animals. Male mice (SAL-LAL, TA-TNA, NC900-NC100) obtained through different artificial-selection breeding programs for aggression were observed in a resident-intruder test. The prefrontal cortex level of 5-HT and its metabolite 5-HIAA were determined by means of HPLC. The activity of the 5-HT(1A) receptors was assessed by means of the hypothermic response to the selective 5-HT(1A) agonists S-15535 (preferential autoreceptor agonist) and 8-OHDPAT (full pre- and postsynaptic receptor agonist). Highly aggressive mice had lower serotonin levels in the prefrontal cortex and two out of three aggressive strains had higher 5-HT(1A) (auto)receptor sensitivity. The results strengthen the validity of the serotonin-deficiency hypothesis of aggression and suggest that chronic exaggerated activity of the 5-HT(1A) receptor may be a causative link in the neural cascade of events leading to 5-HT hypofunction in aggressive individuals.

A new animal welfare concept based on allostasis.

Animal welfare is an increasing issue of public concern and debate. As a result, many countries are reconsidering the way animal welfare is embedded in the legislation and rules for housing and care of animals. This requires general agreement of what animal welfare is. Unfortunately, the current science of animal welfare is less scientific than what has been claimed. In our view, it is overly guided by anthropocentric thinking about how animals ought to be handled and neglects the latest concept of physiology: 'The Allostasis Concept'. Allostasis, which means stability through change, has the potential to replace homeostasis as the core model of physiological regulation. Not constancy or freedoms, but capacity to change is crucial to good physical and mental health and good animal welfare. Therefore, not homeostasis but allostasis is at the basis of our new animal welfare concept. This paper is aimed at a broader scientific discussion of animal welfare that includes knowledge from the latest scientific developments in neurobiology and behavioral physiology, and generates views that are extremely relevant for the animal welfare discussion.

Social stress during adolescence in Wistar rats induces social anxiety in adulthood without affecting brain monoaminergic content and activity.

Adolescence has been described as an important period to acquire social competences required for adult life. It has been suggested that early stress experiences could affect the development of the brain at different levels. These changes in the brain during adolescence may be related with the development of psychopathologies such as depression and social anxiety in adulthood. In the first experiment, we examined long-term effects of repeated social stress during adolescence on adult social approach-avoidance behavior. For that purpose, adolescent male Wistar rats were exposed twice at postnatal day (Pnd) 45 and Pnd48 to the resident-intruder paradigm followed by three times psychosocial threat with the same resident. Three weeks after the last psychosocial threat experience the animals were behaviorally tested in a social approach-avoidance test. Socially stressed animals spent less time in the interaction zone with an unfamiliar male adult rat. These data suggest that animals exposed to social stress during adolescence show a higher level of social anxiety in adulthood. In the second experiment, we investigated whether these long-term effects of social stress during adolescence on behavior draw a parallel with changes in brain monoamine content, biosynthesis and turnover. Using the same experimental design as in the first experiment, HPLC analysis of various brain regions showed that there were no differences in monoamine content, monoamine biosynthesis and monoamines activity in the prefrontal cortex, hippocampus, hypothalamus and striatum in adulthood. These results indicate that long-lasting changes in social behavior following social stress during adolescence are not accompanied by changes in brain monoamine content, biosynthesis and turnover.

Individual variation in coping with stress: a multidimensional approach of ultimate and proximate mechanisms.

Ecological studies on feral populations of mice, fish and birds elucidate the functional significance of phenotypes that differ individually in their behavioral and neuroendocrine response to environmental challenge. Within a species, the capacity to cope with environmental challenges largely determines individual survival in the natural habitat. Recent studies indicate that individual variation within a species may buffer the species for strong fluctuations in the natural habitat. A conceptual framework will be presented that is based on the view that individual variation in aggressive behavior can be considered more generally as a variation in actively coping with environmental challenges. Highly aggressive individuals adopt a proactive coping style whereas low levels of aggression indicate a more passive or reactive style of coping. Coping styles have now been identified in a range of species and can be considered as trait characteristics that are stable over time and across situations. The dimension of coping style seems to be independent of an emotionality dimension. Hence, in the analysis of the proximate mechanisms of stress and adaptation, one has to consider the possibility that the mechanisms which determine the type of stress response might be independent from those underlying the magnitude of the response. The two coping styles differ in a number of important neurobiological and neuroendocrine systems. For example, proactive males differ significantly from reactive males in the homeostatic control of serotonergic activity resulting in completely opposite dose response relationships of various serotonergic drugs. The results so far show that proactive coping is characterized by a strong inhibitory control of the 5-HT neuron via its somatodendritic 5-HT(1A) autoreceptor. It is hypothesized that the regulation of serotonin release is causally related to coping style rather than emotionality. Understanding the functional individual variation as it occurs in nature and the underlying neurobiology and neuroendocrinology is fundamental in understanding individual vulnerability to stress related disease.

Untangling the neurobiology of coping styles in rodents: Towards neural mechanisms underlying individual differences in disease susceptibility.

Considerable individual differences exist in trait-like patterns of behavioral and physiological responses to salient environmental challenges. This individual variation in stress coping styles has an important functional role in terms of health and fitness. Hence, understanding the neural embedding of coping style variation is fundamental for biobehavioral neurosciences in probing individual disease susceptibility. This review outlines individual differences in trait-aggressiveness as an adaptive component of the natural sociobiology of rats and mice, and highlights that these reflect the general style of coping that varies from proactive (aggressive) to reactive (docile). We propose that this qualitative coping style can be disentangled into multiple quantitative behavioral domains, e.g., flexibility/impulse control, emotional reactivity and harm avoidance/reward processing, that each are encoded into selective neural circuitries. Since functioning of all these brain circuitries rely on fine-tuned serotonin signaling, autoinhibitory control mechanisms of serotonergic neuron (re)activity are crucial in orchestrating general coping style. Untangling the precise neuromolecular mechanisms of different coping styles will provide a roadmap for developing better therapeutic strategies of stress-related diseases.

Trait aggressiveness does not predict social dominance of rats in the Visible Burrow System.

Hierarchical social status greatly influences health and well-being in mammals, including humans. The social rank of an individual is established during competitive encounters with conspecifics. Intuitively, therefore, social dominance and aggressiveness may seem intimately linked. Yet, whether an aggressive personality trait may predispose individuals to a particular rank in a social colony setting remains largely unclear. Here we tested the hypothesis that high trait aggressiveness in Wildtype Groningen (WTG) rats, as assessed in a classic resident-intruder offensive aggression paradigm predicts social dominance in a mixed-sex colony housing using the Visible Burrow System (VBS). We also hypothesized that hierarchical steepness, as reflected in the number and intensity of the social conflicts, positively correlates with the average level of trait aggressiveness of the male subjects in the VBS. Clear and stable hierarchical ranking was formed within a few days in VBS colonies as indicated and reflected by a rapid loss of body weight in subordinates which stabilized after 2-3days. Social conflicts, that occurred mainly during these first few days, also resulted in bite wounds in predominantly subordinate males. Data clearly showed that trait aggressiveness does not predict dominance status. The most aggressive male in a mixed sex group of conspecifics living in a closed VBS environment does not always become the dominant male. In addition, data did not convincingly indicate that in colonies with only highly aggressive males, agonistic interactions were more intense. Number of bite wounds and body weight loss did not positively correlate with trait-aggressiveness of subordinates. In this study, rats from this wild-derived rat strain behave differently from Long-Evans laboratory rats that have been studied up till now in many experiments using the VBS. Strain dependent differences in the capacity to display appropriate social behavior fitting an adaptive strategy to a high or low social ranking position probably play an important role in the level of perceived stress in mixed sex social colonies like the VBS.