Sietse F. de Boer

Coping styles and behavioural flexibility: towards underlying mechanisms

A coping style (also termed behavioural syndrome or personality) is defined as a correlated set of individual behavioural and physiological characteristics that is consistent over time and across situations. This relatively stable trait is a fundamental and adaptively significant phenomenon in the biology of a broad range of species, i.e. it confers differential fitness consequences under divergent environmental conditions. Behavioural flexibility appears to be an important underlying attribute or feature of the coping style that might explain consistency across situations. Proactive coping is characterized by low flexibility expressed as rather rigid, routine-like behavioural tendencies and reduced impulse control (behavioural inhibition) in operant conditioning paradigms. This article summarizes some of the evidence that individual differentiation in behavioural flexibility emerges as a function of underlying variability in the activation of a brain circuitry that includes the prefrontal cortex and its key neurochemical signalling pathways (e.g. dopaminergic and serotonergic input). We argue that the multidimensional nature of animal personality and the terminology used for the various dimensions should reflect the differential pattern of activation of the underlying neuronal network and the behavioural control function of its components. Accordingly, unravelling the molecular mechanisms that give rise to individual differences in the coping style will be an important topic in biobehavioural neurosciences, ecology and evolutionary biology.

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-HT1A 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.

Defensive burying in rodents: ethology, neurobiology and psychopharmacology

Defensive burying refers to the typical rodent behavior of displacing bedding material with vigorous treading-like movements of their forepaws and shoveling movements of their heads directed towards a variety of noxious stimuli that pose a near and immediate threat, such as a wall-mounted electrified shock-prod. Since its introduction 25 years ago by Pinel and Treit [J. Comp. Physiol. Psychol. 92 (1978) 708], defensive (shock-prod) burying has been the focus of a considerable amount of research effort delineating the methodology/ethology, psychopharmacology and neurobiology of this robust and species-specific active avoidance or coping response. The present review gives a summary of this research with special reference to the behavioral (face and construct) and pharmacological (predictive) validity of the shock-prod burying test as an animal model for human anxiety. Emphasis is also placed on some recent modifications of the paradigm that may increase its utility and reliability as to individual differences in expressed emotional coping responses and sensitivity to pharmacological treatments. Overall, the behavioral and physiological responses displayed in the shock-prod paradigm are expressions of normal and functionally adaptive coping patterns and the extremes of either active (i.e., burying) or passive (i.e., freezing) forms of responding in this test cannot simply be regarded as inappropriate, maladaptive or pathological. For this reason, the shock-prod paradigm is not an animal model for anxiety disorder or for any other psychiatric disease, but instead possesses a high degree of face and construct validity for normal and functionally adaptive human fear and anxious apprehension. However, the apparent good pharmacological validation (predictive validity) of this test reinforces the view that normal and pathological anxiety involves, at least partly, common neurobiological substrates. Therefore, this paradigm is not only suitable for screening potential anxiolytic properties of new drugs, but seems to be especially valuable for unraveling the neural circuitry and neurochemical mechanisms underlying the generation of active and passive coping responses as different expressions of anxiety.

Long-term effects of social stress on brain and behavior: a focus on hippocampal functioning.

In order to study mechanisms involved in the etiology of human affective disorders, there is an abundant use of various animal models. Next to genetic factors that predispose for psychopathologies, environmental stress is playing an important role in the etiology of these mental diseases. Since the majority of stress stimuli in humans that lead to psychopathology are of social nature, the study of consequences of social stress in experimental animal models is very valuable. The present review focuses on one of these models that uses the resident-intruder paradigm. In particular the long-lasting effects of social defeat in rats will be evaluated. Data from our laboratory on the consequences of social defeat on emotional behavior, stress responsivity and serotonergic functionality are presented. Furthermore, we will go into detail on hippocampal functioning in socially stressed rats. Very recent results show that there is a differential effect of a brief double social defeat and repetitive social defeat stress on dendritic remodeling in hippocampal CA3 neurons and that this has repercussions on hippocampal LTP and LTD. Both the structural and electrophysiological changes of principal neurons in the hippocampal formation after defeat are discussed as to their relationship with the maintenance in cognitive performance that was observed in socially stressed rats. The results are indicative of a large dynamic range in the adaptive plasticity of the brain, allowing the animals to adapt behaviorally to the previously occurred stressful situation with the progression of time.

Individual differences in plasma catecholamine and corticosterone stress responses of wild-type rats: Relationship with aggression

Plasma noradrenaline (NA), adrenaline (A), and corticosterone (CS) responses to social and nonsocial stressors were studied in male members of a strain of wild-type rats, widely differing in their level of aggression. The aggressiveness was preliminarily established by measuring the latency time to attack (ALT) a male intruder in a standard resident-intruder test. Animals were then provided with a jugular vein cannula for blood sampling during stress exposure. Implanted rats were randomly assigned to 3 experimental treatments: social stress (defeat experience, SD), nonsocial stress (presentation of a shock-prod, SP) and control (animals undisturbed in their home cages, CTR). A significant correlation was found between ALT and the amount of time spent in burying the probe in SP rats: the more aggressive the animal, the higher the rate of burying behavior. SD induced a much stronger effect on plasma NA, A, and CS concentrations than SP. A significant negative correlation was found between ALT scores and values of the area under the response time curve for NA and A, in both SD and SP situations: the more aggressive the animal, the higher the catecholaminergic reactivity to the stressors. On the contrary, no evidence of a correlation between aggressiveness and plasma corticosterone responses was found, neither in SD nor in SP rats. These findings in an unselected strain of wild-type rats confirmed that an aggressive/active coping strategy is associated with a high sympathetic-adrenomedullary activation and support the concept of individual differentiation in coping styles as a coherent set of behavioral and neuroendocrine characteristics.

Neurobiology of escalated aggression and violence.

Psychopathological violence in criminals and intense aggression in fruit flies and rodents are studied with novel behavioral, neurobiological, and genetic approaches that characterize the escalation from adaptive aggression to violence. One goal is to delineate the type of aggressive behavior and its escalation with greater precision; second, the prefrontal cortex (PFC) and brainstem structures emerge as pivotal nodes in the limbic circuitry mediating escalated aggressive behavior. The neurochemical and molecular work focuses on the genes that enable invertebrate aggression in males and females and genes that are expressed or suppressed as a result of aggressive experiences in mammals. The fruitless gene, immediate early genes in discrete serotonin neurons, or sex chromosome genes identify sexually differentiated mechanisms for escalated aggression. Male, but not female, fruit flies establish hierarchical relationships in fights and learn from previous fighting experiences. By manipulating either the fruitless or transformer genes in the brains of male or female flies, patterns of aggression can be switched with males using female patterns and vice versa. Work with Sts or Sry genes suggests so far that other genes on the X chromosomes may have a more critical role in female mouse aggression. New data from feral rats point to the regulatory influences on mesocortical serotonin circuits in highly aggressive animals via feedback to autoreceptors and via GABAergic and glutamatergic inputs. Imaging data lead to the hypothesis that antisocial, violent, and psychopathic behavior may in part be attributable to impairments in some of the brain structures (dorsal and ventral PFC, amygdala, and angular gyrus) subserving moral cognition and emotion.

Individual Variation in Aggression of Feral Rodent Strains: A Standard for the Genetics of Aggression and Violence?

This article summarizes the broad individual differences in aggressiveness and its relationship with several other behavioral, physiological, and neurobiological characteristics that exist in an outbred laboratory strain of male feral rats. 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 they react to various other environmental challenges, it is argued that the individuals level of offensiveness is an important indicator and component of a more traitlike behavioral physiological response pattern (coping strategy) to environmental demands. The coping style of aggressive animals is principally aimed at a (pro)active prevention or manipulation of a stressor, whereas the nonaggressive individuals tend to passively accept or react to it. The (pro)active and reactive/passive behavioral coping styles are clearly associated with distinct patterns of autonomic/endocrine (re)activity and underlying neurobiological correlates and determinants. Consequently, these individual differences in aggression/coping style may not only determine the individual vulnerability to stress-related disease, and hence be an important factor in the population dynamics of the species, but may also determine responsivity to pharmacotherapeutic treatments. From an animal modeling point of view, it is argued that the aggressive extremes of this variation may, under the proper testing conditions, have an enhanced propensity to develop pathological forms of aggression and/or coping, for example, antisocial traits, violence, or impulsivity disorders. Finally, it is proposed that the use of these feral animals as base “material” for genetic association (i.e., QTL search, mRNA differential expression, nucleic acid microarray analysis) and manipulation (i.e., gene silencing or amplification by antisense ODN, siRNA, and/or viral gene-transfer methodologies) studies would most likely be the best option for dissecting successfully the genetic basis of both normal and pathological forms of aggression and/or coping.

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.

Serotonin transporter deficiency in rats improves inhibitory control but not behavioural flexibility

Impulsivity and aggression have been suggested to inversely correlate with central serotonin (5‐HT) levels in a trait‐like manner. However, this relationship is far from straightforward. In the present study we addressed the effect of lifelong reduced or absent serotonin transporter (SERT) function, which is associated with constitutively increased extracellular 5‐HT levels, on impulsivity and aggression. We used unique SERT knockout rats in a resident–intruder test, five‐choice serial reaction time task and serial reversal learning task to assay aggression, inhibitory control and behavioural flexibility, respectively. Homozygous SERT knockout rats (SERT –/–) displayed reduced aggression and improved inhibitory control, but unchanged behavioural flexibility. The behavioural phenotype of heterozygous SERT knockout rats (SERT +/–) was not different from that of wild‐type controls in any of the behavioural paradigms. We determined monoamine (metabolite) tissue levels in the medial prefrontal cortex, orbitofrontal cortex, lateral hypothalamus, raphe nuclei and cerebrospinal fluid, and found that the 5‐HT levels, but not other monoamine tissue levels, were reduced in SERT –/– rats. In addition, the 5‐hydroxyindoleacetic acid (5‐HIAA)/5‐HT ratio in cerebrospinal fluid was increased in these rats. In conclusion, our data show that the absence of the SERT affects aggression and inhibitory control, but not behavioural flexibility, characteristics that may reflect the trait‐like consequences of constitutive changes in central 5‐HT levels.

The resident-intruder paradigm: a standardized test for aggression, violence and social stress.

This video publication explains in detail the experimental protocol of the resident-intruder paradigm in rats. This test is a standardized method to measure offensive aggression and defensive behavior in a semi natural setting. The most important behavioral elements performed by the resident and the intruder are demonstrated in the video and illustrated using artistic drawings. The use of the resident intruder paradigm for acute and chronic social stress experiments is explained as well. Finally, some brief tests and criteria are presented to distinguish aggression from its more violent and pathological forms.