Post-weaning social isolation induces abnormal forms of aggression in conjunction with increased glucocorticoid and autonomic stress responses

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Abstract

We showed earlier that social isolation from weaning (a paradigm frequently used to model social neglect in children) induces abnormal forms of attack in rats, and assumed that these are associated with hyperarousal. To investigate this hypothesis, we deprived rats of social contacts from weaning and studied their behavior, glucocorticoid and autonomic stress responses in the resident-intruder paradigm at the age of 82 days. Social isolation resulted in abnormal attack patterns characterized by attacks on vulnerable targets, deficient social communication and increased defensive behaviors (defensive upright, flight, freezing). During aggressive encounters, socially deprived rats rapidly switched from one behavior to another, i.e. showed an increased number of behavioral transitions as compared to controls. We tentatively term this behavioral feature “behavioral fragmentation” and considered it a form of behavioral arousal. Basal levels of plasma corticosterone regularly assessed by radioimmunoassay between 27 and 78 days of age were not affected. In contrast, aggression-induced glucocorticoid responses were approximately doubled by socially isolation. Diurnal oscillations in heart rate assessed by in vivo biotelemetry were not affected by social isolation. In contrast, the aggression-induced increase in heart rate was higher in socially isolated than in socially housed rats. Thus, post-weaning social isolation induced abnormal forms of aggression that developed on the background of increased behavioral, endocrine and autonomic arousal. We suggest that this paradigm may be used to model aggression-related psychopathologies associated with hyperarousal, particularly those that are triggered by adverse rearing conditions.

Graphical abstract

Research highlights

► Post-weaning social isolation induced abnormal forms of aggression in adult rats. ► Abnormal aggression was associated with a marked hyperarousal. ► Hyperarousal entailed the behavioral, stress-endocrine and autonomic levels. ► This paradigm may model emotional violence elicited by adverse rearing conditions.

Introduction

Brain mechanisms of aggression control are usually studied in the resident/intruder paradigm in rodents. In order to identify the brain centers involved in, and their role in aggressive behavior, this paradigm was employed in conjunction with a variety of techniques including brain lesions, electrophysiology, immunocytochemistry, systemic and local pharmacologic manipulations, transgenic techniques, in vivo microdialysis of neuropeptide release during aggression, etc. (Abrahams et al., 2005, Albert et al., 1989, Chiavegatto et al., 2001, Ferris et al., 2006, Gobrogge et al., 2009, Kruk et al., 1979, Lonstein and Stern, 1997, Veenema et al., 2010).

Recently, this basic model of aggression research was enriched by novel behavioral approaches that allow the identification of abnormal patterns of aggression (de Almeida and Miczek, 2002, de Boer et al., 2003, Haller and Kruk, 2006, Haller et al., 2001, Miczek et al., 2002, Natarajan et al., 2009). These approaches are based on the fact that aggressiveness in animals follows certain behavioral “rules” that mitigate the conflict between potentially dangerous forms of behavior and survival. It was suggested that animal aggression can be considered abnormal if there was a mismatch between provocation and response (i.e. the aggressive response surpassed species-typical levels; de Almeida and Miczek, 2002, Miczek et al., 2002), if attacks were targeted on inappropriate partners (e.g. females; de Boer et al., 2003, Natarajan et al., 2009) or inappropriate body parts (i.e. those prone to serious injury like the head, throat and belly; Haller and Kruk, 2006, Haller et al., 2005, Haller et al., 2001), if attacks were not signaled by threats, and/or the submissive signals of opponents were ignored (de Boer et al., 2003, Haller and Kruk, 2006, Haller et al., 2001, Natarajan et al., 2009). In general, these criteria are similar to particularities of human aggressiveness that are expressed in certain aggression-related psychopathologies (Haller and Kruk, 2006, Haller et al., 2005). Three laboratory models of abnormal aggression were developed so far. The escalated aggression model involves aggressiveness that surpasses species-typical levels and is induced by frustration or provocation (de Almeida and Miczek, 2002, Miczek et al., 2002). This model is based on the attack priming phenomenon discovered by Potegal (1992). The hypoarousal model involves the chronic limitation of glucocorticoid secretion, which mimics the low glucocorticoid levels seen in violent, antisocially disordered people (Haller et al., 2001, Haller and Kruk, 2006). Finally, genetic models make use of mice selected for high aggressiveness, rats selected for low anxiety, or selected subpopulations of feral rats (de Boer et al., 2003, Natarajan et al., 2009, Neumann et al., 2010). Abnormal features of aggression were observed in all these models. Aggressive behavior was increased on the long run by a variety of early adverse experiences (maternal separation: Suomi, 1997, Veenema et al., 2006, Veenema et al., 2007; early defeat: Delville et al., 1998; Wommack et al., 2003). Although abnormal features of aggression were not investigated in these models, they have the potential to become valuable novel models of abnormal aggression.

The models briefly reviewed above have translational value and allow the study of regulatory mechanisms that underlie abnormal responses to provocation, the development of callous-unemotional traits, and the impact of genetic predispositions on aggressiveness. Neither of these models covers an important form of abnormal aggression, namely the one that is precipitated by exacerbated emotional responses. It is generally believed that abnormal human aggression is of two major types: emotional and callous-unemotional violence (Blair, 2001, Meloy, 2006, Scarpa and Raine, 1997, Vitiello et al., 1990). Emotional violence appears to be driven by strong stress responses, which feature is believed to be causally related to aggressive traits (Chida and Hamer, 2008, Murray-Close et al., 2008, Smith and Gallo, 1999, Suls and Wan, 1993). Early determinants of emotional aggression often are adverse experiences suffered during childhood, particularly social neglect (Chapple et al., 2005, Goldstein et al., 2006, Heinrichs et al., 2003, Pesonen et al., 2010, Teicher et al., 2003, Uchino et al., 1996). Therefore, one can hypothesize that models of early social isolation would mimic aspects of psychopathologies that involve outbursts of emotional aggression.

In line with this assumption, adult aggressiveness was increased in animals that were submitted to post-weaning social isolation (also called social deprivation) (rats: Day et al., 1982, Potegal and Einon, 1989; rhesus monkeys: Harlow et al., 1965, Kempes et al., 2008; guinea pigs: Sachser et al., 1994). Increased levels of aggressiveness, however, cannot be considered abnormal per se, at least not according to the criteria outlined above. We have recently shown that post-weaning social isolation not only increases attack counts, but leads to a dramatic increase in attacks aimed at vulnerable body parts of opponents, and to a similarly dramatic decrease in the social signaling of attacks. In addition, the aggressiveness of socially deprived rats was ambiguous, as increased attack counts were associated with increased defensiveness. We hypothesized that this abnormal behavioral pattern is associated with aggression-induced hyperarousal (Toth et al., 2008). This assumption was based on literature findings, which, however, are conflicting to a certain extent. For example, post-weaning social isolation increased stress response under certain conditions, but decreased it or was without consequences under other conditions (Gentsch et al., 1981, Sanchez et al., 1998, Schrijver et al., 2002, van den Berg et al., 1999, Weiss et al., 2004). Therefore, the present study aimed at studying glucocorticoid and autonomic stress responses in socially reared and socially deprived rats that were exposed to aggressive encounters, to assess whether abnormal features of behavior develop under conditions of hyperarousal in socially deprived rats. Observations made during these experiments prompted a third one, where the frequency and duration of behaviors were compared to investigate the possibility of identifying symptoms of behavioral hyperarousal in socially deprived rats. Ultimately, these studies aimed at developing a model of hyperarousal-driven aggressiveness that may be used in future studies to study the brain mechanisms underlying this specific form of abnormal aggression.

Section snippets

Animals and housing conditions

Subjects were male Wistar rats (Charles-River) from the breeding facility of our Institute. Pups were weaned on the 21th postnatal day and housed socially or individually for 7–8 weeks in Makrolon cages measuring 45 × 35 × 25 cm. Food and water were available ad libitum throughout, while temperature and relative humidity were kept at 22 ± 2 °C and 60 ± 10%, respectively. Rats were maintained in a light cycle of 12:12 h with lights off at 1000 h. The weight of subjects was 400–450 g during testing. The

Experiment 1—endocrine arousal

To control for the effects of repeated blood sampling during the developmental period, data were analyzed by two-factor ANOVA (Factor 1, social background; Factor 2, blood sampling history). In line with earlier observations, social isolation increased the frequency of hard attacks (Fsocial background(1,45) = 4.8; p < 0.04) without altering the number of soft bites (Fsocial background(1,45) = 0.04; p > 0.8). Total attack counts showed a marginal increase (Fsocial background(1,45) = 2.66; p < 0.08). Blood

Discussion

Social deprivation from weaning increased the percentage of vulnerable attacks and decreased the signaling of attack intentions. In addition and surprisingly, socially deprived rats frequently attacked from unusual positions e.g. from submissive posture, defensive upright or during escape. In the third experiment, where behavior was analyzed in detail, defensive behaviors were also increased by social deprivation. These findings replicate those published earlier (Toth et al., 2008), and support

Conflicts of interest

The authors declare no conflict of interest.

Acknowledgments

This work was supported by OTKA Grant No. 82069.

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