Research report
The neural background of hyper-emotional aggression induced by post-weaning social isolation

https://doi.org/10.1016/j.bbr.2012.04.025Get rights and content

Abstract

Post-weaning social isolation in rats is believed to model symptoms of early social neglect-induced externalizing problems including aggression-related problems. We showed earlier that rats reared in social isolation were hyper-aroused during aggressive contacts, delivered substantially more attacks that were poorly signaled and were preferentially aimed at vulnerable body parts of opponents (head, throat and belly). Here we studied the neural background of this type of aggression by assessing the expression of the activation marker c-Fos in 22 brain areas of male Wistar rats submitted to resident–intruder conflicts. Post-weaning social isolation readily produced the behavioral alterations noticed earlier. Social isolation significantly increased the activation of brain areas that are known to directly or indirectly control inter-male aggression. Particularly, the medial and lateral orbitofrontal cortices, anterior cingulate cortex, bed nucleus of the stria terminalis, medial and basolateral amygdala, hypothalamic attack area, hypothalamic paraventricular nucleus and locus coeruleus showed increased activations. This contrasts our earlier findings obtained in rats with experimentally induced hypoarousal, where abnormal attack patterns were associated with over-activated central amygdala, lateral hypothalamus, and ventrolateral periaqueductal gray that are believed to control predatory attacks. We have observed no similar activation patterns in rats socially isolated from weaning. In summary, these findings suggest that despite some phenotypic similarities, the neuronal background of hypo and hyperarousal-associated abnormal forms of aggression are markedly different. While the neuronal activation patterns induced by normal rivalry and hypoarousal-driven aggression are qualitative different, hyperarousal-associated aggression appears to be an exaggerated form of rivalry aggression.

Highlights

► Post-weaning isolation induces hyper-emotional, exaggerated, abnormal aggression. ► Brain (c-Fos) activation patterns were compared to normal rivalry aggression. ► Amygdalar, hypothalamic over-activations might be linked to exaggerated aggression. ► The over-activated stress-related areas might be associated to hyper-emotionality. ► These mechanisms are different from those of hypoarousal-driven abnormal aggression.

Introduction

Early life stressors have long-term consequences for emotion control and may contribute to the development of psychopathologies in later life. Particularly, early social neglect emerged as a predictor and a worsening factor of externalizing problems and it is believed to significantly contribute to emotionally laden aggressive behavior that is expressed from childhood into adulthood [1], [2], [3], [4], [5], [6]. Similar to humans, aggressiveness was increased in adult animals that were submitted to post-weaning social isolation, a putative model of early social neglect [7], [8], [9], [10], [11].

Recently, novel techniques were developed to identify abnormal patterns of aggression [12], [13], [14], [15], [16], [17]. By making use of such novel behavioral approaches, we showed that rats socially isolated from weaning not only showed increased attack counts but poorly signaled their attacks, preferentially aimed bites towards vulnerable body parts of opponents (head, throat and belly), and showed increased defensive behavior despite increased attack counts [18]. This increase in defensiveness was shown on the expense of grooming behavior, while other social (offense, dominance, submission, social investigation) and nonsocial (exploration, resting) behaviors were unaltered [18]. These behavioral malfunctions were associated with high emotional arousal as shown by increased glucocorticoid and autonomic responses to aggressive encounters [19]. In the present study, we used the post-weaning social isolation model to study the interaction between emotional states and the brain mechanisms that control aggression.

The neural background of normal (rivalry) aggression was addressed in several studies by means of c-Fos immunohistochemistry [20], [21], [22]. Activation patterns were shown to be highly similar across species: the medial amygdala, the bed nucleus of the stria terminalis, hypothalamic mechanisms involved in attack control (called “hypothalamic attack area” in the rat), the hypothalamic paraventricular nucleus and the periaqueductal gray were implicated in hamsters [20], rats [21] and mice [22]. Markedly different activation patterns were seen in models of abnormal aggression. Mice genetically selected for heightened aggression showed abnormal attack patterns, decreased autonomic reactivity, as well as altered brain activation patterns in the prefrontal cortex, lateral septum, central amygdala and the periaqueductal gray [23]. In a rat model of hypoarousal-associated abnormal aggression, i.e. in rats with experimentally reduced corticosterone levels, altered activations in the lateral hypothalamus, central amygdala and the periaqueductal gray were observed [24]. In summary, the neural control of abnormal aggression observed in these two hypoarousal-associated models showed multiple similarities, but was qualitatively different from that of normal (rivalry) aggression, suggesting that the physiological state of animals has a large impact on the neural background of aggressive behavior.

The post-weaning social isolation model offers a new paradigm to study the interaction between emotional states and the brain mechanisms that control aggression. In physiological terms, the hypo and hyperarousal models represent two extremes. At behavioral level, the models partly overlap, as faulty attack targeting and deficient social signaling were noticed in both. Yet, post-weaning social isolation induced higher levels of attack on the background of increased defensiveness that was not observed in the hypoarousal model. Studying the neural background of post-weaning isolation-induced abnormal aggression aims at clarifying putative similarities and differences in the control of hypoarousal and hyperarousal-associated aggression. At the same time, this study may provide hints on the neural background of externalizing problems that are triggered by a comparable developmental factor, e.g. social neglect and shows phenomenological similarities in terms of both behavioral (aggressiveness shows abnormal features) and physiological (exacerbated emotionality) responses.

Here we studied aggression-induced neural activation patterns in rats submitted to post-weaning social isolation by focusing on aggression-related and stress-related structures. We also studied brain areas that are believed to control predation (e.g. mouse killing in rats, and attacks on rats by cats [25], [26]), as a comparison to chronic glucocorticoid deficiency-induced (hypoarousal-driven) aggression, where such brain areas (e.g. the central amygdala, lateral hypothalamus, and ventral aspects of the periaqueductal gray) were activated ([24]). Finally, we investigated the dorsal premammillary nucleus, which was shown to be a very important brain center for defensive behavior against a predator or a dominant conspecific [27], [28].

Section snippets

Animals

Male Wistar rats obtained from the breeding facility of our Institute were used in the present study. The breeding line originally derived from Charles River Laboratories. Pups were weaned on the 21st postnatal day and were either housed individually (n = 25), or in groups of 4 rats (n = 20) for 7 weeks in Makrolon cages measuring 42 × 26 × 19 cm. When group-housed animals reached the weight of approximately 200 g, they were moved to Makrolon cages measuring 60 × 38 × 19 cm. Rats were not handled except for

Behavioral findings

Subjects showed attack patterns similar to our earlier findings. Compared to group-housed animals, isolated animals attacked more frequently during aggressive encounters (soft bites: U = 30; p = 0.032; hard bites: U = 22; p = 0.011; Total bites: U = 18; p = 0.01; Fig. 1). The latency of the first attack was significantly reduced as compared to the group-housed rats (soft bites: 503.5 ± 119.7 vs. 862.7 ± 128.9; U = 97.5; p = 0.044; hard bites: 406.6 ± 127.4 vs. 1066.6 ± 75.5; U = 110.5; p = 0.01; total bites: 332.2 ± 112.9

Discussion

We believe that this study led to two interesting observations. Firstly, brain areas directly or indirectly involved in the control of attacks (prefrontal cortex, bed nucleus of the stria terminalis, medial and basolateral amygdala, hypothalamic attack area) and those controlling stress responses (hypothalamic paraventricular nucleus, locus coeruleus) were over-activated by aggression in rats submitted to post-weaning social isolation. Secondly, the activation of brain areas involved in the

Acknowledgements

This work was supported by OTKA Grants nos. 76283 and 82069. Gabor Nyiri contributed to the preparation of the 3D image shown in the graphical abstract.

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