Research reportThe neural background of hyper-emotional aggression induced by post-weaning social isolation
Graphical abstract
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.
References (55)
- et al.
Identifying and predicting problem behavior trajectories among pre-school children investigated for child abuse and neglect
Child Abuse and Neglect
(2011) - et al.
The environment, hormones, and aggressive behaviour: a 5-year-study in guinea pigs
Psychoneuroendocrinology
(1994) - et al.
Aggression escalated by social instigation or by discontinuation of reinforcement (frustration) in mice: inhibition by anpirtoline: a 5-HT1B receptor agonist
Neuropsychopharmacology
(2002) - et al.
Normal and abnormal aggression: human disorders and novel laboratory models
Neuroscience and Biobehavioral Reviews
(2006) - et al.
Post-weaning social isolation induces abnormal forms of aggression in conjunction with increased glucocorticoid and autonomic stress responses
Hormones and Behavior
(2011) - et al.
Mating and agonistic behavior produce different patterns of Fos immunolabeling in the male Syrian hamster brain
Neuroscience
(1995) - et al.
Patterns of violent aggression-induced brain c-fos expression in male mice selected for aggressiveness
Physiology and Behavior
(2006) Attack elicited in rats by electrical stimulation of the lateral hypothalamus
Physiology and Behavior
(1971)- et al.
Neuropharmacology of brain-stimulation-evoked aggression
Neuroscience and Biobehavioral Reviews
(1999) The medial hypothalamic defensive system: hodological organization and functional implications
Pharmacology Biochemistry and Behavior
(2002)
The effect of neurokinin1 receptor blockade on territorial aggression and in a model of violent aggression
Biological Psychiatry
Hypothalamic substrates for brain stimulation-induced attack, teeth-chattering and social grooming in the rat
Brain Research
Functional mapping of the prosencephalic systems involved in organizing predatory behavior in rats
Neuroscience
Aggression, and some related psychological constructs (anger, hostility, and impulsivity); some comments from a research project
Neuroscience and Biobehavioral Reviews
Problems in the study of rodent aggression
Hormones and Behavior
Increased volume and neuronal number of the basolateral nuclear group of the amygdaloid body in aggressive dogs
Behavioural Brain Research
Reductions in aggression and dominance status in guinea pigs following bilateral lesions in the basolateral amygdala or lateral septum
Physiology and Behavior
Differential effects of excitotoxic basolateral and corticomedial lesions of the amygdala on the behavioural and endocrine responses to either sexual or aggression-promoting stimuli in the male rat
Brain Research
Regulation of feline aggression by the bed nucleus of stria terminalis
Brain Research Bulletin
Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates
Neuroscience and Biobehavioral Reviews
The activation of prefrontal cortical neurons in aggression – a double labeling study
Behavioural Brain Research
Emotion and attention interactions in social cognition: brain regions involved in processing anger prosody
Neuroimage
Behavioural and neurochemical effects of post-weaning social isolation in rodents-relevance to developmental neuropsychiatric disorders
Neuroscience and Biobehavioral Reviews
The hypothalamus: cross-roads of endocrine and behavioural regulation in grooming and aggression
Neuroscience and Biobehavioral Reviews
Genomic and non-genomic effects of glucocorticoids on aggressive behavior in male rats
Psychoneuroendocrinology
Molecular basis of aggression
Trends in Neurosciences
The activation of raphe serotonergic neurons in normal and hypoarousal-driven aggression: a double labeling study in rats
Behavioural Brain Research
Cited by (63)
Early life stress and altered social behaviors: A perspective across species
2023, Neuroscience ResearchThe role of social isolation stress in escalated aggression in rodent models
2022, Neuroscience ResearchCitation Excerpt :Therefore, the findings of these studies indicate that PWSI decreases neural activation in response to social encounters. A contrasting pattern was observed in other male Wistar rat studies, which reported that PWSI induced qualitatively abnormal patterns of aggressive behavior (Tóth et al., 2012, 2011, 2008). The analysis of c-Fos expression after agnostic encounter revealed that PWSI Wistar rats exhibited hyperactivation of several brain areas, including the mPFC, orbitofrontal cortex, cingulate cortex, BNST, medial amygdala, BLA, and mediobasal hypothalamus (which include VMH), as well as hyperactivation of stress-related structures, such as the PVN and locus coeruleus, when compared with group-housed controls (Biro et al., 2017; Tóth et al., 2012).
Neurobiology of the lateral septum: regulation of social behavior
2022, Trends in Neurosciences