Neural mechanisms of predatory aggression in rats-implications for abnormal intraspecific aggression

Our recent studies showed that brain areas that are activated in a model of escalated aggression overlap with those that promote predatory aggression in cats. This finding raised the interesting possibility that the brain mechanisms that control certain types of abnormal aggression include those involved in predation. However, the mechanisms of predatory aggression are poorly known in rats, a species that is in many respects different from cats. To get more insights into such mechanisms, here we studied the brain activation patterns associated with spontaneous muricide in rats. Subjects not exposed to mice, and those which did not show muricide were used as controls. We found that muricide increased the activation of the central and basolateral amygdala, and lateral hypothalamus as compared to both controls; in addition, a ventral shift in periaqueductal gray activation was observed. Interestingly, these are the brain regions from where predatory aggression can be elicited, or enhanced by electrical stimulation in cats. The analysis of more than 10 other brain regions showed that brain areas that inhibited (or were neutral to) cat predatory aggression were not affected by muricide. Brain activation patterns partly overlapped with those seen earlier in the cockroach hunting model of rat predatory aggression, and were highly similar with those observed in the glucocorticoid dysfunction model of escalated aggression. These findings show that the brain mechanisms underlying predation are evolutionarily conservative, and indirectly support our earlier assumption regarding the involvement of predation-related brain mechanisms in certain forms of escalated social aggression in rats

Median raphe region stimulation alone generates remote, but not recent fear memory traces

The median raphe region (MRR) is believed to control the fear circuitry indirectly, by influencing the encoding and retrieval of fear memories by amygdala, hippocampus and prefrontal cortex. Here we show that in addition to this established role, MRR stimulation may alone elicit the emergence of remote but not recent fear memories. We substituted electric shocks with optic stimulation of MRR in C57BL/6N male mice in an optogenetic conditioning paradigm and found that stimulations produced agitation, but not fear, during the conditioning trial. Contextual fear, reflected by freezing was not present the next day, but appeared after a 7 days incubation. The optogenetic silencing of MRR during electric shocks ameliorated conditioned fear also seven, but not one day after conditioning. The optogenetic stimulation patterns (50Hz theta burst and 20Hz) used in our tests elicited serotonin release in vitro and lead to activation primarily in the periaqueductal gray examined by c-Fos immunohistochemistry. Earlier studies demonstrated that fear can be induced acutely by stimulation of several subcortical centers, which, however, do not generate persistent fear memories. Here we show that the MRR also elicits fear, but this develops slowly over time, likely by plastic changes induced by the area and its connections. These findings assign a specific role to the MRR in fear learning. Particularly, we suggest that this area is responsible for the durable sensitization of fear circuits towards aversive contexts, and by this, it contributes to the persistence of fear memories. This suggests the existence a bottom-up control of fear circuits by the MRR, which complements the top-down control exerted by the medial prefrontal cortex

Effects of adverse early-life events on aggression and anti-social behaviours in animals and humans

We review the impact of early adversities on the development of violence and antisocial behaviour in humans, and present three aetiological animal models of escalated rodent aggression, each disentangling the consequences of one particular adverse early-life factor. A review of the human data, as well as those obtained with the animal models of repeated maternal separation, post-weaning social isolation and peripubertal stress, clearly shows that adverse developmental conditions strongly affect aggressive behaviour displayed in adulthood, the emotional responses to social challenges and the neuronal mechanisms activated by conflict. Although similarities between models are evident, important differences were also noted, demonstrating that the behavioural, emotional and neuronal consequences of early adversities are to a large extent dependent on aetiological factors. These findings support recent theories on human aggression, which suggest that particular developmental trajectories lead to specific forms of aggressive behaviour and brain dysfunctions. However, dissecting the roles of particular aetiological factors in humans is difficult because these occur in various combinations; in addition, the neuroscientific tools employed in humans still lack the depth of analysis of those used in animal research. We suggest that the analytical approach of the rodent models presented here may be successfully used to complement human findings and to develop integrative models of the complex relationship between early adversity, brain development and aggressive behaviour. © 2014 British Society for Neuroendocrinology

Alternating Hemiplegia of Childhood-Related Neural and Behavioural Phenotypes in Na+,K+-ATPase α3 Missense Mutant Mice

Missense mutations in ATP1A3 encoding Na(+),K(+)-ATPase α3 have been identified as the primary cause of alternating hemiplegia of childhood (AHC), a motor disorder with onset typically before the age of 6 months. Affected children tend to be of short stature and can also have epilepsy, ataxia and learning disability. The Na(+),K(+)-ATPase has a well-known role in maintaining electrochemical gradients across cell membranes, but our understanding of how the mutations cause AHC is limited. Myshkin mutant mice carry an amino acid change (I810N) that affects the same position in Na(+),K(+)-ATPase α3 as I810S found in AHC. Using molecular modelling, we show that the Myshkin and AHC mutations display similarly severe structural impacts on Na(+),K(+)-ATPase α3, including upon the K(+) pore and predicted K(+) binding sites. Behavioural analysis of Myshkin mice revealed phenotypic abnormalities similar to symptoms of AHC, including motor dysfunction and cognitive impairment. 2-DG imaging of Myshkin mice identified compromised thalamocortical functioning that includes a deficit in frontal cortex functioning (hypofrontality), directly mirroring that reported in AHC, along with reduced thalamocortical functional connectivity. Our results thus provide validation for missense mutations in Na(+),K(+)-ATPase α3 as a cause of AHC, and highlight Myshkin mice as a starting point for the exploration of disease mechanisms and novel treatments in AHC

Structural and functional alterations in the prefrontal cortex after post-weaning social isolation: relationship with species-typical and deviant aggression

Although the inhibitory control of aggression by the prefrontal cortex (PFC) is the cornerstone of current theories of aggression control, a number of human and laboratory studies showed that the execution of aggression increases PFC activity; moreover, enhanced activation was observed in aggression-related psychopathologies and laboratory models of abnormal aggression. Here, we investigated these apparently contradictory findings in the post-weaning social isolation paradigm (PWSI), an established laboratory model of abnormal aggression. When studied in the resident-intruder test as adults, rats submitted to PWSI showed increased attack counts, increased share of bites directed towards vulnerable body parts of opponents (head, throat, and belly) and reduced social signaling of attacks. These deviations from species-typical behavioral characteristics were associated with a specific reduction in the thickness of the right medial PFC (mPFC), a bilateral decrease in dendritic and glial density, and reduced vascularization on the right-hand side of the mPFC. Thus, the early stressor interfered with mPFC development. Despite these structural deficits, aggressive encounters enhanced the activation of the mPFC in PWSI rats as compared to controls. A voxel-like functional analysis revealed that overactivation was restricted to a circumscribed sub-region, which contributed to the activation of hypothalamic centers involved in the initiation of biting attacks as shown by structural equation modeling. These findings demonstrate that structural alterations and functional hyperactivity can coexist in the mPFC of rats exposed to early stressors, and suggest that the role of the mPFC in aggression control is more complex than suggested by the inhibitory control theory