Deciphering gene-environment interactions in pathological reactive aggression

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PROJECT SUMMARY/ABSTRACT Pathological aggression is a recurrent pattern of disruptive and violent behavior, which typically emerges in adolescence and peaks in young adulthood. Despite the significant socioeconomic burden imposed by the repercussions of pathological aggression, available treatments are limited and inadequate. A key problem in treating pathological aggression lies in its complex structure, which reflects the overlap of distinct constructs and age-specific mechanisms; thus, identifying the neurodevelopmental bases of the commonalities and differences between these constructs is critical to developing better therapies. To study these neurobiological mechanisms, we focused on the best-characterized gene × environment (G×E) interaction in pathological aggression, occurring between low-activity alleles of the MAOA gene (encoding the enzyme monoamine oxidase A) and child maltreatment. During our previous funding period, we developed the first animal model of this G×E interaction, by subjecting a line of mice with a MAOA hypomorphic mutation to early-life stress during the first week of life. Unlike their unstressed and wild type (WT) controls, these mice develop aggression following a two-stage process: the first stage occurs in early life, before the onset of aggression, and reflects progressive functional deficits of the prefrontal cortex and its downstream connectivity; conversely, the second stage occurs around puberty, after the onset of aggression, and is characterized by an age-dependent escalation of fighting behavior. Our preliminary data show that each hit is sustained by a specific mechanism. The first hit involves the activation of serotonin 5-HT2A receptors, while the second is based on an upsurge of testosterone and its metabolites. We also showed that the attacking behavior in our model reflects the hyperactivation of dopaminergic neurotransmission in response to social challenges. Based on these findings, the studies proposed in this application will test the hypothesis that the development of PA is shaped by age-specific mechanisms converging on mesolimbic dopaminergic alterations. The studies in Aims 1 and 2 will determine how dopaminergic neurotransmission and different aggression constructs are influenced by 5-HT2A receptor stimulation during the first stage and steroids during the second stage. The studies in Aim 3 will explore whether the dopaminergic activation during attacks may lead to behavioral reinforcement, ultimately promoting “aggression addiction”. Taken together, this research will help elucidate the neurodevelopmental mechanisms of pathological aggression, and identify new potential targets for the prevention, diagnosis, and treatment of this condition.