Deciphering gene-environment interactions in pathological reactive aggression

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.

Grant Number: 5R01MH104603-09
NIH Institute/Center: NIH
Principal Investigator: Marco Bortolato