Of mice and men: The neurobiological bases of aggression

Of mice and men: The neurobiological bases of aggression

Road rage is one example of pathological aggression that Marco Bortolato hopes to eventually treat and perhaps even prevent. It is estimated that this kind of impulsive, out-of-control and disproportionate aggression is responsible for up to 60 percent of violent crime in the U.S., and its perpetrators are often incarcerated.

Human studies have found that male carriers of a variant of the gene MAOA, which encodes an enzyme called monoamine oxidase A, are very likely to develop impulsive pathological aggression if they also su ered maltreatment early in life.

“This gene variant results in low activity of monoamine oxidase A, which in turn leads to high concentrations of serotonin in the brain during infancy and childhood,” said Bortolato, assistant professor of pharmacology and toxicology, and a neurologist. Serotonin, a neurotransmitter, directs how the cells of the cortex are connected during early development.

Bortolato’s research group generated a mouse model of the human low-activity MAOA carriers. To simulate abuse and neglect in early childhood, the mice were separated from their mothers for a few hours every day during the first week of life. By the time they reached adolescence, the mice were very aggressive, while their littermates without the mutation (or without the stress) did not develop these behavioral traits.

The researchers found that the high aggression in the stressed MAOA transgenic mice was due to the overstimulation of a serotonin receptor called 5-HT2A in the neurons of the prefrontal cortex. ese cells are fundamental to decision-making in the presence of social stimuli, said Bortolato. In this mouse model, however, the cells are incapable of processing critical information for social responses, such as deciding whether an unfamiliar individual poses a threat or not.

But there’s good news. “If the transgenic mice are treated with pharmaceuticals that block 5-HT2A receptors in the early stages of life, we can completely rectify the pathological trajectory,” said Bortolato.

Eventually, the research could lead to new diagnostic and therapeutic interventions for children who are highly predisposed to the disorder.

What’s more, Bortolato’s team is getting good results treating adult mice with riluzole, a drug currently approved to treat Lou Gehrig’s disease. If the nal results con rm these ndings, Bortolato plans to initiate a clinical trial to test the e cacy of this drug in violent, aggressive adult patients.