From left: Scott Russo, PhD, with researchers Hossein Aleyasin, MD, PhD, and Caroline Menard, PhD, postdoctoral fellows in the Department of Neuroscience.
A team of researchers at the Icahn School of Medicine at Mount Sinai has conducted a pioneering study of mice behavior and the structure of the brain demonstrating that in some cases, aggressive social interaction— bullying—activates a primary brain reward circuit that makes the activity pleasurable.
The study, led by Scott Russo, PhD, Associate Professor of Neuroscience, appeared in the journal Nature in 2016. Significantly, it was the first time that researchers discovered that specific neural mechanisms between the basal forebrain and lateral habenula mediate the motivation to engage in or avoid this aggressive behavior. Furthermore, they showed that manipulating activity in this circuit alters the activity of brain cells and, ultimately, aggression behavior.
The team used a conventional mouse behavioral model whereby adult mice were placed together with a younger subordinate mouse for three minutes each day for three consecutive days while researchers closely watched their behavior. They determined that with specific conditioning, about 70 percent of mice exhibited aggressive behavior, tending to bully or attack the subordinate mouse, while 30 percent showed no aggression at all. They also observed behavior suggesting that the aggressive mice found the ability to subordinate others rewarding, while the non-aggressive mice developed an aversion to aggression stimuli.
By studying brain activity, the researchers found that the aggressive mice, when given the chance to bully, exhibited increased activity in the basal forebrain neurons that reduce activity in the lateral habenula, an area of the brain that would normally encode an aversion to aggressive stimuli. Conversely, they found that non-aggressive mice exhibited reduced basal forebrain activation and a subsequent increase in lateral habenula neuronal firing, which makes the aggression stimuli aversive.
A scan of tissue from a mouse brain shows an inhibitory neuron (green) in the basal forebrain, which projects directly to the lateral habenula, a circuit that controls aggression.
Researchers then directly manipulated the activity of the neurotransmitter that has a role in this circuit. “When we artificially induced the rapid neuron activation between the basal forebrain and lateral habenula, we watched in real time as the aggressive mice became docile and no longer showed bullying behavior—it was very dramatic,” says Dr. Russo. “Our study is unique in that we took information about the basal forebrain-lateral habenula projections and then actually went back and manipulated these connections within animals to conclusively show that the circuits bi-directionally control aggression behavior.”
Over the years, Dr. Russo says there have been only limited studies on aggression, even though aggression can be a major part of human illness. This research, while promising, is still in its early stages. “It could take 10 years before we have anything ready for testing in humans, but this is a critical first step,” Dr. Russo says. “Targeting shared underlying deficits in motivational circuitry may eventually provide useful information for the development of novel therapeutic drugs for treating aggression-related neuropsychiatric disorders.”
The Mount Sinai research team included investigators from the Fishberg Department of Neuroscience, The Friedman Brain Institute, the Graduate Program in Neuroscience, the Department of Pharmacological Sciences, and the Mount Sinai Institute for Systems Biomedicine.