Aggression is the most common reason for hospitalization in children with autism spectrum disorder (ASD). One of the most reliable triggers of aggression is frustration, the feeling that emerges after failing to achieve an expected reward. Frustration can be adaptive, energizing behavior to overcome barriers. But it can also lead to anger and violence, increasing caregiver burden and reducing quality of life. Despite its high clinical toll, the neurobiology of frustration and aggression in ASD remains poorly understood and current treatment options are grossly inadequate.

In this project, Neir Eshel and colleagues at Stanford University plan to use modern neuroscience tools in mice — including genetically-encoded sensors, fiber photometry and optogenetics — to test the roles of dopamine (DA) and serotonin (5HT) circuits in frustration and aggression. Their central hypothesis is that DA and 5HT act in contrasting ways on their shared target in the nucleus accumbens (NAc) to govern how frustrating outcomes shape behavior.

Specifically, they predict that DA release in the NAc will track aggressive bouts that occur after placing an intruder mouse in the experimental mouse’s home cage. Furthermore, they predict that optogenetic stimulation of DA terminals in this region will heighten aggression induced by a frustrating omission of expected reward. In contrast, they predict that 5HT release in the NAc will decrease after frustration and that larger decreases will correlate with greater aggression. As such, optogenetic excitation of 5HT terminals in the NAc should reduce aggressive behavior after frustration.

Finally, Eshel and colleagues plan to run their frustration task in a mouse model of ASD to determine if these mice have heightened aggressive responses and to explore whether manipulating DA or 5HT release can rescue these deficits. They will base their choice of mouse model on a screen of SFARI databases for ASD-linked genetic variants that are associated with aggression. Insight into the neural mechanisms of frustration and aggression, and how they dovetail with genetic variants in ASD, may lead to more effective therapies for people with ASD.