The ability to suppress inappropriate behaviors is a hallmark of executive control and impairments of this ability contribute to multiple defining symptoms of autism spectrum disorder (ASD). Previous studies have identified fronto-striatal regions and the dopamine system as the core substrates for impulse control but a mechanistic, circuit-level understanding of how these systems mediate behavioral inhibition is lacking.

Adam Kepecs’ lab aims to establish a new model system for the neural circuits underlying behavioral inhibition by bringing together two lines of research: the circuit-specific study of the dopamine system during impulsivity and a precision medicine approach to studying mouse models for neurofibromatosis 1 (NF1) pioneered by David H. Gutmann¹.

NF1 is the most common autosomal dominant single-gene neurodevelopmental disorder with high quantitative autistic burden (ASD prevalence of about 25 percent). Moreover, attention deficit hyperactivity disorder (ADHD) traits track with autistic traits in NF1 in an apparently dopamine-dependent manner^2,3, supporting NF1 as a promising single-gene syndromic model for understanding the role of the dopamine system in behavioral inhibition.

To understand how the dopaminergic system contributes to impulsivity, Kepecs’ lab has developed a cued-reward lick-withholding impulsivity task in which mice must withhold anticipatory licking during water reward predicting cues, placing their innate approach in conflict with self-restraint to maximize reward. This task provides a quantitative readout of impulsivity in real time, enabling researchers to evaluate the underlying neural dynamics.

Kepecs’ lab will test the hypothesis that the dynamic balance between tonic and phasic dopamine controls competition between reward pursuit and behavioral inhibition. They will measure striatal and prefrontal dopamine in NF1 mutant mice during an impulsivity task and manipulate dopamine release to determine its causal contributions to behavioral inhibition.

Findings from these studies will lay the groundwork for a circuit-level understanding of behavioral impulse control in ASD, specifically in neurofibromatosis 1, and provide direct clinical links.

1. Anastasaki C. et al. Stem Cell Reports 14, 541-550 (2020) PubMed
2. Haebich K.M. et al. Child Neuropsychol. Epub ahead of print (2021) PubMed
3. Morris S.M. et al. JAMA Psychiatry 73, 1276-1284 (2016) PubMed