Autism spectrum disorders (ASDs) are characterized by a variety of behavioral deficits including perseverative behavior. This behavioral deficit is characterized by the normal acquisition of stimulus-response associations, but a slowing of response adaptation when contingencies change. While fixated behavior is a core feature of ASDs, its neural bases are poorly understood. In particular, little is known about the way the brains of individuals with ASDs learn and use associations.

Why do individuals with ASDs exhibit difficulties in adjusting to new contingencies? One hypothesis is that although the time course of learning seems normal, the brains of individuals with ASDs may encode associations in a way that make them resistant to change. Testing this hypothesis is a challenge because current rodent assays are too simple to capture the multiple facets of behavioral flexibility. Moreover, neural activity patterns need to be recorded over the time course of learning and during flexible behavior.

To overcome these challenges, Alex Kwan and his colleagues at Yale School of Medicine have developed new methods to study flexible sensorimotor behavior in head-fixed mice¹. Kwan’s laboratory has developed a task in which mice initially learn to associate auditory cues with making left versus right responses. Subsequent to learning these associations, the sensory-motor contingencies are switched, requiring animals to shift their response strategy. Kwan’s team is combining this behavioral paradigm with two-photon calcium imaging to provide a direct view into the activity patterns of hundreds of frontal cortical neurons as the animal learns and solves the task.

Kwan and his team will use this approach to characterize learning-related activity in a SHANK3 knockout mouse model of ASD. The results will generate a rich data set to delineate how associations are represented in the frontal cortex of an ASD mouse model and how such representations differ from those of wild-type mice. The long-term goal of this work is to elucidate the neural circuit mechanisms responsible for inflexible behavior in ASD.