Biased spatiotemporal dynamics of striatal circuits impact behavior in autism

The striatum is the major input structure for the basal ganglia, processing inputs from virtually all cerebral cortical areas and from the thalamus, thus modulating motor, emotional and cognitive behaviors. Autism spectrum disorders (ASDs) are characterized by such core symptoms as repetitive behaviors and restricted interests. The molecular and circuit underpinnings of repetitive behavior dysfunction have remained elusive, but it is assumed that they rely on the same basal ganglia circuits that underlie repetitive behavior control and habit formation. The striatum plays an important role during natural and learned behaviors by regulating downstream basal ganglia circuits via the striatonigral (direct) and the striatopallidal (indirect) pathways. Activity of the direct pathway seems to be related to supporting ongoing actions and to promote the continuation or repetition of the ongoing actions. In contrast, activity of the indirect-pathway seems to be permissive and to control switching or the abortion of ongoing actions1. Rui Costa hypothesizes that there is an imbalance between direct- and indirect-pathway activity in ASD, favoring the direct pathway, and that this imbalance leads to behavioral alterations. Costa proposes to investigate the changes in the spatiotemporal organization of striatal circuits that underlie dysfunctional repetitive behavior in ASD. Using one-photon microendoscopic imaging of direct- and indirect-pathway spiny projection neurons (SPNs) in control mice, Costa's team recently uncovered that SPNs activity has a predominantly local functional organization and that SPNs ensemble activity encodes action identity2. The team now plans to investigate the spatiotemporal correlations of direct- and indirect-pathway activity in the 16p11.2 deletion and CNTNAP2 knockout mice. They will then correlate the neuronal activity with careful characterization of spontaneous movements (using a novel approach to cluster spontaneous behaviors based on continuous accelerometer and video data) and investigate changes in striatal organization during learned sequences, using a novel nose-poke sequence task. These experiments will identify — with unprecedented spatial and temporal resolution — the circuit alterations in the striatum that lead to alterations in spontaneous and learned behavioral sequences in ASD.