SUMMARY The ability to make appropriate actions, as well as to inhibit unbeneficial actions, is a key aspect of sensorimotor learning. Our recent work has used the mouse whisker system as model for sensory-guided learning to identify an important and previously unknown role for synaptic input from primary somatosensory cortex (S1) to the dorsal striatum (DStr) as a substrate for response inhibition. This renewal proposal aims to test the idea that the relative synaptic innervation of striatal parvalbumin-expressing (PV) interneurons compared to the spiny projection neurons (SPNs) is a circuit mechanism for behavioral response inhibition. We will use a suite of in vivo imaging and optogenetics experiments, as well as ex vivo electrophysiology experiments to measure and manipulate neural circuitry from two important brain areas: S1 and thalamic posterior medial nucleus (POm) to test their roles in modulation of DStr. Preliminary results suggest that S1 and POm influence behavioral performance of a texture discrimination task in opposing ways, allowing for focused tests of our hypotheses of the synaptic circuitry mediating these learned behaviors. Our integrative in vivo and ex vivo approach, combining manipulation of specific neural pathways, longitudinal tracking of genetically identified neurons, anatomical analysis, and ex vivo synaptic measurements will allow us to investigate the neural circuit basis of learned response inhibition at a scale not before achieved. A major goal is to address the gap in knowledge on the roles of S1 and POm projections to the striatum and their influence on behavior. The results will have implications for the neural circuitry underlying cognitive control, which will aid our understanding the basis of neurological disorders involving deficits in cognitive control.

PROJECT NARRATIVE Response inhibition is a key aspect of learned behavior and is impaired in a variety of neurological disorders that involve impulsivity, including Huntington’s disease, Tourette’s syndrome, and obsessive-compulsive disorder. This project uses in vivo and ex vivo approaches in mouse models to investigate cortical and thalamic influences on the neural circuits of the dorsal striatum, an important site of sensory-motor integration and learning. The results of this project will further our understanding of the neural circuit mechanisms underlying learned response inhibition and have implications for understanding and treatment of impulsive behavior.