Response inhibition, the ability to inhibit actions in the appropriate contexts, is important for the cognitive control of behavior and its dysfunction has been implicated in numerous neurological disorders. This proposal aims to understand corticostriatal signaling underlying response inhibition in mice during performance and learning of a whisker-based tactile discrimination task. A major goal is to address the gap in knowledge that exists for the role of primary somatosensory cortex (S1) in response inhibition. Based on its prominent projections to striatum and increasingly appreciated sensorimotor functionality, S1 is an overlooked candidate for brain stimulation in behavioral control that could have therapeutic advantages compared to frontal brain areas. The proposed experiments first aim to establish a causal relationship between cortical input from S1 and behavioral task performance. The hypothesis is that signaling from S1 to dorsal striatum (DStr), via its massive axonal projection, is necessary and sufficient to drive behavioral responses and response inhibition in the appropriate behavioral context. We will test this hypothesis by expressing optogenetic actuators and silencers (ChR2, ArchT) in S1 and manipulating axonal activity in DStr during task performance. The results will establish the causal influence of S1 on sensory-guided behavior. The next series of experiments will investigate the cellular basis of task-related activity in S1 using chronic in vivo two-photon imaging and electrophysiology. Chronic imaging of genetically encoded calcium indicators will allow for imaging of deep layer striatal projection neurons in S1 to determine the behavioral selectivity of S1-DStr populations. The hypothesis is that subpopulations of S1-DStr neurons encode response activation and inhibition, respectively. The timing of behavior-related neuronal activity will be resolved using targeted electrophysiological recordings. The final series of experiments will determine the emergence of cellular behavioral selectivity by tracking activity changes in S1 using chronic two-photon imaging. Experiments will be performed both through initial learning and stimulus reversal to dissociate stimulus and response. Our experimental approach will provide critical information about the capacity of S1-DStr projections for eliciting response inhibition, which will have implications for improved treatment of neurological disorders involving deficits in cognitive/behavioral control.
Response inhibition is critical for the control of behavior and is impaired in a wide variety of neurological disorders that involve impulsivity, including Huntington's disease, Tourette's syndrome, and obsessive- compulsive disorder. Primary sensory cortex (S1) is an unconventional but potentially powerful driver of response inhibition via projections to striatum. By investigating the causal role of S1 corticostriatal projections in response inhibition, as well as how plasticity occurs in S1 during sensorimotor learning, the results of this project will further our understanding of the neural circuit mechanisms underlying response inhibition and have implications for novel treatment of impulsive behaviors.
