Striatum Wide Dynamics and Neuromodulation of Cell-Type Specific Striatum Populations during Learning

PROJECT SUMMARY/ABSTRACT The striatum, the principle input nucleus of the basal ganglia, is a central mediator of associative learning for evaluating, motivating, and directing appropriate actions in response to external stimuli. Behavioral studies have suggested that distinct sub-regions of the striatum make unique contributions to adaptive learning, and that dysfunction in particular corticostriatal circuits may explain the range of learning and motivational deficits observed in basal ganglia disorders such as Parkinson’s Disease and addiction. Learning related changes in striatum neurons are widely believed to be driven by dopamine dependent bi-directional synaptic plasticity in distinct populations of direct and indirect pathway output neurons. This proposal will investigate how large scale, cell-type specific neural dynamics across distinct sub-networks of the striatum evolve to evaluate external cues, select appropriate actions, and invigorate movement over the course of sensori-motor learning. We will use a new optical approach we have developed to monitor and manipulate signals from two distinct output pathways of the striatum across a large 3-dimensional volume in head-fixed behaving mice during types of learning known to depend on different striatal sub-circuits. We will investigate the causal contribution of distributed dopaminergic signaling to bi-directional learning related changes in striatum output neurons by measuring and manipulating patterns of region specific dopamine release across the striatum volume during learning. Finally, we will employ 2-photon calcium imaging to track activity in hundreds of individual striatum neurons across days and determine how large scale learning related changes in striatum ensembles result from day to day changes at the single cell and network levels. Results from the proposed studies will provide new insight into how spatiotemporal changes in cell-type specific striatum output mediate central aspects of adaptive learning and action selection, and ultimately, how neurological disorders of learning and motivation might result from regional dysfunctions in distinct striatum networks.