Project Summary/Abstract The long-term goal of these investigations is to understand the circuit plasticity underlying the association of an arbitrary sensory stimulus with an arbitrary action. Understanding this circuitry is likely to have an impact on the diagnosis and treatment of clinically important central neuropathologies, including Huntington's disease, Parkinson's disease, addiction, schizophrenia, and obsessive compulsive disorder. The central goal of this proposal is to test the hypothesis that differential plasticity at the cortical projection to two different neuronal subpopulations in the striatum underlie the acquisition of a sensorimotor discrimination behavior. We use mice as a model system because they allow sophisticated interrogation of genetically defined subpopulations of neurons. In Aim 1 we use in vitro electrophysiological methods in acute brain slices to study the strength of corticostriatal synapses in animals trained on a simple task associating sounds with a left or right choice. In Aim 2 we will use the same methods to study animals trained on a task requiring greater behavioral flexibility. Finally in Aim 3, we test whether association of the sound and action leads to differential changes at the two subpopulations of striatal neurons. These studies will provide insight into how animals acquire arbitrary associations, and provide a foundation for further study of role of these neurons in normal function and disease, facilitating the development of treatments for psychiatric and neurological diseases.