Project Summary/Abstract A hallmark of mental health is the ability to flexibly interact with our surroundings accord to situational context and internal goals. A long-standing theory of cortical physiology is that context-dependent neural processing is mediated by cortical feedback pathways. According to this theory, internal states related to context or goal-direction are encoded in fronto-parietal cortices. These signals propagate throughout cortex along cortical feedback pathways, whereby they set the initial conditions that influence the representation and routing of sensory responses. Mechanistic descriptions of cortical feedback function, however, are limited due to the difficulty of studying specific cortical pathways in behaving subjects. Innovations in this proposal come from combining a well-defined model system, quantitative behavior, and advanced genetic and physiological tools. We study a motor-to-sensory cortical feedback pathway in the mouse whisker system. Our experiments are designed to test hypotheses for how motor cortex feedback informs sensory cortex about processing incoming sensory stimuli. We implement a quantitative sensory detection task, in which mice learn to respond to target stimuli and ignore distractor stimuli. Thus, our proposal will reveal cortical feedback contributions to both target stimulus detection and non-target stimulus (‘noise’) suppression. We specifically hypothesize that motor-to-sensory cortical feedback improves task performance by reducing non-target responses through sensory cortex noise suppression. We study these processes at the resolution of behavior, cortical feedback population activity and sensory cortex single unit sensory processing. We use a host of cutting-edge physiological tools including pathway-specific cortical feedback optogenetic suppression, Ca2+ imaging of axons and terminals and multielectrode recordings of identified neuronal cell-types. Together, these studies will provide mechanistic understandings of cortical feedback signaling during goal-directed behavior. Additionally, these studies will generate new hypotheses for how disturbances of cortical feedback may contribute to dysfunctions of context-dependent processing in neuropsychiatric disease.