PROJECT SUMMARY Nearly all sensory signals enter the neocortex by way of the thalamus, and the sensory cortex, in turn, distributes this information to several downstream cortical and subcortical areas. A prominent but often neglected feature of the sensory cortex is numerous feedback projections from other cortical areas. This key organizational feature of the brain implies that the ongoing activities in other cortical regions may influence local information processing and the outputs of the sensory cortex. Indeed, corticocortical communication is thought to mediate cognitive processes such as attention, prediction, expectation, and awareness. Communication problems between cortical areas are also associated with certain neuropsychiatric disorders, including epilepsy, autism, and schizophrenia. Despite its obvious importance, a thorough understanding of how cortical feedback activity influences sensory processing has been elusive. The central goal of this investigation is to determine how long-range cortical feedback projections influence cortical sensory processing at the level of cellular, synaptic, and circuit mechanisms. We address this goal in three specific aims using the mouse sensorimotor system, a leading model for studying forebrain circuits and active sensation. Aim 1 will focus on the connections between the motor cortex and layer 2/3 of the somatosensory cortex. Using specific Cre-expressing mouse lines and optogenetics, we will test the hypothesis that motor feedback engages two parallel but dynamically distinct systems of inhibition in layer 2/3 of the somatosensory cortex. Aim 2 will focus on infragranular layers, which contained a mixed population of excitatory projection neurons. Using both isolated and intact brain preparations, we will test the hypothesis that the dynamic balance of excitation and inhibition caused by motor cortex activity is dramatically different across deep-layer projection neurons depending on their cortical and subcortical projection target. Aim 3 will use optogenetics to unravel the inhibitory circuits mediating motor integration in layer 5/6 of the somatosensory cortex. This project will provide much-needed insight into how cortical feedback systems influence sensory processing. Such information will be essential for understanding neuropsychiatric disorders involving feedback communication.