A fundamental goal for understanding the brain and mammalian and human intelligence, and to understand how processing goes awry in genetic and developmental diseases, is to understand the principles of operation of cerebral cortex. A key step is to understand "canonical" operations carried out by cortex. Here we will explore the operations of cortical circuitry in experiments guided by a new theory of a candidate canonical circuit operation. Sensory cortex must globally integrate localized sensory input to parse objects and support perception. In individual neurons, this manifests as modulation of responses to local stimuli by context or top-down influences such as attention and as interactions between local stimuli in driving responses ("normalization"). These interactions tend to be suppressive for stronger stimuli but more weakly suppressive or facilitative for weaker stimuli. Recent theoretical work in Dr. Miller's lab has proposed a novel cortical circuit motif, the stabilized supralinear network (SSN), that provides a simple unified explanation for a wide variety of neural responses related to global integration. The model serves as a guide for new experimental explorations of cortical circuitry in Dr. Van Hooser's laboratory, using both traditional experimental recording techniques and his recently developed novel optical methods for manipulating cortical activity with high spatial and temporal resolution. The SSN model, if successful, will be elaborated to best explain experimental results. In Aim 1, the light-activated channel channelrhodopsin2 (ChR2) and an optical stimulation system are used to drive activity of cortical circuits in precise spatial and temporal patterns to test the contribution of cortical circuits to normalization and contextual modulation including various SSN predictions about them. In Aim 2, the balance of drive to excitatory (E) vs. inhibitory (I) cells within the cortex will be altered using viruses that largely restrict expression of ChR2 to E or I cells. This will test SSN model predictions involving modulation of network gain by modulatory input biased toward E or I cells, mechanisms of attentional modulation, and the dependence of a "paradoxical" result -­ adding drive to I cells reduces steady-state I responses -- on the spatial pattern of drive to I cells and level of cortical activation. RELEVANCE (See instructions): We will test the predictions of a powerful framework for understanding how sensory cortex globally integrates multiple sources of input, bottom-up and top-down, to produce neuronal responses and ultimately perception. Understanding circuit changes that cause breakdown of this cortical operation may provide insight into disorders such as autism and schizophrenia, which show deficits in contextual or global processing. Understanding global integration will be necessary for the creation of prosthetic devices to treat blindness and other disorders.