Understanding the cerebral cortex requires data-based theoretical models that can yield in- sight into the circuit mechanisms of cortical computation, and reproduce detailed cortical dynamics across stimuli and brain states. The primary visual cortex (V1) is the best-studied cortical area by both theorists and experimen- talists, yet current models - whether statistical or circuit based – only poorly capture how V1 neurons respond to complex stimuli, such as natural scenes. The ultimate goal of this team project is to obtain the necessary experimental data and build the detailed circuit-based models that explain how V1 circuits encode natural visual stimuli. In so doing, we aim not only to provide a mechanistic understanding for how V1 dynamics forms the basis of vision, but also to establish a more generalizable paradigm for understanding any cortical area. Our assumption is that current models fall short for two reasons: on the experimental side, we are still missing most of the fundamental details about the synaptic connectivity and physiological responses of V1 cell types; while on the theory side, prevailing circuit-based models reduce V1 to just a few cell types, and either capture the static responses of V1 neurons to simple stimuli but not their trial to trial fluctuations, or capture fluctuations, but not their rich array of non-linear responses properties that are central to visual computation. Our hypothesis is that we can achieve a circuit-based model that explains cortical responses and dynamics to natural stimuli by implementing the following three steps: 1) identify and incorporate all the differentiable V1 neuronal cell types into our model; 2) measure and incorporate the synaptic connectivity and intrinsic properties of these cell types; 3) measure and accurately predict the visual responses of each of these cell types to diverse visual stimuli and in multiple brain states. We focus on circuit-based rather than statistical models of V1 for two reasons: they can provide insight into neural mechanisms of visual computation and the regimes of cortical operation, and because they will permit us to test their accuracy by validating their predictions for how V1 responds to defined experimen- tal perturbations. To implement these perturbations, we will employ multiphoton holographic optogenetics, which allows us to manipulate V1 circuits with the level of precision formerly only possible in the realm of theory. Here we bring together an outstanding team of theorists, experimentalists, and data scientists to leverage cutting edge new brain mapping technologies that we will use to build and validate dramatically improved models of visual cortical function and dynamics.

Understanding the function and dynamics of the cerebral cortex requires new experimental and theoretical approaches. This BRAIN Initiative application proposes to combine powerful new technologies for monitoring and manipulating neural circuits and genetically identifying cell types to motivate and constrain the most accurate and predictive theoretical models of the primary visual cortex. Through the collaborative efforts of experimentalists and theorists, we aim to achieve fundamental new insights into visual cortical function, and cortical function in general, that should help us understand the origins of various neurological disorders.