UC Berkeley

Understanding what aspects of neural activity causally drive sensory perception is essential to understanding the nature of the neural code. Direct perturbation of neural activity is needed to conclusively distinguish between competing theories, and in many cases precise perturbations that alter neural activity patterns in specific ways are needed to distinguish coding mechanisms. Optogenetics has ushered in a new era of causal manipulation, but conventional methods have several shortcomings. We addressed several of these and used our new methods to study detection of contrast in the mouse visual system, focusing on the primary visual cortex (V1). We first established that visual cortex provides necessary information for contrast detection. To do this we developed an all-optical “reversible lesion” paradigm to enable interpretation of the necessity of a region for a task in the face of oft-contradicting optogenetic and mechanical lesion results. Next, we leveraged new 2-photon targeted optogenetics to test a long-held theory that the more stimulus sensitive neurons, i.e. the neurons that carry the most information about the stimulus, are responsible for detection and perception of that stimulus. We stimulated small ensembles of V1 neurons during visual task performance and found that small groups could exert a large influence on behavioral output. Surprisingly, the visual response properties of the stimulated neurons had no bearing on their behavioral influence. Instead, the network influence of the ensemble strongly predicted the behavioral effect of stimulation. This result supports the idea that perception requires large-scale network activity and suggests that the neural code for stimulus detection may be a simple summation of activity. Finally, we developed a new method to enable testing theories of coding that go beyond neural identity, such as the high-dimensional geometry of population codes or spike synchrony. These ideas are not testable with conventional targeted optogenetics because of the inability to write specific spike trains. To overcome this obstacle, we first developed a transgenic mouse line that co-expresses a soma-targeted opsin fused to a strong calcium indicator for all-optical experiments. We leveraged this line to create a paradigm for all-optical read-out and write-in of precise population vectors of neural activity using cell-by-cell calibration. This will enable new testing of how the topology of the neural code influences behavior. All together, these studies establish the role of visual cortex in contrast detection and argue that the code for detection is a simple summation of all excitatory activity within visual cortex. The new methods developed in Chapter 4 should enable further investigation and confirmation of this theory, and the methods presented in Chapters 2-4 can be applied to other sensory tasks to determine how these conclusions generalize across regions and tasks.