Large-scale calcium and voltage imaging to illuminate neural mechanisms of visual experience

Project Summary: The majority of lived experience depends on neural activity conveying sensory information about the world. Neural trauma and stroke are leading causes of disorders such as coma and spatial neglect, which severely damage visual experience, and there are no viable treatment options. Similarly, life saving medical treatments depend on the ability for general anesthesia to temporarily disconnect patients from the sensory world. Current anesthetics do so by inhibiting the entire brain, including the brainstem, which is a significant health risk. Even so, for unknown reasons, general anesthesia sometimes fails to prevent experiences during surgery, resulting in severe trauma for patients. These problems persist, creating negative health outcomes, in part because despite substantial research into the mechanisms of sensory encoding, particularly in vision, it remains unclear how neural activity transforms sensory information into conscious experience. There are many theories, each suggesting different mechanisms. Visual experience may emerge from the activity of higher-order neural ensembles, or depend on hidden, complex interactions built into network structures. Experience may involve local, recurrent network interactions, long-range computations, or global events that subsume and unify network activity. Unfortunately, concrete evidence supporting any of these theories is limited. Existing technologies lack either the specificity to identify the microscopic encoding properties of individual neurons and subtypes, or the necessary scope to detect activity simultaneously across sizable visual networks. New emerging technology in the Schnitzer lab overcomes these technical limitations. Advanced microscopes and complimentary optical techniques now make it possible to simultaneously record thousands of neurons across the entire visual network, with Ca2+ imaging revealing activity related to neural firing, and voltage imaging revealing subthreshold wave dynamics associated with neural communication. In this project, we will 1.) develop a task designed to isolate visual experience in mouse models to optimize the benefits of neural recording techniques; 2.) use state-of-the- art optical instrumentation to resolve the dynamics of thousands of individual neurons of specific types across all visual cortical areas, characterizing activity patterns that differentiate seen from unseen percepts; 3) use chemogenetic manipulations to test mechanisms of perception by inhibiting the pulvinar, a subcortical area that modulates visual networks. The results of this work, as preliminary data supports, will reveal detailed evidence of neural mechanisms associated with conscious visual perception that can differentiate predictions made by current theories. This will drive the field towards a data-driven consensus and illuminate mechanisms that will be instrumental in treating disorders.