Coding and wiring in a million cortical neurons

This project will reveal the collective function of vast populations of neurons across all areas of the mouse visual cortex, by combining advanced techniques that we perfected with a transformational new imaging method. Cortical function is organized by the collective firing of a myriad neurons, whose joint activity constitutes a code that we have been able to read only in fragments. Key to revealing this code and the wiring that supports it, is the ability to record from vast populations of individual neurons across cortical areas. This is now possible thanks to the Light Beads Microscope (LBM), which allows unprecedented recordings from ~1 million cortical neurons. First, we will use the LBM to characterize the code used by the joint activity of neurons across all areas of the visual cortex. We will image the activity of ~1 million neurons across all visual areas while mice view images, run, and navigate in virtual reality. We will thus test key hypotheses about the visual code across visual areas, and about the influence of internal signals related to behavior, brain state, and navigation. Second, we will reveal the wiring that supports this neural code. We will pair LBM imaging with rabies tracing techniques established in our laboratory, and relate the responses of one neuron to those of its presynaptic neurons across all visual areas. We will thus test hypotheses on the wiring of feedforward and feedback connections that determine visual responses and that carry internal signals related to behavior, brain state, and navigation. Finally, we will explore how the responses of one cortical neuron arise from the thousands of synapses that it receives. We will use the LBM at higher resolution to image a neuron's full dendritic tree and use rabies tracing to image the synapses that connect to it. We will thus reveal the synaptic organization of signals related to vision, behavior, and navigation, and test their causal role through dendrotomies. The results will deliver unprecedented data that will reveal the coding and wiring underlying activity in a major portion of the cerebral cortex, providing an experimental test of fundamental theories of cortical function.