An optical-genetic toolbox for reading and writing neural population codes in functional maps

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The overarching goal of this proposal is to develop an optical-genetic toolbox for reading and writing neural population codes in functional maps of awake, higher mammals. Such tools could ultimately be used to restore perceptual capabilities in patients with damage to peripheral sensory pathways by direct stimulation of early sensory cortex. Advanced optical methods for reading and writing neural codes using genetically-encoded reporters and actuators have become powerful tools for studying neural circuits in rodents. However, rodents are a suboptimal model for human perception because of their vastly different sensory representations and perceptual capabilities. For example, rodents' primary visual cortex (V1) lacks the functional columnar organization which is a hallmark of primate vision. In contrast to rodents, the macaque monkeys' sensory representations and perceptual capabilities are highly similar to those of humans. Furthermore, the behaving macaque provides a unique opportunity to develop and test tools for reading and writing neural codes at the level of functional domains such as the orientation columns in V1. However, multiple technical hurdles remain before the optical-genetic methods currently available in rodents could be readily applied in larger, non- transgenic mammals. Here we propose to take advantage of the unique expertise of our team members to develop optical techniques that utilize virally delivered transgenes for monitoring and manipulating neural population codes in behaving macaques. Specifically, we will address three technical goals. First, we will develop and test new genetic methods that will provide long-term expression of transgenes in primates with cell-type and activity- dependent specificity. Second, we will develop a two-photon microscope for behaving monkeys that will allow one to monitor these signals with cellular resolution and complement current imaging techniques with larger coverage but coarser resolution. Finally, we will develop methods for writing neural population codes in functional maps by combining patterned light stimulation that target specific functional domains and selective expression of actuators. We will validate and optimize these techniques by linking V1 responses (elicited by both visual and direct patterned optogenetic stimulation) and monkeys' behavior in visual discrimination tasks. The tools that we will develop will enable a deeper understanding of the neural code and a better characterization of the capabilities and limitations of methods for reading and writing neural population codes in functional maps in humans.