This project consists of engineering a system for producing selective expression of light-inducible molecules in targeted neuron population in non-genetically modified animals of any species. The result will be a set of reagents that will be made freely available to the scientific community through nonprofit repositories and service centers. This new set of tools will enable the study of neural circuitry with greater resolution, power, and throughput than is currently possible, allowing major advances to be made in understanding the organization of the complex neural systems underlying perception, cognition, and behavior. This increased understanding could also result in improved artificial intelligence and machine learning. Finally, the future direct application of the technology in human patients holds promise for potentially treating conditions such as Parkinson's disease and epilepsy, by allowing the selective activation or inactivation of distinct components of the compromised neural circuitry that is associated with these disorders.
Over the last decade, sophisticated genetic tools have been developed that allow control and monitoring of neuron electrical activity using light alone. "Optogenetics", as this area of technology has become known, is only useful if optogenetic molecules can be specifically expressed in functionally meaningful groups of neurons instead of broadly in all the diverse neuron types that are present in any brain region. This requirement has confined their use almost entirely to genetically modified (transgenic) mice and rats. The approach of using transgenic animals has three major disadvantages. First, the production and maintenance of transgenic rodents is very expensive. Second, even within transgenic rodents, it allows the optogenetic study and manipulation of only one or two cell types at a time, preventing powerful combinatorial experiments in which different neuron types are independently controlled within the same tissue. These combinatorial experiments will be critical for deciphering the complex interactions between cell types. Third, it restricts the experiments to rodents, preventing studies in other important taxa including primates, in which optogenetic experimentation during complex cognitive tasks would almost certainly provide major insights into the neural circuitry underlying cognition. This project aims to create engineered binding proteins that recognize selected endogenous proteins that will then act as scaffolds for assembly of transcription factors that will activate gene expression in specific neurons.
