DESCRIPTION (provided by applicant): In previous work we developed a light-activated ion channel channelrhodopsin-2 (ChR2) for genetically targeted, millisecond-timescale optical excitation of neurons. We now report that we have identified a high-speed optically-activated chloride pump (NpHR) from N. pharaonis for temporally-precise inhibition of neural activity. The action spectrum of NpHR is strongly red-shifted relative to ChR2, and like ChR2, NpHR functions in mammalian neurons without exogenous cofactors. Together NpHR and ChR2 form a complementary system for multimodal, high-speed, genetically-targeted, all-optical interrogation of intact neural circuits. Here we propose a broad effort for inter-institutional technology-development, capitalizing on the novel NpHR reagent and the unique skills of our Duke/Stanford collaborative team to develop multimodal high-speed optical tools for excitable cell physiology, and responding specifically to the NIMH call for neural technology development. Together these approaches will develop the general power of optogenetic control by targeting bidirectional photosensitivity to important neuronal subtypes and by defining precise optical methods for neural circuit activation. This proposal for developing next-generation optical technologies for precise control of living neural circuitry therefore squarely targets areas of fundamental importance to public health, and is directly responsive to the call of the National Institute of Mental Health for new technology development relevant to neuropsychiatric disease.