1. Department of Bioengineering, Stanford University, Stanford, California 94305, USA
2. Institute of Biochemistry, and,
3. Institute of Biophysical Chemistry, Department of Biochemistry, Chemistry and Pharmacy, Johann Wolfgang Goethe-University, Frankfurt Biocenter N220, Max-von-Laue Strae 9, D-60438 Frankfurt, Germany
4. Max-Planck-Institute of Biophysics, Max-von-Laue-Strae 3, D-60438 Frankfurt am Main, Germany
5. University Wuerzburg, Botanik I, Julius-von-Sachs-Platz 2, D-97082 Wuerzburg, Germany

Correspondence to: Karl Deisseroth¹ Correspondence and requests for materials should be addressed to K.D. (Email: deissero@stanford.edu).

Abstract

Our understanding of the cellular implementation of systems-level neural processes like action, thought and emotion has been limited by the availability of tools to interrogate specific classes of neural cells within intact, living brain tissue. Here we identify and develop an archaeal light-driven chloride pump (NpHR) from Natronomonas pharaonis for temporally precise optical inhibition of neural activity. NpHR allows either knockout of single action potentials, or sustained blockade of spiking. NpHR is compatible with ChR2, the previous optical excitation technology we have described, in that the two opposing probes operate at similar light powers but with well-separated action spectra. NpHR, like ChR2, functions in mammals without exogenous cofactors, and the two probes can be integrated with calcium imaging in mammalian brain tissue for bidirectional optical modulation and readout of neural activity. Likewise, NpHR and ChR2 can be targeted together to Caenorhabditis elegans muscle and cholinergic motor neurons to control locomotion bidirectionally. NpHR and ChR2 form a complete system for multimodal, high-speed, genetically targeted, all-optical interrogation of living neural circuits.

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