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.
| Kim, Yoon Seok; Kato, Hideaki E; Yamashita, Keitaro et al. (2018) Crystal structure of the natural anion-conducting channelrhodopsin GtACR1. Nature 561:343-348 |
| Kato, Hideaki E; Kim, Yoon Seok; Paggi, Joseph M et al. (2018) Structural mechanisms of selectivity and gating in anion channelrhodopsins. Nature 561:349-354 |
| Kim, Christina K; Adhikari, Avishek; Deisseroth, Karl (2017) Integration of optogenetics with complementary methodologies in systems neuroscience. Nat Rev Neurosci 18:222-235 |
| Kim, Christina K; Ye, Li; Jennings, Joshua H et al. (2017) Molecular and Circuit-Dynamical Identification of Top-Down Neural Mechanisms for Restraint of Reward Seeking. Cell 170:1013-1027.e14 |
| Ye, Li; Allen, William E; Thompson, Kimberly R et al. (2016) Wiring and Molecular Features of Prefrontal Ensembles Representing Distinct Experiences. Cell 165:1776-1788 |
| Berndt, Andre; Lee, Soo Yeun; Wietek, Jonas et al. (2016) Structural foundations of optogenetics: Determinants of channelrhodopsin ion selectivity. Proc Natl Acad Sci U S A 113:822-9 |
| Kim, Hoseok; Ährlund-Richter, Sofie; Wang, Xinming et al. (2016) Prefrontal Parvalbumin Neurons in Control of Attention. Cell 164:208-218 |
| Jennings, Joshua H; Ung, Randall L; Resendez, Shanna L et al. (2015) Visualizing hypothalamic network dynamics for appetitive and consummatory behaviors. Cell 160:516-27 |
| Jorgenson, Lyric A; Newsome, William T; Anderson, David J et al. (2015) The BRAIN Initiative: developing technology to catalyse neuroscience discovery. Philos Trans R Soc Lond B Biol Sci 370: |
| Deisseroth, Karl (2015) Optogenetics: 10 years of microbial opsins in neuroscience. Nat Neurosci 18:1213-25 |
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