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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH075957-04
Application #
7997244
Study Section
Special Emphasis Panel (ZRG1-MDCN-K (90))
Program Officer
Freund, Michelle
Project Start
2007-12-11
Project End
2012-10-31
Budget Start
2010-11-01
Budget End
2011-10-31
Support Year
4
Fiscal Year
2011
Total Cost
$550,630
Indirect Cost
Name
Stanford University
Department
Biomedical Engineering
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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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
Deisseroth, Karl (2015) Optogenetics: 10 years of microbial opsins in neuroscience. Nat Neurosci 18:1213-25
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Adhikari, Avishek; Lerner, Talia N; Finkelstein, Joel et al. (2015) Basomedial amygdala mediates top-down control of anxiety and fear. Nature 527:179-85
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:

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