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 #
5R01MH075957-05
Application #
8196829
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
2011-11-01
Budget End
2012-10-31
Support Year
5
Fiscal Year
2012
Total Cost
$349,679
Indirect Cost
$77,033
Name
Stanford University
Department
Biomedical Engineering
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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
Kim, Hoseok; Ährlund-Richter, Sofie; Wang, Xinming et al. (2016) Prefrontal Parvalbumin Neurons in Control of Attention. Cell 164:208-218
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
Deisseroth, Karl (2015) Optogenetics: 10 years of microbial opsins in neuroscience. Nat Neurosci 18:1213-25
Rajasethupathy, Priyamvada; Sankaran, Sethuraman; Marshel, James H et al. (2015) Projections from neocortex mediate top-down control of memory retrieval. Nature 526:653-9
Adhikari, Avishek; Lerner, Talia N; Finkelstein, Joel et al. (2015) Basomedial amygdala mediates top-down control of anxiety and fear. Nature 527:179-85

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