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Novel Platforms for Systematic Optical Control of Complex Neural Circuits In Vivo

Award Number: R01DA029639
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2010
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Novel Platforms for Systematic Optical Control of Complex Neural Circuits In Vivo - This grant application is for a second renewal of our group’s key NIH grant that supports development of optogenetic tools -- microbial opsins that enable safe, temporally precise, and high-magnitude control of neural activity in neurons in awake behaving mammals and other species of importance in neuroscience. Since our grant was first awarded in 2010, it has supported the development of optogenetic tools such as Arch (the first optogenetic neural silencer to result in ~100% optogenetic silencing of neural activity in awake behaving mice), ArchT (a 3x more light-sensitive relative of Arch), Chronos (an ultrafast optogenetic activator, used in contexts where speed is essential), Chrimson (the most redshifted optogenetic activator, useful for activation of large volumes of brain tissue as well as avoiding behavioral artifacts in Drosophila), Jaws (the most redshifted optogenetic silencer), SoCoChR (which enables single-cell, single-spike resolution optogenetics) and ChromeQ (a potassium- and sodium-selective optogenetic activator), resulting in 50 peer reviewed papers, and resulting in wide distribution of next-generation optogenetic tools throughout neuroscience. To date, we have primarily used genomic search to discover novel opsins, mining public and private databases to identify new candidates. Having screened through a large number of genomic resources to identify these molecules, however, one concern is that there are diminishing returns, and that some goals will not be met purely through genomic search, or even structure-guided site-directed mutagenesis. Directed evolution, which sifts through a large number of mutants of a parent gene to identify versions improved towards some goal, offers hope, but has not been applied to optogenetic tools due to the difficulty of performing directed evolution in mammalian cells (essential, since optogenetic tools that express well in cells commonly used in directed evolution, such as E. coli, do not express well in mammalian cells, and evolving optogenetic tools in such cells would likely de- optimize them for expression in mammalian cells), and the difficulty of performing multidimensional directed evolution (essential, because we need to optimize optogenetic tools towards multiple goals – for example, localization, spectrum, and magnitude – and optimizing too much along one axis will de-optimize the tool along other axes). We here propose to develop a directed evolution approach for optogenetic tool engineering (Aim 1), and apply it to several longstanding open needs in optogenetics: the creation of redshifted and blue spectrum-trimmed optogenetic activators, Aim 2; the creation of multiphoton-optimized silencers, Aim 3; and the optimization (by developing and applying automated patch clamp technology) of kinetics and ion selectivity, aiming to improve optogenetic tool kinetics for the aforementioned optogenetic tools as well as potassium conductances of light-gated potassium channels (Aim 4). We aim to deliver to the neuroscience community a powerful toolbox of optogenetic controllers of widespread utility, and to disseminate them freely throughout the research world.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Drug Use and Addiction Research Programs	000	12	7/21/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Drug Use and Addiction Research Programs	000	12	3/8/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $582,848 )
2023	2023	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Drug Use and Addiction Research Programs	000	12	1/27/2023	NON-COMPETING CONTINUATION	$582,848
														Subtotal = $582,848

Issue Date FY: 2022 ( Subtotal = $600,042 )
2022	2022	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Drug Use and Addiction Research Programs	000	11	2/9/2022	NON-COMPETING CONTINUATION	$540,038
2022	2022	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Drug Use and Addiction Research Programs	001	11	3/30/2022	NON-COMPETING CONTINUATION	$60,004
														Subtotal = $600,042

Issue Date FY: 2021 ( Subtotal = $616,679 )
2021	2021	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Drug Use and Addiction Research Programs	000	10	2/5/2021	NON-COMPETING CONTINUATION	$616,679
														Subtotal = $616,679

Issue Date FY: 2020 ( Subtotal = $645,432 )
2020	2020	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Drug Use and Addiction Research Programs	002	9	3/10/2020	COMPETING CONTINUATION	$645,432
2020	2018	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Drug Use and Addiction Research Programs	000	8	1/15/2020	NON-COMPETING CONTINUATION	-$678
2020	2018	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Drug Use and Addiction Research Programs	001	8	1/22/2020	NON-COMPETING CONTINUATION	$678
														Subtotal = $645,432

Issue Date FY: 2018 ( Subtotal = $586,161 )
2018	2018	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Drug Use and Addiction Research Programs	000	8	6/1/2018	NON-COMPETING CONTINUATION	$586,161
														Subtotal = $586,161

Issue Date FY: 2017 ( Subtotal = $594,505 )
2017	2017	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Drug Use and Addiction Research Programs	000	7	5/25/2017	NON-COMPETING CONTINUATION	$594,505
														Subtotal = $594,505

Issue Date FY: 2016 ( Subtotal = $596,578 )
2016	2016	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Drug Use and Addiction Research Programs	000	6	6/3/2016	NON-COMPETING CONTINUATION	$596,578
														Subtotal = $596,578

Issue Date FY: 2015 ( Subtotal = $624,471 )
2015	2015	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Drug Use and Addiction Research Programs	000	5	6/29/2015	COMPETING CONTINUATION	$624,471
														Subtotal = $624,471

Issue Date FY: 2013 ( Subtotal = $443,427 )
2013	2013	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Drug Use and Addiction Research Programs	000	4	6/19/2013	NON-COMPETING CONTINUATION	$443,427
														Subtotal = $443,427

Issue Date FY: 2012 ( Subtotal = $472,488 )
2012	2012	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Drug Use and Addiction Research Programs	000	3	6/18/2012	NON-COMPETING CONTINUATION	$472,488
														Subtotal = $472,488

Issue Date FY: 2011 ( Subtotal = $483,595 )
2011	2011	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Drug Use and Addiction Research Programs	000	2	6/16/2011	NON-COMPETING CONTINUATION	$483,595
														Subtotal = $483,595

Issue Date FY: 2010 ( Subtotal = $425,466 )
2010	2010	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Drug Use and Addiction Research Programs	000	1	6/21/2010	NEW	$425,466
														Subtotal = $425,466

Grand Total All Awards = $6,671,692

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Novel Platforms for Systematic Optical Control of Complex Neural Circuits In Vivo

Award Number: R01DA029639

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2010

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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