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

> **NIH NIH R01** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2021 · $616,679

## Abstract

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 t...

## Key facts

- **NIH application ID:** 10125134
- **Project number:** 5R01DA029639-10
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Edward S. Boyden
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $616,679
- **Award type:** 5
- **Project period:** 2010-07-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10125134

## Citation

> US National Institutes of Health, RePORTER application 10125134, Novel Platforms for Systematic Optical Control of Complex Neural Circuits In Vivo (5R01DA029639-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10125134. Licensed CC0.

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