A high-light sensitivity optical neural silencer: development, and application to optogenetic control of nonhuman primate cortex

Han, X.*, Chow, B. Y.*, Zhou, H., Klapoetke, N. C., Chuong, A., Rajimehr, R., Yang, A., Baratta, M. V., Winkle, J., Desimone, R., Boyden, E. S. (2011) A high-light sensitivity optical neural silencer: development and application to optogenetic control of non-human primate cortex, Frontiers in Systems Neuroscience 5:18. (* co-first authors)

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Technologies for silencing the electrical activity of genetically targeted neurons

in the brain are
important for assessing the contribution of specific cell types and pathways toward

and pathologies. Recently we found that archaerhodopsin-3 from Halorubrum sodomense
(Arch), a light-driven outward proton pump, when genetically expressed in neurons,

them to be powerfully, transiently, and repeatedly silenced in response to pulses of

Because of the impressive characteristics of Arch, we explored the optogenetic

utility of opsins
with high sequence homology to Arch, from archaea of the Halorubrum genus. We found

the archaerhodopsin from Halorubrum strain TP009, which we named ArchT, could

photocurrents of similar maximum amplitude to those of Arch (~900 pA in vitro), but

with a
>3-fold improvement in light sensitivity over Arch, most notably in the optogenetic

range of
1–10 mW/mm2, equating to >2x increase in brain tissue volume addressed by a typical

optical fiber. Upon expression in mouse or rhesus macaque cortical neurons, ArchT

well on neuronal membranes, including excellent trafficking for long distances down

axons. The high light sensitivity prompted us to explore ArchT use in the cortex of

the rhesus
macaque. Optical perturbation of ArchT-expressing neurons in the brain of an awake

macaque resulted in a rapid and complete (~100%) silencing of most recorded cells,

suppressed cells achieving a median firing rate of 0 spikes/s upon illumination. A

small population
of neurons showed increased firing rates at long latencies following the onset of

light stimulation,
suggesting the existence of a mechanism of network-level neural activity balancing.

The powerful
net suppression of activity suggests that ArchT silencing technology might be of

great use not
only in the causal analysis of neural circuits, but may have therapeutic



Optogenetics: molecules enabling neural control by light

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