High-Performance Genetically Targetable Optical Neural Silencing via Light-Driven Proton Pumps

By B. Chow, Xue Han, A. Dobry, Xiaofeng Qian, A. Chuong, Mingjie Li, Michael A. Henninger, Gabriel M. Belfort, Yingxi Lin, P. Monahan and 1 more. Nature, 2010

1,122 citations recorded by the source corpus.

The ability to silence the activity of genetically specified neurons in a temporally precise fashion would provide the opportunity to investigate the causal role of specific cell classes in neural computations, behaviours and pathologies. Here we show that members of the class of light-driven outward proton pumps can mediate powerful, safe, multiple-colour silencing of neural activity. The gene archaerhodopsin-3 (Arch) from Halorubrum sodomense enables near-100% silencing of neurons in the awake brain when virally expressed in the mouse cortex and illuminated with yellow light. Arch mediates currents of several hundred picoamps at low light powers, and supports neural silencing currents approaching 900 pA at light powers easily achievable in vivo. Furthermore, Arch spontaneously recovers from light-dependent inactivation, unlike light-driven chloride pumps that enter long-lasting inactive states in response to light. These properties of Arch are appropriate to mediate the optical silencing of significant brain volumes over behaviourally relevant timescales. Arch function in neurons is well tolerated because pH excursions created by Arch illumination are minimized by self-limiting mechanisms to levels comparable to those mediated by channelrhodopsins or natural spike firing. To highlight how proton pump ecological and genomic diversity may support new innovation, we show that the blue–green light-drivable proton pump from the fungus Leptosphaeria maculans (Mac) can, when expressed in neurons, enable neural silencing by blue light, thus enabling alongside other developed reagents the potential for independent silencing of two neural populations by blue versus red light. Light-driven proton pumps thus represent a high-performance and extremely versatile class of ‘optogenetic’ voltage and ion modulator, which will broadly enable new neuroscientific, biological, neurological and psychiatric investigations.

Subfields: Cellular and Molecular Neuroscience, Plant Science

View Paper: https://www.semanticscholar.org/paper/faa10f4a9934b99187956b5045b5a0d469a7c7c4

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

In Plant Science

Citations in the corpus

Activation of Specific Interneurons Improves V1 Feature Selectivity and Visual Perception (2012, neutral): “…the activation of inhibitory neurons rather than a decreased spiking of excitatory neurons, as archaerhodopsin-3 (Arch)-mediated optical silencing 7 of calcium/calmodulin-dependent protein kinase II a (CAMKII a )-positive excitatory neurons caused no significant change in V1 stimulus selectivity.”
Neuromodulation of brain states. (2012, neutral): “Optogenetic manipulation of their activity in a bidirectional manner (Chow et al., 2010; Deisseroth, 2011), which has been achieved in various neuronal circuits, can further establish the causal role of these neurons in brain state regulation (Figure 4).”
Parvalbumin-Expressing Interneurons Linearly Transform Cortical Responses to Visual Stimuli (2012, neutral): “To control the activity of PV cells we conditionally expressed the light-sensitive proton pump Archeorhodopsin (Arch-GFP; to suppress activity; Chow et al., 2010) or the light-sensitive cation channel Channelrhodopsin-2 (ChR2-tdTomato; to increase activity; Boyden et al.”
A toolbox of Cre-dependent optogenetic transgenic mice for light-induced activation and silencing (2012, positive): “23 ) and various forms of Arch 6,24 , with great improvement in membrane expression and related increase in photoconductance, making reliable genetic silencing achievable now.”
Optogenetic tools for analyzing the neural circuits of behavior (2011, neutral): “…channelrho-dopsins that are faster or slower to turn off after illumination [e.g. several channelrhodopsin mutants, including ChETA, SFO and the ChR2(D156A) mutant [20 – 22]] and color-shifted channelrhodopsins (e.g. VChR1, MChR1 and C1V1 [23 – 26]), with new variants arising at a rapid pace [27].”
Seizure detection, seizure prediction, and closed-loop warning systems in epilepsy. (2014, positive): “Opsins are used to selectively control neurons, leading to better understanding of pathophysiology [148].”
Genetically encoded calcium indicators for multi-color neural activity imaging and combination with optogenetics (2013, neutral): “, 2005), archaerhodopsin-3 (Arch) (Chow et al., 2010), and halorhodopsin (HR) (Zhang et al.”
Physiological properties and behavioral correlates of hippocampal granule cells and mossy cells (2017, neutral): “To obtain expression of channelrhodopsin-2 (ChR2; Boyden et al., 2005) or archaerhodopsin-3 (Arch; Chow et al., 2010; Mattis et al., 2011), SST-Cremice were injected with either AAV5-EF1a-DIO-hChR2(H234R)EYFP-WPRE-pA (n = 6 mice) or AAV5-EF1a-DIO-eArch3.”
Molecular and cellular approaches for diversifying and extending optogenetics. (2010, neutral): “an opsin (AR) from Acetabularia acetabulum (Tsunoda et al., 2006; Chow et al., 2010) engineered for improved trafficking; AR generates little current alone but was initially aggregate free and required only addition of the TS signal between AR and EYFP for functional membrane localization and spike ”
Origins of Cell-Type-Specific Olfactory Processing in the Drosophila Mushroom Body Circuit. (2017, neutral): “REAGENT or RESOURCE SOURCE IDENTIFIER Antibodies Mouse anti-bruchpilot (nc82) Developmental Studies Hybridoma Bank nc82; RRID: AB_2314866 Rat anti-GFP monoclonal Nacalai tesque 04404-84; RRID: AB_10013361 Rabbit anti-GABA Sigma A2052; RRID: AB_477652 Vectashield mounting medium antibody Vector labor”