Noninvasive optical inhibition with a red-shifted microbial rhodopsin

Chuong, Amy S.; Miri, Mitra L; Busskamp, Volker; Matthews, Gillian A.; Acker, Leah; Sørensen, Andreas T.; Young, Andrew J.; Klapoetke, Nathan C.; Henninger, Mike A.; Kodandaramaiah, Suhasa B.; Ogawa, Masaaki; Ramanlal, Shreshtha; Bandler, Rachel C.; Allen, Bruce C.; Forest, Craig R.; Chow, Brian Y.; Han, Xue; Lin, Yingxi; Tye, Kay M.; Roska, Botond; Cardin, Jessica A.; Boyden, Edward S.

doi:10.1038/nn.3752

Cited by 490 publications

(444 citation statements)

References 66 publications

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“…Moreover, potential long-term effects of expressing a light-driven channel (CatCh) with increased calcium permeability need to be taken into account when using this approach. To avoid potential blue light toxicity while stimulating the retina at high light intensities, developments in opsin engineering 47 and discovery 48,49 will help further refine optogenetic vision restoration strategies. In the future, we anticipate that developments in both viral technologies and surgical techniques will aid in obtaining better distribution of the optogenetic protein across the primate retina.…”

Section: Discussionmentioning

confidence: 99%

A New Promoter Allows Optogenetic Vision Restoration with Enhanced Sensitivity in Macaque Retina

et al. 2017

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The majority of inherited retinal degenerations converge on the phenotype of photoreceptor cell death. Second-and third-order neurons are spared in these diseases, making it possible to restore retinal light responses using optogenetics. Viral expression of channelrhodopsin in the third-order neurons under ubiquitous promoters was previously shown to restore visual function, albeit at light intensities above illumination safety thresholds. Here, we report (to our knowledge, for the first time) activation of macaque retinas, up to 6 months post-injection, using channelrhodopsin-Ca 2+ -permeable channelrhodopsin (CatCh) at safe light intensities. High-level CatCh expression was achieved due to a new promoter based on the regulatory region of the gamma-synuclein gene (SNCG) allowing strong expression in ganglion cells across species. Our promoter, in combination with clinically proven adeno-associated virus 2 (AAV2), provides CatCh expression in peri-foveolar ganglion cells responding robustly to light under the illumination safety thresholds for the human eye. On the contrary, the threshold of activation and the proportion of unresponsive cells were much higher when a ubiquitous promoter (cytomegalovirus [CMV]) was used to express CatCh. The results of our study suggest that the inclusion of optimized promoters is key in the path to clinical translation of optogenetics.

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Section: Discussionmentioning

confidence: 99%

A New Promoter Allows Optogenetic Vision Restoration with Enhanced Sensitivity in Macaque Retina

et al. 2017

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“…By expressing these molecules in specific neurons, regions, or projection pathways, the targeted circuit elements can then be silenced or activated in response to light. Halorhodopsins and archaerhodopsins are commonly used for optical silencing of neural activity with light (Han and Boyden 2007;Zhang et al 2007a;Chow et al 2010;Gradinaru et al 2010;Han et al 2011;Chuong et al 2014). Channelrhodopsins are commonly used for optical activation of neural activity with light (Boyden et al 2005;Nagel et al 2005;Yizhar et al 2011;Klapoetke et al 2014).…”

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confidence: 99%

Principles of designing interpretable optogenetic behavior experiments

2015

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Over the last decade, there has been much excitement about the use of optogenetic tools to test whether specific cells, regions, and projection pathways are necessary or sufficient for initiating, sustaining, or altering behavior. However, the use of such tools can result in side effects that can complicate experimental design or interpretation. The presence of optogenetic proteins in cells, the effects of heat and light, and the activity of specific ions conducted by optogenetic proteins can result in cellular side effects. At the network level, activation or silencing of defined neural populations can alter the physiology of local or distant circuits, sometimes in undesired ways. We discuss how, in order to design interpretable behavioral experiments using optogenetics, one can understand, and control for, these potential confounds.

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“…Through molecular engineering, these tools have been optimized to allow for faster alteration of channels [114,115], response to different wavelengths [116][117][118][119][120], more robust gene expression [114,117,121,122], and channels with stepwise kinetics [117,123,124]. Having tools activated with different wavelengths makes it possible to manipulate the same neuron bidirectionally with both excitatory and inhibitory channels.…”

Section: Optogeneticsmentioning

confidence: 99%

“…To reduce invasiveness channels that respond to longer wavelength light have been developed; longer wavelength light penetrates tissue more deeply than short [135][136][137][138][139][140]. Red light-activated opsins such as excitatory red lightactivated channelrhodopsin and inhibitory red-shifted cruxhalorhodopsin (Jaws) can be applied to the surface of the brain or through a thinned skull [119,120].…”

Section: Optogeneticsmentioning

confidence: 99%

Selective Manipulation of Neural Circuits

Park

Carmel

2016

Neurotherapeutics

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Unraveling the complex network of neural circuits that form the nervous system demands tools that can manipulate specific circuits. The recent evolution of genetic tools to target neural circuits allows an unprecedented precision in elucidating their function. Here we describe two general approaches for achieving circuit specificity. The first uses the genetic identity of a cell, such as a transcription factor unique to a circuit, to drive expression of a molecule that can manipulate cell function. The second uses the spatial connectivity of a circuit to achieve specificity: one genetic element is introduced at the origin of a circuit and the other at its termination. When the two genetic elements combine within a neuron, they can alter its function. These two general approaches can be combined to allow manipulation of neurons with a specific genetic identity by introducing a regulatory gene into the origin or termination of the circuit. We consider the advantages and disadvantages of both these general approaches with regard to specificity and efficacy of the manipulations. We also review the genetic techniques that allow gain-and loss-of-function within specific neural circuits. These approaches introduce light-sensitive channels (optogenetic) or drug sensitive channels (chemogenetic) into neurons that form specific circuits. We compare these tools with others developed for circuit-specific manipulation and describe the advantages of each. Finally, we discuss how these tools might be applied for identification of the neural circuits that mediate behavior and for repair of neural connections.

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Noninvasive optical inhibition with a red-shifted microbial rhodopsin

Cited by 490 publications

References 66 publications

A New Promoter Allows Optogenetic Vision Restoration with Enhanced Sensitivity in Macaque Retina

A New Promoter Allows Optogenetic Vision Restoration with Enhanced Sensitivity in Macaque Retina

Principles of designing interpretable optogenetic behavior experiments

Selective Manipulation of Neural Circuits

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