Selective Optogenetic Control of Purkinje Cells in Monkey Cerebellum

El-Shamayleh, Yasmine; Kojima, Yoshiyuki; Soetedjo, Robijanto; Horwitz, Gregory D.

doi:10.1016/j.neuron.2017.06.002

Cited by 85 publications

(73 citation statements)

References 116 publications

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“…Optogenetic applications in NHPs have facilitated our understanding of sensory processing, decision making, and the bases of cognition 11,12,16,21,37 , and will likely play a key role in future brain-computer-interfaces, neural prosthetics, and methods to counteract cognitive decline in the aging human brain. As such, optogenetic techniques are undergoing rapid translation to human clinical use.…”

Section: Discussionmentioning

confidence: 99%

“…Cortex. Channelrhodopsin-2 (ChR2) is a commonly used optogenetic actuator for NHPs, though it often requires high laser power to evoke neuronal and behavioral responses [14][15][16][17]21 . The high conductance and red-shifted absorption spectrum of C1V1 makes it a preferable choice 12,34,38,39 .…”

Section: Expression Of Optogenetic Actuator and Calcium Indicator In mentioning

confidence: 99%

“…Yet, repeated electrode recordings of the same neurons are difficult to achieve in NHPs. In addition, examining opsin expression patterns online within the area targeted by viral vector infusions, while maintaining the health of the neurons, is not currently possible without 2P laser-scanning microscopy 16,21 . These combined hurdles call for an AOI approach to the application of optogenetic methods in NHPs.…”

Section: Introductionmentioning

confidence: 99%

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Long-term all-optical interrogation of cortical neurons in awake-behaving non-human primates

Jiang

Macknik

et al. 2018

Preprint

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Whereas optogenetic techniques have proven successful in their ability to manipulate neuronal populations in species ranging from insects to rodents-with high spatial and temporal fidelity-significant obstacles remain in their application to non-human primates (NHPs). Robust optogenetics-activated behavior and long-term noninvasive monitoring of target neurons, have been challenging in NHPs. Here we present a method for all-optical interrogation (AOI), integrating optical stimulation and simultaneous two-photon imaging of neuronal populations in the primary visual cortex (V1) of awake rhesus macaques. A red-shifted channel-rhodopsin transgene (C1V1) and genetically-encoded calcium indicators (GCaMP5 or GCaMP6s) were delivered by AAVs, and subsequently expressed in V1 neuronal populations for months with high stability. We achieved optogenetic stimulation using both single-photon (1P) activation of neuronal populations and two-photon (2P) activation of single-cells, while simultaneously recording 2P calcium imaging in awake monkeys. Optogenetic manipulations of V1 neuronal populations produced reliable artificial visual percepts. Together, our advances show the feasibility of precise and stable all-optical interrogation of cortical neurons in awake NHPs, which may facilitate broad applications in high-level cognition and pre-clinical testing studies.

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Section: Discussionmentioning

confidence: 99%

Section: Expression Of Optogenetic Actuator and Calcium Indicator In mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Long-term all-optical interrogation of cortical neurons in awake-behaving non-human primates

Jiang

Macknik

et al. 2018

Preprint

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“…This is the scale at which electrical microstimulation has proven most effective, but primate systems neuroscience has lacked an inactivation counterpart with comparable spatial and temporal specificity, relying instead on pharmacological and cooling methods that last minutes to days and affect larger swaths of tissue. There is understandable excitement surrounding the development of optogenetic methods for targeting particular cell types or projections (El-Shamayleh et al, 2017;Klein et al, 2016;Stauffer et al, 2016;Ohayon & DiCarlo, Soc. Neurosci.…”

Section: Focal Optogenetic Suppressionmentioning

confidence: 99%

Focal optogenetic suppression in macaque area MT biases direction discrimination and choice confidence, but only transiently

Fetsch

Odean

Jeurissen

et al. 2018

Preprint

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Insights from causal manipulations of brain activity depend on targeting the spatial and temporal scale most relevant for behavior. Using a sensitive perceptual decision task in monkeys, we examined the effects of randomly-interleaved, rapid, reversible inactivation on a spatial scale previously achieved only with electrical microstimulation. Inactivating neurons in area MT with consistent direction tuning produced systematic effects on choice and confidence. Behavioral effects were attenuated over the course of each session, suggesting compensatory adjustments in the downstream readout of MT over tens of minutes. Compensation also occurred on a sub-second time scale: behavior was largely unaffected on trials with visual stimuli (and concurrent suppression) longer than ~350ms. These trends were similar for choice and confidence, consistent with the idea of a common mechanism underlying both measures. The findings demonstrate the utility of hyperpolarizing opsins for linking neural population activity at fine spatial and temporal scales to cognitive functions in primates.

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“…Indeed, even the development of optogenetic techniques for NHPs in the central nervous system (CNS) has proven challenging with examples of successful viral transduction studies slowly beginning to accumulate [27][28][29][30][31][32][33]. A handful of studies have demonstrated viral transduction of peripheral neuromuscular tissue with fluorescent proteins in NHP models [34,35], but optogenetic modulation of peripheral neural activity in primates similar to the aforementioned rodent studies has not been reported to date.…”

Section: Introductionmentioning

confidence: 99%

Viral-mediated optogenetic stimulation of peripheral motor nerves in non-human primates

Williams

Vazquez

Schwartz

2018

Preprint

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Abstract:Objective: Reanimation of muscles paralyzed by disease states such as spinal cord injury remains a much sought after therapeutic goal of neuroprosthetic research. Optogenetic stimulation of peripheral motor nerves expressing light-sensitive opsins is a promising approach to muscle reanimation that may overcome several drawbacks of traditional methods such as functional electrical stimulation (FES). However, the utility of these methods has only been demonstrated in rodents to date, while translation to clinical practice will likely first require demonstration and refinement of these gene therapy techniques in non-human primates.Approach: Two rhesus macaques were injected intramuscularly with either one or both of two optogenetic constructs (AAV6-hSyn-ChR2-eYFP and/or AAV6-hSyn-Chronos-eYFP) to transduce opsin expression in the corresponding nerves. Neuromuscular junctions were targeted for virus delivery using an electrical stimulating injection technique. Functional opsin expression was periodically evaluated up to 13 weeks post-injection by optically stimulating targeted nerves with a 472 nm fiber-coupled laser while recording electromyographic (EMG) responses.Main Results: One monkey demonstrated functional expression of ChR2 at 8 weeks post-injection in each of two injected muscles, while the other monkey briefly exhibited contractions coupled to optical stimulation in a muscle injected with the Chronos construct at 10 weeks. EMG responses to optical stimulation of ChR2-transduced nerves demonstrated graded recruitment relative to both stimulus pulse-width and light intensity, and were able to track stimulus trains up to 16 Hz. In addition, the EMG response to prolonged stimulation showed delayed fatigue over several minutes.Significance: These results demonstrate the feasibility of viral transduction of peripheral motor nerves for functional optical stimulation of motor activity in non-human primates. Subsequently, they represent an important step in translating these optogenetic techniques as a clinically viable gene therapy.

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Selective Optogenetic Control of Purkinje Cells in Monkey Cerebellum

Cited by 85 publications

References 116 publications

Long-term all-optical interrogation of cortical neurons in awake-behaving non-human primates

Long-term all-optical interrogation of cortical neurons in awake-behaving non-human primates

Focal optogenetic suppression in macaque area MT biases direction discrimination and choice confidence, but only transiently

Viral-mediated optogenetic stimulation of peripheral motor nerves in non-human primates

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