Biology subjects

Picaud, S.

Publications and source records attributed to Picaud, S..

At least 19 recordsLinked to original sources

bioRxiv2026

From Functional Organization to Vascular Structure in the Primate Visual Cortex Using Ultrasound Imaging

The primary visual cortex (V1) provides an exceptional structure to assess information encoding in the cortex thanks to its highly controlled visual input. However, optical measures and electrophysiology are limited to very superficial layers while fMRI provides low spatial resolution. Taking advantages of functional ultrasound imaging (fUSi), we examined large volumes of V1 in two awake non-human primates. We showed the conservation of retinotopic maps within deep sulcal regions and across cortical layers. We then assessed the cortical point image and compared it to its vasculature distribution through ultrasound localization microscopy (ULM). We further identified the smallest vascular compartment underlying the signal. Together, these results establish fUSi, complemented by ULM, as a minimally invasive mesoscale approach for resolving functional organization of the cortex in deep sulci.

neuroscience↗

bioRxiv2025

Endothelial NMDA receptor involvement in retinal neurovascular damage following prenatal alcohol exposure in mouse model

Prenatal alcohol exposure (PAE) induces neurodevelopmental damage leading to fetal alcohol spectrum disorders (FASD) by altering both brain and ocular development. Recent data showed that PAE impairs brain cortical and retinal vasculature leading to defective positioning of interneurons. In the retina, PAE disturbs vascular development and the association of calretinin neurons with vessels. The NMDA receptor (NMDAR) is a major target of alcohol in the brain, and both ligand binding to NMDARs and the expression of NMDAR subunits are altered in FASD. Given that NMDAR is also expressed in endothelial cells and that glutamate stimulation of endothelial NMDAR (eNMDAR) regulates cortical interneuron positioning along blood vessels, we hypothesize that eNMDAR is critical for retinal vascular development and mediates PAE-induced defects. Using an in vivo model of FASD and transgenic mice lacking, specifically in endothelial cells, the GluN1 subunit of the NMDAR, this study aimed to characterize the neurovascular phenotype of the developing retina. The results show that eNMDAR knockout delays the formation of the superficial vascular plexus and prevents the alterations in vascular organization and neuronal density induced by PAE, particularly cells positioned closer to the retinal vasculature, namely ganglion, amacrine, and horizontal cells. Moreover, eNMDAR deletion led to an increased number of calretinin-positive interneurons in contact with perforating vessels and prevents the decrease induced by PAE. Together, these findings demonstrate that eNMDARs are essential for normal retinal neurovascular development and mediate, at least in part, the detrimental effects of ethanol exposure in FASD. Significance statementUsing a murine model of Fetal Alcohol Spectrum Disorder (FASD) and transgenic mice lacking the GluN1 subunit of the NMDA receptor specifically in endothelial cells (eNMDAR), this study demonstrates that eNMDAR plays a critical role in mediating prenatal alcohol exposure (PAE)-induced neurovascular abnormalities in the retina. Loss of eNMDAR alters the progression of the superficial vascular plexus and prevents the vascular impairments typically observed following PAE. In addition, eNMDAR deletion protects against PAE-induced neuronal damage, particularly affecting retinal ganglion cells, calbindin-positive, and calretinin-positive interneurons. Notably, this study identifies, for the first time, a role for endothelial NMDAR in regulating neurovascular interactions between retinal vessels and calretinin-positive neurons, highlighting this receptor as a key molecular mediator of ethanol-induced retinal damage.

neuroscience↗

bioRxiv2025

WFS1E864K in humans and mice causes Wolfram-like syndrome optic atrophy via early axonal mitochondrial dysfunction

Wolfram-like syndrome leads to retinal ganglion cell degeneration and vision loss. Wolfram-like syndrome is primarily caused by variants in the WFS1 gene, which encodes an endoplasmic reticulum resident transmembrane protein, Wolframin. To date, the disease mechanism remains unclear, and no therapies are available. Here, we generated a mouse model carrying the pathogenic WFS1E864K allele that recapitulated key features of human Wolfram-like syndrome, including bilateral optic atrophy, retinal nerve fiber thinning and lamination of the outer plexiform layer. We demonstrated, using the Wfs1E864K mouse model, that alteration of the protein leads to impairments of retinal ganglion cell function, associated with a thinning of the inner retina layer and nerve fibers. These alterations are associated with myelin disorganization, axonal death, mitochondrial alterations in the axons, and impairment of endoplasmic reticulum-mitochondria communication in the soma. Our data showed that primary deficits are localized in the optic nerve before progressing towards the retinal ganglion cell soma. RNAseq analysis identified several altered signaling pathways such as in lipid metabolism, glia activation response, metabolic stress, organelle transport and quality control. These findings highlighted the critical role of Wolframin in optic nerve mitochondrial physiology, providing us with a pertinent model to develop novel innovative therapeutic strategies.

neuroscience↗

bioRxiv2025

Increased sensitivity to myopia and altered retinal ON/OFF balance in a mouse model lacking Dusp4

Myopia, influenced by environmental and genetic factors, occurs when the emmetropization process fails to stop, causing excessive eyeball growth. Highly myopic animal models lacking a functional ON-pathway identified Dusp4 as a potential gene implicated in myopia. Here, we used a mouse model lacking DUSP4 to gain a better understanding of its retinal role and the mechanisms implicated in myopia development. Dusp4-/- mice have a reduced basal level of retinal dopamine and a higher susceptibility to lens-induced myopia. Dusp4 is expressed in ON-bipolar cells and a subset of OFF-bipolar cells in a light dependent manner. The absence of DUSP4 causes a hyperactivation of the MAPK/ERK pathway. Dusp4-/- mice showed reduced optomotor responses, increased ON-bipolar cell depolarization, reduced oscillatory potentials together with altered OFF and ON-OFF RGC responses to light flashes. These data provide insights into retina-driven mechanisms of myopization, nuancing the impact of ON and OFF pathways upon emmetropization.

neuroscience↗

bioRxiv2025

Ectopic expression of two cone opsins in mouse RGCs results in opposite responses to light stimulation, likely due to differential G protein activation

Retinitis pigmentosa, a leading cause of inherited blindness, results in photoreceptor degeneration that current optogenetic approaches aim to address through microbial opsin expression in retinal ganglion cells (RGCs). While these microbial proteins restore light sensitivity, their clinical potential remains limited by low light sensitivity and immunogenicity risks. Recent efforts have focused on vertebrate opsins as safer alternatives, with mid-wavelength cone opsin (MW-opsin) demonstrating RGC depolarization via endogenous G-protein signaling. In this study, we reveal a surprising divergence in signaling outcomes of expressing short-wavelength mouse cone opsin (Opn1sw) in RGCs of blind mice. Using multielectrode array recordings and whole-cell patch clamping, we demonstrate that Opn1sw induces membrane hyperpolarization in RGCs - a stark contrast to MW-opsins depolarizing effects. This unexpected inversion suggests differential engagement of intracellular signaling pathways, potentially stemming from distinct G-protein coupling preferences. Comparative analysis of native G-protein expression profiles in RGCs versus cone photoreceptors supports this hypothesis, revealing mismatches that may explain ectopic opsin behavior. Our findings challenge the assumption of conserved opsin signaling across spectral subtypes and cell types, highlighting critical gaps in understanding vertebrate opsin-G protein interactions in non-native cellular environments. This discovery points to the necessity of systematic characterization of opsin signaling networks in target retinal cells, a prerequisite for engineering optimized optogenetic tools that reliably produce desired electrophysiological outcomes. By establishing spectral subtype-dependent signaling divergence, our work redefines parameters for developing next-generation vision restoration therapies.

neuroscience↗

bioRxiv2024

Bidirectional control of neurovascular coupling by cortical somatostatin interneurons

Neurovascular coupling, linking neuronal activity to cerebral blood flow, is altered early in neurological disorders and underlies functional brain imaging. This process involves numerous cellular players. Among them inhibitory interneurons receive increasing attention, but how they control blood flow remains elusive. This study elucidates the mechanisms by which somatostatin interneurons bidirectionally control neurovascular coupling. Patch clamp recordings in, ex vivo, cortical slices from mice expressing channelrhodopsin-2 in somatostatin interneurons, revealed that these neurons are supralinearly activated at low-frequencies (< 5 Hz) and efficiently photostimulated at frequencies up to 20 Hz. Ex vivo vascular imaging showed that low-frequency (2 Hz) photostimulation triggered vasodilation whereas high-frequency (20 Hz) photostimulation induced vasoconstriction. Histochemistry revealed that subpopulations of cortical somatostatin interneurons expressed the neuronal nitric oxide synthase, and/or neuropeptide Y to a greater extent. Consistently, pharmacological investigations showed that vasodilation induced by low-frequency photostimulation involves nitric oxide release and activation of soluble guanylate cyclase. In contrast, the vasoconstriction induced at high-frequency photostimulation involves neuropeptide Y release and activation of the Y1 vascular receptor. These findings provide valuable insights into neurovascular coupling and help to understand the cellular mechanism underlying the functional brain imaging signals.

neuroscience↗

bioRxiv2024

A flexible high-precision photoacoustic retinal prosthesis

Retinal degenerative diseases of photoreceptors are a leading cause of blindness with no effective treatment. Retinal prostheses aim to restore sight by stimulating residual retinal cells. Here, we present a photoacoustic retinal stimulation technology. We designed a polydimethylsiloxane and carbon-based flexible film that converts near-infrared laser pulses into a localized acoustic field with 56-{micro}m lateral resolution, allowing precise stimulation of mechanosensitive retinal cells. This photoacoustic stimulation robustly and locally modulated retinal ganglion cell activity in both wild-type and degenerated ex vivo rat retinae. In animals subretinally implanted with a millimeter-sized photoacoustic film, pulsed laser stimulation generated neural modulation along the visual pathway to the superior colliculus, as measured by functional ultrasound imaging. The biosafety of the film was confirmed by the absence of short-term adverse effects , while local thermal increases were measured below 1 {degrees}C. These findings demonstrate the potential of photoacoustic stimulation for high-acuity visual restoration in blind patients.

neuroscience↗

bioRxiv2024

Systematic profiling of the acetyl lysine machinery reveals a role for MAPKAPK2 in bromodomain inhibitor resistance

Bromodomain (BRD)-containing proteins are chemically tractable multi-domain scaffolding molecules involved in acetyl lysine (Kac) signaling. BRD inhibitors have shown promise in clinical oncology, including melanomas; however, their narrow therapeutic windows and issues with resistance in pre-clinical models highlight the need to better understand the functions of and interconnection between BRD-containing proteins. Here, we use complementary interaction-mapping techniques (affinity purification and proximity-dependent biotinylation) to map the interactions of 39 of the 42 BRD-containing proteins and 110 additional proteins that physically or functionally associate with them. We uncover 3,892 novel interactions and reveal the intricate connectivity of the Kac machinery. Chemical inhibition of multiple BRD classes revealed that inhibiting BETs--but not mSWI/SNF or CREBBP/EP300 proteins--dramatically rewired the interactome. Finally, we identified MAPKAPK2 activity as a critical determinant of BET inhibitor sensitivity in melanoma through its impact on chromatin composition remodeling. In BriefKougnassoukou Tchara et al. generate a static protein interaction map of the human acetyl lysine machinery by coupling two complementary functional proteomics approaches (FLAG affinity purification and proximity-dependent biotinylation) to mass spectrometry. They also investigate network changes upon bromodomain inhibition, and describe a novel resistance mechanism mediated by the p38 stress signaling pathway that causes significant metabolic changes. HighlightsO_LITwo complementary interaction proteomics analyses of the human acetyl lysine machinery were performed. C_LIO_LINovel target- and compound-specific impacts of bromodomain inhibitors were identified. C_LIO_LIMAPKAPK2 was identified as a novel resistance gene to BET bromodomain inhibitors in melanoma. C_LIO_LIBET bromodomain inhibition leads to metabolic adaptation in melanoma. C_LI

cancer biology↗

bioRxiv2024

Elevated pyramidal cell firing orchestrates arteriolar vasoconstriction through COX-2-derived prostaglandin E2 signaling

Neurovascular coupling, linking neuronal activity to cerebral blood flow, is essential for brain function and underpins functional brain imaging. Whereas mechanisms involved in vasodilation are well-documented, those controlling vasoconstriction remain overlooked. This study unravels the mechanisms by which pyramidal cells elicit arteriole vasoconstriction. Using patch-clamp recording, vascular and Ca2+ imaging in mouse cortical slices, we show that strong optogenetic activation of layer II/III pyramidal cells induces vasoconstriction, correlating with firing frequency and somatic Ca2+ increase. Ex vivo and in vivo pharmacological investigations indicate that this vasoconstriction predominantly recruits prostaglandin E2 through the cyclooxygenase-2 pathway, and activation of EP1 and EP3 receptors. We also present evidence that specific interneurons releasing neuropeptide Y, and astrocytes, through 20-hydroxyeicosatetraenoic acid, contribute to this process. By revealing the mechanisms by which pyramidal cells lead to vasoconstriction, our findings shed light on the complex regulation of neurovascular coupling. Significance statementCerebral blood flow is tightly controlled by neuronal activity, a process termed neurovascular coupling which serves as the physiological basis for functional brain imaging widely used to map neuronal activity in health and diseases. While the prevailing view links increased neuronal activity with enhanced blood perfusion, our data suggest that elevated neuronal activity can also reduce cerebral blood flow. By optically controlling the activity of pyramidal cells, we demonstrate that these excitatory neurons induce vasoconstriction when their action potential firing is increased by releasing glutamate and lipid messengers. These findings update the interpretation of functional brain imaging signals and help to better understand the etiopathogenesis of epilepsy and Alzheimers disease, in which hyperactivity, hypoperfusion and cognitive deficits overlap.

neuroscience↗

bioRxiv2024

Consequences of neuronal morphology for spatially precise optogenetic stimulation

Single-photon optogenetic stimulation is a crucial tool in neuroscience, enabling precise, cell-type-specific modulation of neuronal circuits. Miniaturization of this technique in the form of fully implantable wide-field stimulator arrays enables interrogation of cortical circuits in long-term experiments and promises to enhance Brain-Machine Interfaces for restoring sensory and motor functions. However, for both basic science and clinical applications, it is essential that this technique achieves the precision needed for selective activation of sensory and motor representations at the single-column level. Yet studies report differing and sometimes conflicting neuronal responses within the stimulated cortical areas. While recurrent network mechanisms contribute to complex responses, here we demonstrate that complexity starts already at the level of neuronal morphology. Simulating optogenetic responses in detailed models of layer-2/3 and layer-5 pyramidal neurons, we accounted for realistic physiological dynamics across different stimulation intensities, including threshold, sustained, and depolarization-block responses. Our findings suggest that the spatial distribution of activated neurons from a single stimulator location at the cortical surface can be inhomogeneous and varies with stimulation intensity and neuronal morphology across layers, potentially explaining the observed response heterogeneity in earlier experiments. We found that activation spreads laterally up to several hundred micrometers from the light source due to neuronal morphology. To enhance precision, we explored two strategies: preferentially somatic expression of channelrhodopsin, which was effective only in layer-5 neurons, and narrowing the stimulating light beam, which improved precision in both layers. Our results indicate that, under the right optical setup, single-column precision of stimulation is achievable, and that optical enhancements to the stimulator may offer more significant precision improvements than genetic modifications targeting the soma.

neuroscience↗

bioRxiv2023

DNA damage-induced interaction between a lineage addiction oncogenic transcription factor and the MRN complex shapes a tissue-specific DNA Damage Response and cancer predisposition

Since genome instability can drive cancer initiation and progression, cells have evolved highly effective and ubiquitous DNA Damage Response (DDR) programs. However, some cells, in skin for example, are normally exposed to high levels of DNA damaging agents. Whether such high-risk cells possess lineage-specific mechanisms that tailor DNA repair to the tissue remains largely unknown. Here we show, using melanoma as a model, that the microphthalmia-associated transcription factor MITF, a lineage addition oncogene that coordinates many aspects of melanocyte and melanoma biology, plays a non-transcriptional role in shaping the DDR. On exposure to DNA damaging agents, MITF is phosphorylated by ATM/DNA-PKcs, and unexpectedly its interactome is dramatically remodelled; most transcription (co)factors dissociate, and instead MITF interacts with the MRE11-RAD50-NBS1 (MRN) complex. Consequently, cells with high MITF levels accumulate stalled replication forks, and display defects in homologous recombination-mediated repair associated with impaired MRN recruitment to DNA damage. In agreement, high MITF levels are associated with increased SNV burden in melanoma. Significantly, the SUMOylation-defective MITF-E318K melanoma predisposition mutation recapitulates the effects of ATM/DNA-PKcs-phosphorylated MITF. Our data suggest that a non-transcriptional function of a lineage-restricted transcription factor contributes to a tissue-specialised modulation of the DDR that can impact cancer initiation.

molecular biology↗

bioRxiv2022

Inducible non-human primate models of retinal degeneration for testing end stage therapies and understanding disease mechanisms

The anatomical differences between the retinas of humans and most animal models pose a challenge for testing novel therapies. Non-human primate (NHP) retina is anatomically closest to the human retina with the presence of a high acuity region called the fovea. However, there is a lack of relevant NHP models for retinal degeneration that can be used for preclinical studies of vision restoration. To address this unmet need we aimed to generate inducible NHP models of photoreceptor degeneration. We generated three cynomolgus macaque models using distinct strategies. We used two genetically targeted strategies using optogenetics and Crispr-Cas9 to ablate specifically rods to mimic rod-cone dystrophy. Additionally, we created an acute model by physical separation of the photoreceptors and retinal pigment epithelium using a polymer patch. Retinal degeneration was evaluated in all three models by in-life exams such as fundus imaging, optical coherence tomography, adaptive optics and electroretinography. In the genetic models we observed punctuate areas of degeneration in the injected area marked by disorganization of outer segments, loss of rod photoreceptors and thinning of the outer nuclear layer. In the acute model, the degeneration was faster and involved both rods and cones. Among the three distinct NHP models, the Crispr-Cas9 based approach was the most advantageous model in view of recapitulating disease specific features and its ease of implementation. The acute model however resulted in the fastest degeneration making it the most relevant model for testing end-stage vision restoration therapies such as stem cell transplantation.

bioengineering↗

bioRxiv2022

Covariations of cerebral blood volume and single neurons discharge during resting state and behavioral visual cognitive tasks in non-human primates

To better understand how the brain allows primates to perform various set of tasks, the ability to simultaneously record the activity of the brain at multiple temporal and spatial scales is challenging but necessary. In non-human primates, combined fMRI and electrophysiological recordings have not disentangle the contributions of spiking activity to the neurovascular response. Here, we combined functional ultrasound imaging (fUS) of cerebral blood volume (CBV) and recording of single-unit activities (SUA) in visual and fronto-medial cortices of behaving macaques. We computed task-induced and SUA-induced CBV activation maps. We demonstrate that SUA provides a significant estimate of the neurovascular response below the typical fMRI voxel spatial resolution of 2mm3. Furthermore, our results also show that single unit and CBV activities are statistically uncorrelated during the resting states but correlate during behaving tasks. Conversely, during the resting states, CBV activities across known connected brain areas are correlated but decorrelate at the onset of the tasks as expected if participating in the default mode network (DMN). These results have important implications for interpreting functional imaging findings collected with fMRI or fUS while one constructs inferences of spiking activities during resting-state or while primates perform tasks.

neuroscience↗

bioRxiv2022

Failed remyelination of the non-human primate optic nerve leads to axon degeneration, retinal damages and visual dysfunction.

White matter disorders of the CNS such as MS, lead to failure of nerve conduction and long-lasting neurological disabilities affecting a variety of sensory and motor systems including vision. While most disease-modifying therapies target the immune and inflammatory response, the promotion of remyelination has become a new therapeutic avenue, to prevent neuronal degeneration and promote recovery. Most of these strategies are developed in short-lived rodent models of demyelination, which spontaneously repair and do not reflect the size, organization, and biology of the human CNS. Thus, well-defined non-human primate models are required to efficiently advance therapeutic approaches for patients. Here, we followed the consequence of long-term toxin-induced demyelination of the macaque optic nerve on remyelination and axon preservation, as well as its impact on visual functions. Findings from oculo-motor behavior, ophthalmic examination, electrophysiology, and retinal imaging indicate visual impairment involving the optic nerve and retina. These visual dysfunctions fully correlated at the anatomical level, with sustained optic nerve demyelination, axonal degeneration, and alterations of the inner retinal layers. This non-human primate model of chronic optic nerve demyelination associated with axonal degeneration and visual dysfunction, recapitulates several key features of MS lesions and should be instrumental in providing the missing link to translate emerging repair pro-myelinating/neuroprotective therapies to the clinic for myelin disorders such as MS. Significance StatementPromotion of remyelination has become a new therapeutic avenue, to prevent neuronal degeneration and promote recovery in white matter diseases such as MS. To date most of these strategies are developed in short-lived rodent models of demyelination, which spontaneously repair. Well-defined non-human primate models closer to man would allow to efficiently advance therapeutic approaches. Here we present a non-human primate model of optic nerve demyelination that recapitulates several features of MS lesions. The model leads to failed remyelination, associated with progressive axonal degeneration and visual dysfunction, thus providing the missing link to translate emerging pre-clinical therapies to the clinic for myelin disorders such as MS.

neuroscience↗

bioRxiv2021

Sonogenetic stimulation of the brain at a spatiotemporal resolution suitable for vision restoration

Remote, precisely controlled activation of the brain is a fundamental challenge in the development of brain-machine interfaces providing feasible rehabilitation strategies for neurological disorders. Low-frequency ultrasound stimulation can be used to modulate neuronal activity deep in the brain1-7, but this approach lacks spatial resolution and cellular selectivity and loads the brain with high levels of acoustic energy. The combination of the expression of ultrasound-sensitive proteins with ultrasound stimulation ( sonogenetic stimulation) can provide cellular selectivity and higher sensitivity, but such strategies have been subject to severe limitations in terms of spatiotemporal resolution in vivo8-10, precluding their use for real-life applications. We used the expression of large-conductance mechanosensitive ion channels (MscL) with high-frequency ultrasonic stimulation for a duration of milliseconds to activate neurons selectively at a relatively high spatiotemporal resolution in the rat retina ex vivo and the primary visual cortex of rodents in vivo. This spatiotemporal resolution was achieved at low energy levels associated with negligible tissue heating and far below those leading to complications in ultrasound neuromodulation6,11. We showed, in an associative learning test, that sonogenetic stimulation of the visual cortex generated light perception. Our findings demonstrate that sonogenetic stimulation is compatible with millisecond pattern presentation for visual restoration at the cortical level. They represent a step towards the precise transfer of information over large distances to the cortical and subcortical regions of the brain via an approach less invasive than that associated with current brain-machine interfaces and with a wide range of applications in neurological disorders.

neuroscience↗

bioRxiv2021

In vivo optogenetic stimulation of the primate retina activates the visual cortex after long-term transfection

Over the last 15 years, optogenetics has changed fundamental research in neuroscience, and is now reaching toward therapeutic applications. Vision restoration strategies using optogenetics are now at the forefront of these new clinical opportunities. But applications to human patients suffering from retinal diseases leading to blindness rise important concerns on the long-term functional expression of optogenes and the efficient signal transmission to higher visual centers. Here we demonstrate in non-human primates, continued expression and functionality at the retina level [~]20 months after delivery of our construct. We also performed in-vivo recordings of visually evoked potentials in the primary visual cortex of anaesthetized animals. Using synaptic blockers, we isolated the in-vivo cortical activation resulting from the direct optogenetic stimulation of primate retina. In conclusion, our work indicates long-term transgene expression and transmission of the signal generated in the macaque retina to the visual cortex, two important features for future clinical applications.

neuroscience↗

bioRxiv2021

Functional ultrasound imaging of the spreading activity following optogenetic stimulation of the rat visual cortex

Optogenetic stimulation of the primary visual cortex (V1) is a promising therapy for sight restoration, but it remains unclear what total cerebral volume is activated after surface stimulation. In this study, we expressed the red-shifted opsin ChrimsonR in excitatory neurons within V1 in rats, and used the fine spatial resolution provided by functional ultrasound imaging (fUS) over the whole depth of the brain to investigate the brain response to focal surface stimulation. We observed optogenetic activation of a high proportion of the volume of V1. Extracellular recordings confirmed the neuronal origin of this activation. Moreover, neuronal responses were even located in deep layers under conditions of low irradiance, spreading to the LGN and V2, consistent with a normal visual information process. This study paves the way for the use of optogenetics for cortical therapies, and highlights the value of coupling fUS with optogenetics.

neuroscience↗

bioRxiv2020

Optogenetic therapy: High spatiotemporal resolution and pattern recognition compatible with vision restoration in non-human primates

Restoring vision using optogenetics is an ideal medical application because the eye offers a direct window to access and stimulate the pathological area: the retina. Optogenetic therapy could be applied to diseases with photoreceptor degeneration such as retinitis pigmentosa. Here, we select the specific optogenetic construct that is now used in the clinical trial and assess the opsin functional efficacy on non-human primates retinal ganglion cells (RGCs). We chose the microbial opsin ChrimsonR and showed that the vector AAV2.7m8 produced greater transfection in RGCs compared to AAV2, and that ChrimsonR attached to tdTomato (ChR-tdT) is more efficiently expressed than ChrimsonR. The 600 nm light activates the RGCs transfected with the vector AAV2.7m8-ChR-tdT from an irradiance of 1015 photons.cm-2.s-1. Vector doses of 5.1010 and 5.1011 vg/eye transfect up to 7000 RGCs/mm2 in the perifovea, with no significant immune reaction. Furthermore, using a multielectrode array we recorded RGCs responses starting from 1ms stimulus duration. Using the recorded activity we were able to decode stimulus information and estimate a theoretical visual acuity of 20/249, above legal blindness. Altogether, our results pave the way for the ongoing clinical trial with the AAV2.7m8-ChrimsonR-tdT vector for vision restoration in patients affected by retinitis pigmentosa. One Sentence SummaryWe select here the vector and genetic construct best suited to provide vision restoration in patients suffering from retinopathies, we demonstrate temporal resolution compatible with high dynamic visual scenes and a visual acuity above legal blindness.

neuroscience↗