Biology subjects

Sahel, J.-A.

Publications and source records attributed to Sahel, J.-A..

21 records · Page 2Linked to original sources

bioRxiv2018

Optogenetic vision restoration with high resolution

The majority of inherited retinal degenerations are due to photoreceptor cell death. In many cases ganglion cells are spared making it possible to stimulate them to restore visual function. Several studies (Bi et al., 2006; Lin et al., 2008; Sengupta et al., 2016; Caporale et al., 2011; Berry et al., 2017) have shown that it is possible to express an optogenetic protein in ganglion cells and make them light sensitive. This is a promising strategy to restore vision since optical targeting may be more precise than electrical stimulation with a retinal prothesis. However the spatial resolution of optogenetically-reactivated retinas has not been measured with fine-grained stimulation patterns. Since the optogenetic protein is also expressed in axons, it is unclear if these neurons will only be sensitive to the stimulation of a small region covering their somas and dendrites, or if they will also respond to any stimulation overlapping with their axon, dramatically impairing spatial resolution. Here we recorded responses of mouse and macaque retinas to random checkerboard patterns following an in vivo optogenetic therapy. We show that optoge-netically activated ganglion cells are each sensitive to a small region of visual space. A simple model based on this small receptive field predicted accurately their responses to complex stimuli. From this model, we simulated how the entire population of light sensitive ganglion cells would respond to letters of different sizes. We then estimated the maximal acuity expected by a patient, assuming it could make an optimal use of the information delivered by this reactivated retina. The obtained acuity is above the limit of legal blindness. This high spatial resolution is a promising result for future clinical studies.

neuroscience↗

bioRxiv2018

Ultrasound functional neuroimaging reveals propagation of task-related brain activity in behaving primates

In recent decades, neuroimaging has played an invaluable role in improving the fundamental understanding of the brain. At the macro scale, neuroimaging modalities such as MRI, EEG, and MEG, exploit a wide field of view to explore the brain as a global network of interacting regions. However, this comes at the price of either limited spatiotemporal resolution or limited sensitivity. At the micro scale, electrophysiology is used to explore the dynamic aspects of neuronal activity with a very high temporal resolution. However, this modality requires a statistical averaging of several tens of single task responses. A large-scale neuroimaging modality of sufficient spatial and temporal resolution and sensitivity to study brain region activation dynamically would open new territories of possibility in neuroscience\n\nWe show that neurofunctional ultrasound imaging (fUS) is both able to assess brain activation during single cognitive tasks within superficial and deeper areas of the frontal cortex areas, and image the directional propagation of information within and between these regions. Equipped with an fUS device, two macaque rhesus monkeys were instructed before a stimulus appeared to rest (fixation) or to look towards (saccade) or away (antisaccade) from a stimulus. Our results identified an abrupt transient change in activity for all acquisitions in the supplementary eye field (SEF) when the animals were required to change a rule regarding the task cued by a stimulus. Simultaneous imaging in the anterior cingulate cortex and SEF revealed a time delay in the directional functional connectivity of 0.27 {+/-} 0.07 s and 0.9 {+/-} 0.2 s for animals S and Y, respectively. These results provide initial evidence that recording cerebral hemodynamics over large brain areas at a high spatiotemporal resolution and sensitivity with neurofunctional ultrasound can reveal instantaneous monitoring of endogenous brain signals and behavior.

animal behavior and cognition↗

bioRxiv2018

Restoration of visual function by transplantation of optogenetically engineered photoreceptors

A major challenge in the treatment of retinal degenerative diseases, with the transplantation of replacement photoreceptors, is the difficulty in inducing the grafted cells to grow and maintain light sensitive outer segments (OS) in the host retina, which depends on proper interaction with the underlying retinal pigment epithelium (RPE). For a RPE-independent treatment approach, we introduced a hyperpolarizing microbial opsin into photoreceptor precursors from new-born mice, and transplanted them into blind mice lacking the photoreceptor layer. These optogenetically transformed photoreceptors were light responsive and their transplantation lead to the recovery of visual function, as shown by ganglion cell recordings and behavioral tests. Subsequently, we generated cone photoreceptors from human induced pluripotent stem cells (hiPSCs), expressing the chloride pump Jaws. After transplantation into blind mice, we observed light-driven responses at the photoreceptor and ganglion cell level. These results demonstrate that structural and functional retinal repair is possible by combining stem cell therapy and optogenetics.

bioengineering↗