Restoration of Vision with Ectopic Expression of Human Rod Opsin

Current Biology, Journal Year: 2015, Volume and Issue: 25(16), P. 2111 - 2122

Published: July 30, 2015

Highlights•Ectopic human rod opsin restores visual functions in advanced retinal degeneration•Rod has greater sensitivity than current optogenetic strategies•Rod opsin-treated animals respond to spatial stimuli, flicker, and natural scenes•As a protein ordinarily found tissue, barriers clinic are minimizedSummaryMany dystrophies result photoreceptor loss, but the inner neurons can survive, making them potentially amenable emerging therapies. Here, we show that ectopically expressed opsin, driven by either non-selective or ON-bipolar cell-specific promoter, function outside native photoreceptors restore mouse model of degeneration. Electrophysiological recordings from explants thalamus revealed changes firing (increases decreases) induced simple light pulses, luminance increases, naturalistic movies treated mice. These responses could be elicited at intensities within physiological range substantially below those required other strategies. Mice with expression specific promoter displayed behavioral increases luminance, coarse patterns, elements movie levels contrast illuminance (≈50–100 lux) typical indoor environments. data reveal virally mediated ectopic vision under viewing conditions moderate intensities. Given inherent advantages employing protein, simplicity this intervention, quality restored, suggest merits consideration as an actuator for treating patients

Language: Английский

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Photoresponse diversity among the five types of intrinsically photosensitive retinal ganglion cells

The Journal of Physiology, Journal Year: 2014, Volume and Issue: 592(7), P. 1619 - 1636

Published: Jan. 7, 2014

Intrinsically photosensitive retinal ganglion cells (ipRGCs) mediate non-image-forming visual responses, including pupillary constriction, circadian photoentrainment and suppression of pineal melatonin secretion. Five morphological types ipRGCs, M1-M5, have been identified in mice. In order to understand their functions better, we studied the photoresponses all five cell types, by whole-cell recording from fluorescently labelled ipRGCs visualized using multiphoton microscopy. All ipRGC generated melanopsin-based ('intrinsic') as well synaptically driven ('extrinsic') light responses. The intrinsic M1 were lower threshold, higher amplitude faster than those M2-M5. peak amplitudes extrinsic responses differed among types; however, had comparable thresholds, kinetics waveforms, received rod input. While exhibited inhibitory amacrine-cell excitatory bipolar-cell inputs 'on' channel, M3 additional 'off'-channel inhibition, possibly through 'off'-sublamina dendrites. M2-M5 centre-surround-organized receptive fields, implicating a capacity detect spatial contrast. contrast, fields lacked surround antagonism, which might be caused input nullifying responded robustly wide range motion speeds, M1-M4 appeared tuned different suggesting that they analyse speed motion. Retrograde labelling revealed project superior colliculus, contrast information signalled these could used this sensorimotor area novel objects field.

Language: Английский

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Diverse Cell Types, Circuits, and Mechanisms for Color Vision in the Vertebrate Retina

Physiological Reviews, Journal Year: 2019, Volume and Issue: 99(3), P. 1527 - 1573

Published: May 29, 2019

Synaptic interactions to extract information about wavelength, and thus color, begin in the vertebrate retina with three classes of light-sensitive cells: rod photoreceptors at low light levels, multiple types cone that vary spectral sensitivity, intrinsically photosensitive ganglion cells contain photopigment melanopsin. When isolated from its neighbors, a photoreceptor confounds photon flux wavelength so by itself provides no color. The has evolved elaborate color opponent circuitry for extracting comparing activities different broadly tuned parts visible spectrum. We review studies concerning circuit mechanisms mediating range species, tetrachromatic fish diverse cell common dichromatic mammals where opponency is restricted subset specialized circuits. Distinct among mammals, primates have reinvented trichromatic vision using novel strategies incorporate evolution an additional gene into foveal structure supports high-resolution vision. Color absent scotopic levels when only rods are active, but interact signals influence perception mesopic levels. Recent evidence suggests melanopsin-mediated signals, which been identified as substrate setting circadian rhythms, may also perception. consider circuits mediate these interactions. While relatively simple neural computation, it implemented vertebrates not yet fully understood.

Language: Английский

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Diversity of intrinsically photosensitive retinal ganglion cells: circuits and functions

Cellular and Molecular Life Sciences, Journal Year: 2020, Volume and Issue: 78(3), P. 889 - 907

Published: Sept. 23, 2020

Language: Английский

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Optogenetic Vision Restoration Using Rhodopsin for Enhanced Sensitivity

Molecular Therapy, Journal Year: 2015, Volume and Issue: 23(10), P. 1562 - 1571

Published: July 3, 2015

Retinal disease is one of the most active areas gene therapy, with clinical trials ongoing in United States for five diseases. There are currently no treatments patients late-stage which photoreceptors have been lost. Optogenetic therapies development, but, to date, suffered from low light sensitivity microbial opsins, such as channelrhodopsin and halorhodopsin, azobenzene-based photoswitches. Several groups shown that photoreceptive G-protein-coupled receptors (GPCRs) can be expressed heterologously, photoactivate endogenous Gi/o signaling. We hypothesized a GPCR could increase due signal amplification. targeted vertebrate rhodopsin retinal ON-bipolar cells blind rd1 mice observed restoration of: (i) responses explants, (ii) visually-evoked potentials visual cortex vivo, (iii) two forms visually-guided behavior: innate avoidance discrimination temporal patterns context fear conditioning. Importantly, both explants behavior occurred reliably at levels were three orders magnitude dimmer than required channelrhodopsin. Thus, therapy native light-gated GPCRs presents novel approach impart useful range illumination.

Language: Английский

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Mammalian Inner Retinal Photoreception

Current Biology, Journal Year: 2013, Volume and Issue: 23(3), P. R125 - R133

Published: Feb. 1, 2013

Language: Английский

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Circadian Photoentrainment in Mice and Humans

Biology, Journal Year: 2020, Volume and Issue: 9(7), P. 180 - 180

Published: July 21, 2020

Light around twilight provides the primary entrainment signal for circadian rhythms. Here we review mechanisms and responses of mouse human systems to light. Both utilize a network photosensitive retinal ganglion cells (pRGCs) expressing photopigment melanopsin (OPN4). In both species action spectra functional expression OPN4 in vitro show that has λmax close 480 nm. Anatomical findings demonstrate there are multiple pRGC sub-types, with some evidence mice, but little humans, regarding their roles regulating physiology behavior. Studies non-human primates rods cones project can modulate light pRGCs. Such an integration signals enables detect dim light, higher intensities intermittent exposure, whilst measures bright over extended periods time. Although photoreceptor similar, sensitivity thresholds differ markedly between mice humans. Mice entrain at approximately 1 lux few minutes, humans require high irradiance (>100's lux) long duration (>30 min). The basis this difference remains unclear. As our exposure is highly dynamic, because interactions complex difficult model, attempts develop evidence-based lighting enhance very challenging. A way forward will be define artificial natural "real world" where intensity, duration, spectral quality, time day, history age each assessed.

Language: Английский

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Functional diversity of human intrinsically photosensitive retinal ganglion cells

Science, Journal Year: 2019, Volume and Issue: 366(6470), P. 1251 - 1255

Published: Dec. 6, 2019

Sensing light without forming images In the rodent retina, intrinsically photosensitive retinal ganglion cells (ipRGCs) entrain circadian rhythms, modulate mood, and signal pupillary accommodation. Such responses are light-driven but not image-based. Working with donated human organ tissues, Mure et al. used electrophysiological approaches to identify ipRGCs in retina. The retina has more cones than retinas of nocturnal mice rats. Differences sensitivity, latency, duration identified three subtypes ipRGCs. Science , this issue p. 1251

Language: Английский

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Neuroimaging, cognition, light and circadian rhythms

Frontiers in Systems Neuroscience, Journal Year: 2014, Volume and Issue: 8

Published: July 8, 2014

In humans, sleep and wakefulness the associated cognitive processes are regulated through interactions between homeostasis circadian system. Chronic disruption of rhythmicity is common in our society there a need for better understanding brain mechanisms regulating sleep, processes. This review summarizes recent investigations which provide first neural correlates combined influence on activity. Markers interindividual variations sleep-wake regulation, such as chronotype polymorphisms clock genes, with changes responses subcortical cortical areas response to manipulations cycle. also includes data showing that activity by light, powerful modulator cognition alertness directly impacts rhythmicity. The effect light varied age, psychiatric status, PERIOD3 genotype phase. These new insights into contribution demographic characteristics, cycle, functioning.

Language: Английский

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Blue Light Stimulates Cognitive Brain Activity in Visually Blind Individuals

Journal of Cognitive Neuroscience, Journal Year: 2013, Volume and Issue: 25(12), P. 2072 - 2085

Published: July 16, 2013

Abstract Light regulates multiple non-image-forming (or nonvisual) circadian, neuroendocrine, and neurobehavioral functions, via outputs from intrinsically photosensitive retinal ganglion cells (ipRGCs). Exposure to light directly enhances alertness performance, so is an important regulator of wakefulness cognition. The roles rods, cones, ipRGCs in the impact on cognitive brain functions remain unclear, however. A small percentage blind individuals retain photoreception offer a unique opportunity investigate impacts absence conscious vision, presumably through ipRGCs. Here, we show that three such patients were able choose nonrandomly about presence despite their complete lack sight. Furthermore, 2 sec blue modified EEG activity when administered simultaneously auditory stimulations. fMRI further showed that, during working memory task, less than minute triggered recruitment supplemental prefrontal thalamic regions involved cognition regulation as well key areas default mode network. These results, which have be considered proof concept, triggers some awareness for can more rapid human previously understood, if processing actively engaged. stimulates higher activity, independently engages perform ongoing process. To our knowledge, results constitute first indication ipRGC signaling may rapidly affect fundamental cerebral organization, it could potentially participate numerous aspects function.

Language: Английский

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