Presseinformation Nr. 052 vom 02. Mai 2018

Fast channelrhodopsins for optogenetic hearing restoration

Future optical cochlear implants might help deaf people to better understand speech and appreciate music. A team of scientists from Frankfurt and Göttingen established ultrafast red-shifted channelrhodopsins that serve neural stimulation at high rates.

Different from the current (top), the optical cochlear implant (bottom) shall use light pulses emitted from small light sources to activate the neurons of the cochlea. GRAFIK: Institute for Auditory Neu-roscience, University Medical Center Göttingen

Prof. Dr. Tobias Moser, Director Institute for Auditory Neuroscience, University Medical Center Göttingen, German Primate Center, Max Planck Institute for Experimental Medicine. Foto: umg

David Lopez de la Morena, first author and student of the MSc/ PhD Program and Internationale Max-Planck-Research School Molecular Biology at the Institute for Auditory Neuroscience, UMG and German Primate Center. Foto: privat

(mpi/umg) When hearing fails, Cochlear Implants (CIs) can partially restore hearing, enabling speech understanding in most of the otherwise deaf users. CIs directly stimulate the auditory nerve in the cochlea of the inner ear, bypassing the dysfunctional or lacking sensory hair cells. The poor frequency resolution of sound coding, which results from the massive spread of the electric shock from each stimulation electrode, is the bottleneck of current CIs. This leads to poor speech recognition in background noise and typically limits music appreciation. Optical stimulation promises better spatial control of the stimulus as light can be confined more conveniently. This, however, requires optogenetic manipulation of the otherwise light-insensitive auditory nerve.

Different from the current cochlear implant (top), the optical cochlear implant (bottom) shall use light pulses emitted from small light sources to activate the neurons of the cochlea. This requires the optogenetic manipulation of the neurons, e.g. to express the fast red-shifted light-gated ion channel Chrimson. GRAFIK: Institute for Auditory Neuroscience, University Medical Center Göttingen

A team of scientists from the Frankfurt Max Planck Institutes for Biophysics and Brain Research and the Göttingen Campus (Institute for Auditory Neuroscience of the University Medical Center Göttingen, the German Primate Center Göttingen, and the Max Planck Institute for Experimental Medicine) have established ultrafast switching channelrhodopsins and applied them to optically stimulate rapidly spiking neurons of the brain and the ear to near their physiological limits. Some of these novel channelrhodopsin variants can be driven by long wavelength light, which avoids potential phototoxicity. The application of these channelrhodopsins marks an important breakthrough on the way towards developing the optical CI that might improve hearing restoration in the deaf.

Talking on the street, enjoying music at the concert hall – normal to many of us are typically not accessible for people with profound hearing impairment. In most cases this results from dysfunction or loss of sensory hair cells in the cochlea. In this snail-like hearing organ, sound-borne vibrations are transduced by the mechanically sensitive hair cells which communicate information on the sound to the spiral ganglion neurons that form the auditory nerve to the brain. Strongly simplified - you can think of the cochlea as a long, curled keyboard with each hair cell and connected neurons corresponding to one frequency. Current CIs use 12-24 electrodes to drive the neurons. Due to the spread of the electrical signal from each electrode contact each stimulus activates many neurons representing several neighbouring frequencies. This leads to poor frequency resolution of coding by CI which limits the hearing performance. Hearing could be improved by better spatial confinement the stimulus. This is where optical stimulation comes into play – “hearing with light” might overcome this bottleneck.

Optogenetics, a recently developed approach, enables control of cells with high specificity and spatial resolution. The optogenetic toolkit is ever expanding and provides solutions for a broad range of manipulations if expressed in the target cell. In a proof of principle study, Dr. Tobias Moser (Institute for Auditory Neuroscience of the University Medical Center Göttingen), Dr. Ernst Bamberg (Max Planck Institutes for Biophysics, Frankfurt) and their colleagues had found that the then tested channelrhodopsins were to slow for stimulating cochlear neurons at the required pace. This presented a major roadblock on the way towards developing the optical CI.

Therefore, Ernst Bamberg and his colleagues at Frankfurt set-out to develop channelrhodopsins with faster gating properties. Building on structural insight they performed site-directed mutagenesis and established a set of fast channelrhodopsins covering the whole spectrum of visible light, including those with red-shifted activation. Such ultrafast and red-shifted channelrhodopsins enable the control of fast spiking neurons of the brain and the ear with high temporal fidelity and without the phototoxic risk of blue optogenetics e.g. by the ultrafast blue channelrhodopsin Chronos discovered by Dr. Edwin Boyden from the MIT. Edwin Boyden had also identified the red-shifted channelrhodopsin Chrimson that Ernst Bamberg and colleagues now “sped up” to the kinetic performance of Chronos. “The excellent membrane expression of the fast Chrimson variants, their red activation range and their ultrafast gating make them excellent tools for eliciting activity of excitable cells at high rates”, Ernst Bamberg says. The group of Dr. Johannes Letzkus from the Max Planck Institute for Brain Research employed the “very fast” Chrimson in brain slices to drive firing in a type of cortical interneuron that is among the fastest cells in the brain to their physiological frequency limit. „Our experiments show that the new Chrimson variants drive fast spiking CNS neurons up to 400 Hz, covering their entire dynamic range and by far exceeding previous approaches“, Johannes Letzkus says.

Tobias Moser and his colleagues tested the potential of fast Chrimson for temporally precise stimulation of the spiral ganglion neurons of mice in vivo. Injecting adeno-associated virus into the postnatal cochlea they established viral transfer of fast Chrimson into the spiral ganglion neurons, which efficiently and long lastingly (for at least a ¾ year) expressed the channelrhodopsin. Implanting a 50 Micrometer optical fiber into the cochlea as akin of a single channel optical CI they studied optogenetic responses at the single neuron and neural population level. Light pulses as short as 50 Microseconds and as week as 0.5 Microwatt were sufficient to drive neural responses in normal hearing mice and mice with age-related hearing loss. Some neurons followed optical stimulation up to several hundred Hz with good temporal precision. “The fast Chrimson variants are promising candidates for optogenetic hearing restoration” Moser says, “Much remains to be done prior to clinical translation of the method, but if successful, we expect that the enhanced coding of spectral information will yield a major improvement in speech recognition”. Moser leads a program on the development of the optical CI on the Göttingen Campus which is funded by the European Research Council (Advanced Grant “OptoHear”), the German Research Foundation and the German Federal Ministry for Science and Education and also involves scientists from Chemnitz and Freiburg.

This structure-guided engineering of channelrhodopsin variants with faster temporal response has great potential for fueling progress in the studies of neural circuit function and in the future restoration of neural function. The authors consider the restoration of hearing and vision prime candidates for clinical applications of optogenetics.

Original publication:
High frequency neural spiking and auditory signaling by ultrafast red-shifted optogenetics. Thomas Mager, David Lopez de la Morena, Verena Senn, Johannes Schlotte, Anna D´Errico, Katrin Feldbauer, Christian Wrobel, Sangyong Jung, Kai Bodensiek, Vladan Rankovic, Lorcan Browne, Antoine Huet, Josephine Jüttner, Phillip G. Wood, Johannes J. Letzkus, Tobias Moser & Ernst Bamberg
Nature Communications; 1. Mai 2018 (DOI: 10.1038/s41467-018-04146-3)


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