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Deaf adult animals can hear again with optogenetic hearing restoration

Researchers from the Institute for Auditory Neuroscience of the University Medical Center Göttingen have established the transduction of the auditory nerve of adult animals with light-sensitive switches. This allows deaf animals to hear again with light and promises major breakthroughs in restoring hearing in deaf patients. Released in “Science Translational Medicine” on July 11, 2018.
Enlarged, 3D-printed model of the mouse cochlea, based on X-ray tomography data. Photo: Daniel Keppeler
Comparison of cochlear implant function. Above: electrical implant in the cochlea. Bottom: future optical implant. Illustration: Institute of Auditory Neurosciences, UMG
Comparison of cochlear implant function. Above: electrical implant in the cochlea with 12 electrode contacts, from which the current spreads widely. Bottom: future optical implant with dozens of microluminescent diodes whose light is focused on nerve cells in the cochlea. Illustration: Institute of Auditory Neurosciences, UMG
Dr. Marcus Jeschke, Head of the Junior Research Group Cognitive Hearing in Primates at the DPZ. Photo: Karin Tilch
Dr. Marcus Jeschke, Head of the Junior Research Group Cognitive Hearing in Primates at the DPZ. Photo: Karin Tilch
Dr. Christian Wrobel, Clinic for Otolaryngology, University Medicine Göttingen. Photo: private
Dr. Christian Wrobel, Clinic for Otolaryngology, University Medicine Göttingen. Photo: private
Prof. Tobias Moser, Head of the Institute of Auditory Neuroscience at the University Medicine Göttingen and the Research Group Auditory Neuroscience and Optogenetics at the DPZ. Photo: Irene Böttcher-Gajewski
Prof. Tobias Moser, Head of the Institute of Auditory Neuroscience at the University Medicine Göttingen and the Research Group Auditory Neuroscience and Optogenetics at the DPZ. Photo: Irene Böttcher-Gajewski
Two gerbils (Meriones unguiculatus). Photo: Baldur123 [GFDL (http://www.gnu.org/copyleft/fdl.html) or CC-BY-SA-3.0 (http://creativecommons.org/licenses/by-sa/3.0/)], Wikimedia Commons
Two gerbils (Meriones unguiculatus). Photo: Baldur123 [GFDL (http://www.gnu.org/copyleft/fdl.html) or CC-BY-SA-3.0 (http://creativecommons.org/licenses/by-sa/3.0/)], Wikimedia Commons

Most of us will face it during our lifetime: we will hear less and less well with age. Hearing disabilities affect an enormous number of people worldwide. Most commonly the hearing disabilities are linked to the loss of tiny hair cells in our ears. Here, just a relatively small number of hair cells in our hearing organ - the cochlea - work tirelessly to translate the sounds we hear into electrical signals that our brain can understand. However, our environment is tough on our hair cells: kids scream into our ears, the streets are loud and we often listen to music through headphones louder than we should. All these factors can lead to loss of hearing. Unfortunately, unlike many other cells in our body which constantly reproduce themselves, once a hair cell is lost it cannot be replaced.

In cases of loss of a large number of hair cells, i.e. severe hearing disabilities, electrical cochlea implants can be used to bypass the lost hair cells and directly stimulate the auditory nerve. These cochlea implants present an enormous success story and are by far the most effective neuroprostheses. It is remarkable that the majority of the around 500,000 cochlea implant users can understand speech again in quiet environments. However, patients have trouble understanding speech in noise and typically do not appreciate music. These drawbacks are linked to a fundamental problem of electric stimulation namely large current spread around each stimulation channel. Instead of allowing us to understand small differences in tones - much smaller than a step on a piano - electrical cochlea implants can only provide up to around ten distinguishable “frequency channels”. Playing beautiful musical pieces by Mozart is hard with only ten piano keys. Here, optical stimulation promises to be a game changer for hearing restoration as light can be focused much better than electric current. However, the auditory nerve is not light sensitive. Thus, in order to achieve optical stimulation, functional, genetically encoded light switches have to be brought into the neurons of the auditory nerve. This approach is termed optogenetic control. Until now this has only been achieved in animals which were manipulated before or shortly after birth.

A team of researchers from Institute for Auditory Neuroscience of the University Medical Center Göttingen led by Tobias Moser have now made a major step forward towards eventual clinical translation in humans. In a tour de force study the authors have developed new techniques to manipulate the auditory nerve of adult rodents via the injection of optogenetic light switches packed into harmless viral vectors. They performed recordings from stations along the auditory system up to the auditory cortex - where we make sense of the sounds that reach our ears – and could show that stimulation with light successfully activates individual neurons. This presents a fundamental necessity for optogenetic hearing restoration which has now been demonstrated for the first time. But the authors did not stop there. In addition, they went on to test whether the manipulations are also successful in deaf animals where all hair cells have been lost. Here, it was possible to show that animals with optogenetically manipulated auditory nerves could indeed use the light stimulation for solving behavioral tasks. Towards this goal the authors implanted deaf animals with a simple optical cochlea implant and asked whether optogenetically manipulated animals could learn to react to light stimulation in the cochlea. Indeed, animals stimulated with light reacted to light pulses as short as tens of microseconds and as low as a few milliwatts, indicating that optical cochlea implants might not need much more energy than electrical cochlea implants. Taken together, these results provide for the first time evidence that deaf animals can hear again with optogenetic hearing restoration. This provides exciting news for many patients worldwide looking for better treatment options for hearing disabilities.

"It was unclear whether the optogenetic manipulation of the auditory nerve would be successful in adult animals," says Marcus Jeschke, a group leader at the Institute for Auditory Neuroscience and one of the senior authors: “Now, we need to understand in detail how the optogenetic stimulation activates the brain in comparison to normal hearing. When we understand the similarities and differences we can start to devise strategies to make hearing with artificial stimulation similar to normal hearing. In turn, this will allow patients a much more natural auditory impression.” First author Christian Wrobel, an otolaryngology resident doing his clinician-scientist training on this project, adds: “Establishing gene therapy and optogenetics in a mature cochlea is far from trivial. I am very excited about the progress we could make towards developing the optical cochlear implant.” Alexander Dieter, second lead author, a student of the Göttingen Neuroscience PhD program and fellow of the German Academic Scholarship Foundation, continues: “One of the key points we focused on is to show that this technology not only triggers physiological responses in the brain, but that the animals can make sense of this information and use it to solve behavioral tasks”.

As often in scientific endeavors the work does not stop here. Tobias Moser, principal investigator of the OptoHear Project funded by the European Research Council for developing the optical cochlear implant, a neuroscientist and otolaryngologist, explains: “Many things remain to be done before we can even start to think about clinical trials with patients. Of course, single channel stimulation as used in our study is not sufficient. Together with our collaborators we work hard on developing many channel stimulation solutions and to test them in our animal models. However, the current study adds further proof of principle and makes us more confident that the approach can be translated into the clinic.”

Original publication

Wrobel C, Dieter A, Huet A, Keppeler D, Duque-Afonso CJ, Vogl C, Hoch G, Jeschke M, Moser T (2018): Optogenetic stimulation of cochlear neurons activates the auditory pathway and restores auditory-driven behavior in deaf adult gerbils. Science Translational Medicine 10(449), DOI: 10.1126/scitranslmed.aao0540