Auditory Neuroscience

Auditory Neuroscience

Group Leaders: Tobias Moser, Carolin Wichmann, Tina Pangršic Vilfan, Christian Vogl, Nicola Strenzke

Our groups are interested in the molecular physiology, pathophysiology and restoration of hearing and balance. Using a range of electrophysiological, imaging, and systems-physiological approaches, we aim to elucidate the specialized molecular and cellular mechanisms that enable indefatigable synaptic encoding and transmission of sensory information with submillisecond temporal precision.

Our complementary approaches enable us to experimentally dissect the developmental organisation and presynaptic plasticity as well as the structure and function of auditory hair cell ribbon synapses in the cochlea and of calyceal synapses of the central auditory system. Additionally, we work towards the restoration of hearing in animal models of acute and hereditary deafness using gene-therapeutic and optogenetic approaches.

Molecular anatomy, physiology and pathology of synaptic encoding and processing of sensory information

The hair cell synapse features ribbon-type active zones, each tethering hundreds of synaptic vesicles, with approximately one dozen release sites and 20-330 voltage-gated Ca2+ channels. When hair cells transduce a sound-driven mechanical stimulus into an electrical signal, Ca2+ channels open and the resulting Ca2+ influx triggers exocytosis of glutamate-filled vesicles at the ribbon synapses. Our work on the hair cell ribbon aims at a comprehensive understanding of synaptic encoding. It follows five main avenues: (i) the characterization of the developmental assembly and refinement of the presynaptic architecture, (ii) the dissection of the synapse’s molecular anatomy and physiology, (iii) the elucidation of the mechanism(s) of release and the control by Ca2+ channels, (iv) the vesicle (re-)cycling at the active zone, and finally (v) the understanding of synaptic sound encoding and the role of synaptic heterogeneity in this.

Over recent years, the molecular composition of these synapses is slowly being elucidated and we have gained new understanding of its role in the synapses’ function. For example, the hair cell synapse seems to operate with an unconventional molecular machinery, on which much was learned from analysis of human deafness genes and the corresponding mouse mutants. Interestingly, proteins with important roles at conventional synapses of the central nervous system, such as neuronal SNAREs, synaptotagmin 1, and complexin, appear not to be required for functional hair cell exocytosis. Conversely, the multi-C2 domain protein otoferlin and the hair cell-specific Ca2+ channel complex are essential for synaptic sound encoding at hair cell active zones but not for signal transmission at conventional synapses. However, some common synaptic proteins, such as the presynaptic scaffold protein bassoon, are critically required for hair cell synaptic function and thus for hearing.

 Transmission of sound in the inner ear.

Left: Sound is funnelled by the pinna into the ear canal, where it oscillates the tympanic membrane. These vibrations are transferred to the inner ear via the ossicles of the middle ear. The inner ear is composed of the vestibular system, namely the semicircular canals and the otholitic organs, and the cochlea, which houses the auditory sensory organ of Corti. Right: The organ of Corti carries the auditory hair cells, the outer (OHC) and inner hair cells (IHC). IHCs convert the mechanical movement of sound vibrations into electrical signals, which are passed on to the spiral ganglion neurons (SGN) which send the signals onward to the brain stem.

Images from Moser T, Grabner CP & Schmitz F (2019) Sensory processing at ribbon synapses in the retina and the cochlea. Physiol Rev 100: 103–144

Ribbon synapses of the inner ear.

The inner ear shows different types of hair cells (left): Inner hair cells, the sensory cells for sound perception, and type 1 and type 2 vestibular hair cells, the sensory cells of the vestibular system. Each of these have their own type of synaptic connectivity, but all of them make use of ribbon-type synapses, which contain an electron-dense presynaptic structure, the synaptic ribbon (middle, orange), which tethers synaptic vesicles close the synapses communication site, the active zone. Electrical activation of the hair cells causes calcium influx through CaV1.3-type calcium channels, which results in the release of synaptic vesicles containing the neurotransmitter glutamate that activates the postsynaptic spiral ganglion neuron. In contrast to neuronal synapses, the release of synaptic vesicles at the inner hair cell synapse is thought to be mediated by the unconventional inner-ear-specific protein otoferlin (right).

Images from Moser T, Grabner CP & Schmitz F (2019) Sensory processing at ribbon synapses in the retina and the cochlea. Physiol Rev 100: 103–144

Calcium signaling at the inner hair cell ribbon synapse.

Left: representative depolarization-evoked Ca2+ domains at individual active zones show the heterogeneity of responses found in inner hair cells. Right: proposed model for sound intensity encoding in an IHC. Differences in the presynaptic control of release, in terms of Ca2+-signaling and Ca2+ channel-exocytosis coupling, enable IHCs to diversify the transfer functions of individual synapses for the same receptor potentials.

Images courtesy of Thomas Frank (left) and Özge Demet Özçete (right).

Restoration of hearing

Approximately 460 million people – 5% of the world’s population – suffer from disabling hearing impairment (HI), commonly causing social isolation, depression, and reduction in professional capabilities. So far, despite major research efforts, a causal treatment based on pharmacology, gene therapy or stem cells is not yet available for its most common form: sensorineural HI. One of our efforts is towards development of gene therapy for monogenic deafness, such as DFNB9 or DNFB93 using replacement of the defective OTOF or CABP2 gene, respectively, via adeno-associated virus. Hearing aids and auditory implants, cochlear implants (CIs) and auditory brainstem implants (ABIs), represent the state-of-the-art approaches for partial restoration of auditory function and they are likely to remain key means for alleviating sensorineural HI also during the coming decades. The cochlear implant, used worldwide by more than 700.000 hearing impaired people, typically enables open speech understanding and is considered the most successful neuroprosthesis. Nonetheless, listening in noisy environments as well as music appreciation remain challenging, mostly because of the poor frequency and intensity resolution that results from broad current spread from of each of the 1-2 dozens of electrode contacts. Since light can be conveniently focused, optogenetic stimulation of the spiral ganglion of the cochlea promises a fundamental improvement of frequency resolution and intensity coding compared to that achievable with electrical cochlear implants. This principle involves the expression of light-sensitive ion channels, so called channelrhodopsins such as ChR2, in spiral ganglion neurons in order to render them light-sensitive. Placing linear emitter arrays into the cochlea in the form of an optical CI, one might be enable true multichannel stimulation with tens of independent information channels, thereby providing a major improvement of frequency resolution over currently employed electrical CIs.

Optogenetic stimulation of the auditory pathway “Cochlear Optogenetics”

Left: In electrical CIs usually 8-24 electrode contacts (blue or red) are used to stimulate spiral ganglion neurons by charge-neutral biphasic stimuli in a monopolar configuration (red contacts). Current spread leads to activation of a large population of neurons along the spiral tonotopic axis by any active contact (blue halo), thereby limiting the frequency resolution of electrical coding.

Right: optical stimulation e.g. light emitted from microscale light emitting diodes (µLEDs) focused by lenses or emitted from waveguide arrays promises spatially confined activation of spiral ganglion neurons allowing for a higher number of independent stimulation channels and improving the frequency and intensity resolution of sound coding.

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