Biology subjects

Huet, A. T.

Publications and source records attributed to Huet, A. T..

3 recordsLinked to original sources

bioRxiv2024

Improved optogenetic modification of the spiral ganglion neurons for future optical cochlear implants

Optogenetic stimulation has become a promising approach for restoring lost body function. For example, partial restoration of vision has been achieved in a blind patient and proof-of-concept has been demonstrated for optogenetic hearing restoration in rodents. In order to prepare clinical translation of hearing restoration, efficient and safe optogenetic modification of spiral ganglion neurons (SGNs) in the mature cochlea remains to be developed. Here, we established microcatheter-based administration adeno-associated virus (AAV) to scala tympani of the cochlea of Mongolian gerbils and compared it to the previously developed AAV-injection into the spiral ganglion. We probed the potential AAV-PHP.S capsid to express channelrhodopsins (ChRs) under the control of the human synapsin promotor in mature SGNs in hearing and deafened gerbils. Using the microcatheter approach, but not with the AAV-modiolus injection, we achieved reliable ChR expression in SGN enabling optogenetic stimulation of the auditory pathway in 80% of the treated animals. Yet, the efficiency of SGN transduction was modest with only [~]30% ChR-expressing SGNs. Moreover, we encountered off-target expression in hair cells in hearing gerbils in both approaches, but not ChR expression in the central nervous system using microcatheter administration. Comparing optogenetic auditory brainstem responses of gerbils with and without hair cell transduction confirmed that SGNs were the primary site of optogenetic stimulation of the pathway.

neuroscience↗

bioRxiv2022

Graded optogenetic activation of the auditory pathway for neural network analysis and hearing restoration

Optogenetic control of neural activity enables innovative approaches to improve functional restoration of diseased sensory and motor systems. For clinical translation to succeed, optogenetic stimulation needs to closely match the coding properties of the targeted neuronal population and employ suitable emitters at their optimal operation. This requires tailoring of channelrhodopsins, emitters and coding strategies. Here, we provide a framework to parametrize optogenetic neural control and apply it to the auditory pathway that requires high temporal fidelity of stimulation. We used viral gene transfer of the ultrafast targeting-optimized Chronos into spiral ganglion neurons (SGNs) of the cochlea. We characterized the light-evoked response by in vivo recordings from individual SGNs and neurons of the anteroventral cochlear nucleus (AVCN) that detect coincident SGN input. Our results demonstrate that spike probability of SGNs can be gradually dialed by adjusting the width of light pulses of constant intensity, which optimally serves efficient laser diode operation. We identified an effective pulse width of 1.6 ms to maximize information encoding in SGNs. An upper boundary of optical stimulation rates results from robust spike rate adaptation that required a few tens of milliseconds to recover. We developed a semi-stochastic stimulation paradigm to rapidly (within minutes) estimate the transfer function from light to SGNs firing. The semi-stochastic stimulus evoked firing of different statistics allowing to approximate the time constant of neuronal integration in the AVCN. Our data pave the way to design the sound coding strategies of future optical cochlear implants.

neuroscience↗

bioRxiv2021

Fast photoswitchable molecular prosthetics control neuronal activity in the cochlea

Artificial control of neuronal activity enables studies of neural circuits and restoration of neural function. Direct, rapid, and sustained photocontrol of intact neurons could overcome shortcomings of established electrical stimulation such as poor selectivity. We have developed fast photoswitchable ligands of glutamate receptors to establish such control in the auditory system. The new photoswitchable ligands produced photocurrents in untransfected neurons upon covalently tethering to endogenous glutamate receptors and activating them reversibly with visible light pulses of few milliseconds. As a proof of concept of these molecular prostheses, we apply them to the ultrafast synapses of auditory neurons of the cochlea that encode sound and provide auditory input to the brain. This drug-based method affords kilohertz rate stimulation of auditory neurons of adult gerbils without genetic manipulation that would be required for their optogenetic control. The new photoswitchable ligands are also broadly applicable to spatiotemporally control fast spiking interneurons in the brain.

neuroscience↗