Differential optogenetic excitation of the auditory midbrain in freely moving behaving mice

In patients with severe sensory impairment due to compromised peripheral function, partial restoration can be achieved by implantation of sensory prostheses for the electrical stimulation of the central nervous system. However, these state of the art approaches suffer from the drawback of limited spectral resolution. Electrical field spread depends on the impedance of the surrounding medium, impeding spatially focused electrical stimulation in neural tissue. To overcome these technical limitations, optogenetic excitation could be applied in such prostheses to achieve enhanced resolution through precise and differential stimulation of nearby neuronal ensembles within the central sensory pathway. Previous experiments have provided a first proof for behavioral detectability of optogenetic excitation in the rodent auditory system. However, little is known about the generation of complex and behaviorally relevant sensory patterns involving differential excitation. In this study, we developed an optogenetic implant to excite two spatially separated points along the tonotopy of the murine central inferior colliculus (ICc). Using a newly-devised reward-based operant Go/No-Go paradigm for the evaluation of optogenetic excitation of the auditory midbrain in freely moving, behaving mice, we demonstrate that differential optogenetic excitation of a sub-cortical sensory pathway is possible and efficient. Here we demonstrate how animals which were previously trained in a frequency discrimination paradigm a) rapidly generalize between sound and optogenetic excitation, b) generally detect optogenetic excitation at two different neuronal ensembles, and c) discriminate between them. Our results demonstrate for the first time that optogenetic excitation at different points of the ICc tonotopy elicits a stable response behavior over time periods of several months. With this study, we provide the first proof of principle for sub-cortical differential stimulation of sensory systems using complex artificial cues in freely moving animals.