Solving the dynamic range problem of hearing: deciphering and harnessing cochlear mechanisms of sound intensity coding

ongoing

Our sense of hearing processes stimuli that differ in sound pressure by more than six orders of magnitude. Yet, while the presynaptic inner hair cells (IHCs) cover this wide dynamic range, each postsynaptic spiral ganglion neuron (SGN) encodes only a fraction and the intensity information is then reconstructed by the brain. This so-called “dynamic range problem” of hearing is known for decades, but how sound intensity information is decomposed into different neural pathways remains elusive. In vivo recordings report major functional SGN diversity and ensembles of such diverse neurons collectively encode intensity for a given sound frequency. Recently, a major heterogeneity of afferent SGN synapses with IHCs as well as different molecular SGN profiles have been discovered. How these relate to the diverse sound coding properties of SGNs remains to be elucidated. DynaHear sets out to close this gap by testing the hypothesis that an interplay of synaptic heterogeneity, molecularly distinct subtypes of SGNs, and efferent modulation serves the neural decomposition of sound intensity information. This is enabled by innovative approaches to cochlear structure and function, some of which we have recently established, while others will be developed in DynaHear. We will combine electrophysiology, optogenetics, molecular labelling and tracing, multiscale and multimodal imaging, with computational modeling. We will elucidate the molecular underpinnings of afferent synaptic heterogeneity, decipher mechanisms establishing such heterogeneity, and relate them to functional SGN diversity. DynaHear promises to fundamentally advance our understanding of sound intensity coding and contribute to solving the dynamic range problem of sound encoding. Moreover, the proposed work will help to better understand synaptic hearing impairment, assist current hearing rehabilitation, and pave the way for innovative therapeutic approaches such as gene therapy and optogenetic restoration of hearing.