Cellular diversity underlying timing- and intensity-based sound localization in the superior olivary complex

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Project abstract The superior olivary complex (SOC) in the brainstem of mammals integrates information from the two ears to localize sound sources and enable selective auditory attention. The lateral superior olive (LSO) plays a critical role in these functions. Principal neurons (PNs) of the lateral superior olive (LSO) compare excitatory inputs driven by the ipsilateral ear with inhibitory inputs driven by the contralateral ear. The cellular properties of LSO PNs are fundamental to how they encode and transmit information; however, critical cellular mechanisms are not yet resolved. The classical view of the LSO is that it extracts ongoing interaural level differences (ILDs). Recent reports challenge this thinking, suggesting the major function of LSO is encoding interaural time differences (ITDs) for brief sounds or amplitude modulations. Currently it is not clear whether the LSO is primarily performing one of these functions or both, however, these roles place disparate demands on the cellular properties of LSO neurons. Furthermore, there is cellular diversity among LSO PNs that is not fully explored. Our overarching hypothesis is that there are LSO PN populations adapted for ILD and ITD coding and that their intrinsic properties, transmitter systems, and projection patterns provide a means to organize this information in higher centers. This project will yield foundational insights into the cellular organization of the SOC which may be disrupted in poorly understood disease states such as auditory processing disorder. There are inhibitory (I) and excitatory (E) LSO PNs that exhibit different projection patterns. A major gap in our knowledge is that intrinsic cellular differences between these I/E cell types has not been examined. We will target I/E cells for ex vivo experiments using established reporter mouse lines. Aim 1 will examine the intrinsic properties of I/E LSO PNs using ex vivo patch-clamp and two-photon imaging in brain slices from transgenic reporter mice, in situ hybridization, tract tracing, and transcriptomic approaches. Synaptic drive and integrative properties of LSO neurons could accentuate or offset intrinsic differences. In Aim 2 we will examine the number, strength, and short-term dynamics of synaptic inputs onto I/E cell types. Biophysically-based computational models that facilitate the systematic study of synaptic differences and firing types on ILD/ITD coding strategies will complement our ex vivo experiments. How signals propagate in dendrites is a critical component of integrative functions in neurons. Almost nothing is known of the dendritic physiology of LSO neurons. In Aim 3 we will use dual dendritic/somatic patch-clamp technique in targeted LSO neuron types to analyze local responses as well as signal transformations that occur with propagation. Higher throughput two-photon calcium imaging methods will also be used to assess signal propagation. Together these experiments will expand our view of the functional role of LSO cell types and sound localization coding strategies. This proposal is conceptually innovative in its treatment of the LSO as a diverse group with cellular properties tuned for multiple functional roles and methodologically innovative in our use of transcriptomics and dendritic patch-clamp.