PROJECT SUMMARY Auditory sensory processing requires neuronal communication via action potentials with precision in the order of microseconds. The nervous system achieves this precision by specializing intrinsic membrane properties and synaptic transmission, particularly neural inhibition. Neural inhibition sharpens sensory processing by increasing the selectivity of neurons to particularly salient stimuli and issues with neural inhibition are thought to underlie sensory problems such as tinnitus, hyperacusis, and age-related hearing loss (ARHL). In the avian auditory brainstem, inhibition stems virtually entirely from the superior olivary nucleus (SON). Neurons in SON receive excitatory input from two distinct, parallel circuits: the ipsilateral cochlear nucleus angularis (NA), which encodes intensity information from the auditory nerve, and from the ipsilateral coincidence-detecting nucleus laminaris (NL), which encodes binaural timing information from the cochlear nucleus magnocellularis (NM). Studies in vitro have demonstrated that there were 2 electrophysiological phenotypes, a single-spiking and a tonic firing response, in SON, however, preliminary data has revealed a third phenotype, a patterned tonic phenotypes. Increasing sound intensity increased phase-locking capabilities in a subset of nucleus laminaris neurons, indicating that there is potentially convergence from NA and NL in SON, however it has not been demonstrated. Importantly, Burger et al. (2005) demonstrated that SON neurons either project ipsilaterally to NA, NL, and the cochlear nucleus magnocellularis, or to the contralateral SON. However, it is unclear if these phenotypes underlie the divergent projections. Research has shown that inhibition increases the precision of timing neurons in NM and NL, but the effect on intensity coding in NA, which contains many different cell types, is less clear. Inhibitory terminals are heterogeneously expressed in NA, which some seemingly clustered on cell bodies and others on distal dendrites. The electrophysiological diversity in NA has been shown to exist along a spectrum of operating modes. It is unclear if the inhibitory terminals are related to the functional heterogeneity in NA, particularly in rate-coding neurons that are encode the dynamic range of spectral information for intensity coding. The goal of this project is to determine how neurons in SON fit into well characterized brainstem circuits and how they influence intensity coding neurons in the following two Specific Aims. Aim 1 – to use in vitro electrophysiology, synaptic stimulation, and neuronal reconstruction to determine how inputs are integrated in SON and the cell-type specific targets of divergent projections from SON neurons. Aim 2- use in vitro electrophysiology, immunohistochemistry, expansion microscopy, and confocal microscopy to determine how inhibitory terminals are expressed along specific NA neurons and how inhibition shapes intensity coding in NA. My results will provide insight into how circuits can utilize specialized inhibitory neurons for sensory processing, and how inhibition can shape spectrotemporal processing through its effect on intensity coding.

PROJECT NARRATIVE Inhibition is crucial for precise processing of the cacophony of sounds in the world and the anatomy of the avian auditory brainstem is ideal for isolating the impact of inhibition. This project will investigate how inhibitory neurons in the avian auditory brainstem integrate inputs from multiple auditory circuits and subsequently project to various brainstem regions, such as the intensity coding cochlear nucleus angularis. Studies like these are critical to understanding how inhibition contributes to dynamic sensory processing of auditory information and can be utilized to inform translational therapeutics, such as cochlear implants.