Roles of Inhibitory Nuclei of the Trapezoid Body in Sound Localization: Model & Optogenetics - Project Summary Deficits in spatial hearing are a common feature of age-related hearing loss and several neurodevelopmental disorders. Affected listeners struggle in “cocktail-party” environments, where separating competing voices requires precise neural encoding of spatial cues. These difficulties not only impair communication but also contribute to social isolation, dementia, and other health burdens. The auditory brainstem is the first stage of the ascending auditory system that integrates binaural cues for sound localization, yet how this high precision is achieved, and the specific contributions of inhibitory nuclei remain incompletely understood. The trapezoid body is a critical inhibitory hub containing the medial (MNTB), lateral (LNTB), and ventral (VNTB) nuclei. Our recent evidence suggests that MNTB and LNTB contribute to spatial acuity by shaping the tuning characteristics of encoded binaural cues, but the role of afferent inhibition through the VNTB remains largely unexplored. Preliminary findings indicate that VNTB feedforward inhibition may emphasize transient features of sounds and stabilize spatial acuity during rapid sequences, yet no model or experimental framework currently incorporates its function. This project addresses this gap using an integrated approach that combines computational modeling, in vivo optogenetics, auditory brainstem responses (ABRs), and behavioral assessment. In the K99 phase, I will (1) extend spiking neural network models of the auditory brainstem to include VNTB inhibition, and (2) test model predictions using optogenetic manipulations and extracellular recordings in Mongolian gerbils. In the R00 phase, I will (3) link nucleus-specific activity to ABR and binaural interaction components as clinically measurable markers, and (4) evaluate perceptual consequences of inhibiting MNTB, LNTB, or VNTB using prepulse inhibition of the acoustic startle reflex. The project is innovative in applying state-of-the-art biophysical models together with in-vivo optogenetic manipulations in deep and small brainstem nuclei, providing a unique opportunity to establish causal roles of these circuits. By iteratively linking computational predictions with electrophysiological, evoked potential, and behavioral outcomes, the work will generate a comprehensive, multi-level framework of how trapezoid body inhibition shapes spatial hearing. Together, these studies will define the causal roles of trapezoid body inhibition in sharpening temporal precision and spatial hearing. The outcomes will resolve a longstanding gap in auditory brainstem physiology, provide mechanistic insight into central auditory processing disorders, and establish computational and translational frameworks to inform future diagnostics, neuromorphic devices, and auditory prostheses.
