Project Summary/Abstract Sound pressure produces force across the mammalian cochlear partition, ultimately creating a vibratory traveling wave that propagates longitudinally up the cochlear duct. The key feature distinguishing this process from the non-mammalian cochlea is amplification, whereby forces produced by thousands of outer hair cells (OHCs) sharpen and amplify the traveling wave. Our overarching objective is to understand how the complex biomechanics of the 3D multi-cellular and acellular arrangement that form the organ of Corti work together to create cochlear amplification. Specifically, we will determine how this process, which stems from the broadly- tuned basilar membrane, creates sharp frequency tuning and high sensitivity. This question is significant on a basic science level because these biophysical processes underlie the ability to hear sounds just above the Brownian motion of molecules in air with an exquisite frequency resolution. This question remains unsolved and is clinically important because hearing loss is typically due to loss of cochlear amplification. Our central hypothesis is that, beyond the broad tuning provided by basilar membrane mechanics, the forces produced by OHCs are also tuned by additional mechanisms. In aim 1, we will use 3D Volumetric Optical Coherence Tomography and Vibrometry (VOCTV) in mice to test whether the forces produced by OHCs are tuned by the mechanics of the supporting cells and acellular structures that form the organ of Corti. In aim 2, we will use 1D VOCTV in awake behaving mice to test whether cochlear amplification is modulated by brain state via the medial olivocochlear efferent (MOC) system by varying OHC force production. Together, these data will be interpreted so as to test our hypothesis. If our hypothesis is true, sharply-tuned differential motion within the organ of Corti is necessary to generate the sensitivity and sharp tuning of the mammalian cochlea and brain state modulates cochlear amplification via the MOC efferent system.