PROJECT SUMMARY/ABSTRACT Age-related hearing loss (ARHL) is one of the most prevalent health conditions in the elderly. Structural degradation and functional decline in the peripheral and central auditory systems underlie the gradual loss of perception with age. In particular, recent findings suggest that preferential damage of selective subtypes of spiral ganglion neurons (SGNs) precedes overt hearing loss. It remains unclear how age-related SGN changes link to structural and physiological alterations in the central auditory system in contributing to the development of ARHL. The cochlear nucleus (CN) is the only target for all SGNs and represents the starting site of central auditory processing. This role emphasizes that understanding changes in structure and function of the CN during aging is essential to elucidate the mechanisms of ARHL. Our overall hypothesis is that age-dependent changes in the cochlea results in alterations in the CN circuit that impact the signal processing of the entire central auditory system. This study of the CN aims to identify age-related plastic alterations in auditory nerve (AN) synapses and their excitatory and inhibitory CN targets to determine the synaptic and cellular mechanisms of ARHL in the CN. Aim 1 will determine the age-dependent changes in the physiology and morphology of different subtypes of AN synapses during ARHL. We will combine electrophysiology and immunohistochemistry to identify three subtypes of AN synapses based on the expression of different SGN molecular markers and determine these synapses' electrophysiological property and morphological features in acute CN slices from different age groups of genetically modified mice. Aim 2 will identify the age-related changes in the physiology and cellular morphology of CN principal neurons during ARHL. We hypothesize that CN principal bushy neurons with different subtypes of AN synaptic input are differentially modified with age in physiology and morphology, resulting in compromised spike output during ARHL. We will determine the age-related changes among different bushy neurons in intrinsic properties, spike output, potassium conductances, and cellular morphology in conjunction with specific subtypes of AN input they receive. Aim3 will elucidate the mechanisms of weakened inhibition in the CN during ARHL. We will test the hypothesis that inhibitory D-stellate neurons are innervated mainly by low spontaneous rate/high threshold SGNs whose selective loss with age results in reduced output and weakened inhibition in the CN. This mechanism of inhibition will be further tested by ablating specific SGN subtypes in pharmacogenetic mice at different ages. Our studies will identify age-related changes in the CN circuit, and in conjunction with selective alterations of SGN subtypes (Project 1), to determine the affected AN synapses and their impact on the output of CN principal and local inhibitory neurons.