PROJECT SUMMARY/ABSTRACT In many excitatory presynaptic terminals, zinc is concentrated within glutamatergic vesicles and co-released with glutamate in response to action potentials. Whereas the role of vesicular zinc in synaptic transmission had remained elusive until recently, recent studies from our lab established zinc as an inhibitory neuromodulator of excitatory signaling. Namely, our studies in the dorsal cochlear nucleus (DCN), an auditory brainstem nucleus that contains high levels of presynaptic zinc, showed that vesicular zinc is released from presynaptic terminals and inhibits postsynaptic NMDA receptors and AMPA receptors. These effects are experience-dependent, because presynaptic zinc release is reduced following prolonged sound exposure. However, the signaling pathways involved in this sound-dependent plasticity mechanism, the relationship between auditory experience and modulation of zinc release, as well as the consequences of zinc plasticity for the DCN output remain unknown. This proposal aims to test the hypothesis that sound-dependent plasticity of vesicular zinc provides homeostatic regulation of the DCN output. Using a combination of fluorescent zinc sensors and electrophysiological techniques, these experiments will examine the dynamics and underlying mechanisms that modulate synaptic zinc, and how synaptic zinc shapes DCN synaptic transmission and plasticity. Because the DCN is centrally involved in spectral and multisensory processing, understanding the mechanisms and roles of zinc plasticity in shaping the DCN output is expected to reveal synaptic mechanisms modulating these forms of sensory processing by the auditory system.