ABSTRACT: Influence of neuronal zinc homeostasis on cortical responses to sound

In the auditory system, as sound properties of the auditory environment change, auditory cells in the brain adjust their dynamic range of their responses to match changing background noise. This type of adaptation to sound is extremely important for brain auditory processing, for it provides a mechanism for allowing us to focus on specific sounds in the presence of variable background sound levels. However, the mechanisms underlying this adaptation remain unknown. This project will establish a previously unknown link between the metal zinc in the brain and control of auditory processing in the brain's cerebral cortex. Thus, findings from this project will advance understanding about mechanisms of adaptations of sound processing and create a new framework for approaching and interpreting the role of the auditory system in the processing of sound. This joint NSF/BSF project will establish a joint US-Israel student exchange program as well as target underserved student populations both in Israel and the United States and train them in problem-solving at behavioral, neural and molecular levels of analysis. Broad dissemination of the work will be made possible by active engagement with the International Society for Zinc Biology through a variety of activities.

Zinc is packaged into glutamatergic vesicles by the ZnT3 zinc transporter, and released from synaptic terminals in an activity-dependent manner. Although the basic principles underlying zinc neurotransmission have begun to be deciphered, the sensory stimuli leading to the modulation of zinc signaling as well as the role of zinc in regulating sensory processing remain unknown. The central hypothesis of this project is that sound-dependent changes in zinc signaling in the auditory cortex play a role in the sound level adaptation of neuronal input-output functions to match the prevailing stimulus intensity of the acoustic environment. This project aims to: 1) identify the consequences of experience-dependent plasticity of zinc-mediated modulation on input-output functions and receptive fields of layers 2/3 auditory cortical neurons in vivo, and 2) establish the cellular and molecular mechanisms mediating the experience-dependent alterations in zinc-dependent auditory cortical processing. These studies will thus provide the first analysis of regulation of neuronal zinc and its effects on auditory processing, at the molecular, cellular and systems levels.