Circuits in the auditory brainstem dorsal cochlear nucleus (DCN) are believed to aid in sound localization in the vertical plane using monaural cues. Moreover, DCN circuitry integrates auditory and non-auditory inputs to aid in orientation toward sounds or to suppress self-generated noise, thereby increasing the salience of external sounds. Our long-term goal is to understand the synaptic mechanisms that contribute to these functions. Multisensory integration is controlled, in part, by high-frequency action potential bursts from inhibitory cartwheel cells;yet the way in which bursts are generated, and the effects of burst inhibition on postsynaptic integration, remain unclear. The objective of this proposal is to define mechanisms governing burst generation, focusing on the role of newly-discovered low-threshold activated calcium channels localized to the site of action potential initiation in the axon initial segment. First, we will use a combination of electrophysiology and 2-photon imaging to identify signaling pathways that control neuronal output by regulating initial segment calcium channel activity. Second, we will take advantage of novel voltage imaging techniques to determine how calcium channels contribute to the generation of bursts in the initial segment. Finally, we will determine how inhibitory synaptic input affects integration in the efferent neurons of the DCN, fusiform cells, contrasting the effects of single action potentials and bursts.
Dysfunctions in low-voltage activated calcium channel activity contributes to hyperexcitability in many brain regions, and may be etiological to tinnitus and epilepsy. This proposal examines the function and regulation of low-voltage activated calcium channels localized to the site of action potential initiation. Understanding how these channels affect neuronal output may uncover new avenues for treatment of hyperexcitability conditions.
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