Identification of inputs to unipolar brush cells and their roles in multisensoryprocessing Identification of inputs to unipolar brush cells and their roles in multisensoryprocessing The unipolar brush cell (UBC) is an excitatory cell type found in the dorsal cochlear nucleus (DCN) and vestibular cerebellum. UBCs are positioned within the circuit to amplify and prolong signals and likely play a major role in multisensory integration, sound source localization and cancellation of self-generated sounds. Previous work in the Trussell Lab identified two types of UBCs- one responds to glutamate released with an increase in firing (ON UBCs) and another that responds with a decrease in firing (OFF UBCs). The synaptic mechanisms that underly their unusual electrical responses have remained unclear. Additionally, the multisensory input carried by mossy fibers to UBCs in DCN have not been identified. During the mentored phase of this award we showed that UBCs postsynaptic responses are due to a relatively high concentration of glutamate that persists at the synapse between synaptic release events. This ambient glutamate causes tonic desensitization of AMPA-type glutamate receptors, which shapes the postsynaptic response of these cells. Tonic activation of mGluR2 receptors hyperpolarize OFF UBCs and reduce their spontaneous firing rate. This incomplete removal of glutamate represents a novel mechanism of synaptic transmission that amplifies the mossy fiber signal in a way that has previously been thought to require a small network of neurons. In another project completed during the mentored phase of this award I showed that the inferior colliculus projects a glutamatergic feedback projection to UBCs in DCN, as well as to numerous other cell types. A combined trans-synaptic viral approach and optogenetics allowed us to probe the postsynaptic actions of the inferior colliculus axons that terminate in DCN. These descending projections from IC could carry multisensory signals, because the inferior colliculus itself receives signals from numerous non-auditory areas. This work will be followed up by studies in the independent phase of this award. The R00 phase will combine the skills I have learned as a postdoc with my background using in vivo electrophysiology. The function of UBCs in the DCN circuit will be tested by recording from the principal output (fusiform) neurons during optogenetic activation of ON or OFF UBCs. How the descending IC input to DCN affects the excitability of fusiform cells and their response to sounds will be tested in vivo. We will also test how UBCs control the flow of extrinsic signals into the DCN circuit. This research will clarify the role of these fascinating excitatory interneurons in multisensory integration. Because of UBCs potential role in the amplification of excitatory signals, this work may provide insights into an etiology of tinnitus. The training acquired during the K99 phase and Dr. Trussells outstanding mentorship has been crucial in obtaining an independent faculty position at Arizona State University. The R00 phase of the proposal will provide key resources that will support my laboratory including funding, teaching relief, and a group of experts that have agreed to act as consultants on the technical and intellectual aspects of the research plan.
|Effective start/end date||1/1/21 → 12/31/23|
- HHS: National Institutes of Health (NIH): $747,000.00
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