Identification of inputs to unipolar brush cells and their roles in multisensory processing

Project Number: 5K99DC016905-02
Contact PI / Project Leader: BALMER, TIMOTHY S

Abstract Text:

PROJECT SUMMARY / ABSTRACT The unipolar brush cell (UBC) is an excitatory interneuron 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. The UBC has a characteristic large dendritic brush that slows the diffusion of glutamate from the synapse and prolongs excitatory signals. Multisensory input is carried to UBCs by mossy fibers. The Trussell Lab has found that there are two types of UBCs- one responds to glutamate released from mossy fibers with an increase in firing (ON UBCs) and another that responds with a decrease in firing (OFF UBCs). I have recently discovered that in the vestibular cerebellum, ON UBCs receive direct primary afferent input from vestibular ganglion cells, whereas OFF UBCs receive indirect secondary input from vestibular nuclei. UBCs are also present in the dorsal cochlear nucleus (DCN), but their mossy fiber inputs are unknown. Aim 1 will use innovative tools and approaches to identify sources of input to UBC subtypes in DCN. Aim 2 will test the UBCs’ synaptic responses to those inputs. Aim 3, the R00 phase, will test the function and circuitry of UBCs in vivo. This proposal utilizes cutting-edge approaches under mentors and consultants with expertise in their use. In Aim 1, motivated by my findings in the vestibular system, I will test the hypothesis that in DCN primary sensory mossy fibers project to ON UBCs and secondary mossy fibers project to OFF UBCs. This Aim utilizes mouse genetics to target ON or OFF UBCs specifically, and monosynaptic transmission of pseudotyped rabies virus to identify presynaptic mossy fiber sources. In Aim 2 the pathways identified will be validated by expressing channelrhodopsin in the projecting sources and recording postsynaptic currents in UBCs using in vitro electrophysiology. Aim 3 during 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. The role of UBCs in gating multisensory inputs to DCN will be tested by inhibiting ON or OFF UBCs optogenetically. 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.

Public Health Relevance Statement:

PROJECT NARRATIVE Diverse multisensory information is carried by mossy fibers to the extraordinary dendritic brush of the unipolar brush cell (UBC), a cell type present in cerebellum-like circuits including the dorsal cochlear nucleus (DCN). The mentored phase of this proposal seeks to identify the multisensory source of input to UBCs, which could underlie enhancement of DCN activity that is associated with tinnitus, a pervasive auditory disorder. The independent phase tests the role of UBCs in multisensory integration in vivo.

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