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

单极刷细胞输入的识别及其在多感官处理中的作用

• 批准号: 10328575
• 负责人: Timothy S Balmer
• 金额: $ 24.9万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-10 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10328575
• 关键词: Acoustics; Acute; Affect; Anatomy; Area; Auditory; Axon; Brush Cell; Cells; Cerebellum; Characteristics; Cochlea; Data; Diffusion; Ear; Electric Fish; Electric Organ; Electrophysiology (science); Environment; Etiology; Eye; Fiber; Fusiform Cell; Genetic Markers; Glutamates; Goals; Head; Hearing problem; Histologic; Image; In Vitro; Interneurons; Ion Channel Gating; Label; Location; Mentors; Modeling; Morphology; Neurons; Organ; Output; Pathway interactions; Phase; Physiological; Play; Positioning Attribute; Postdoctoral Fellow; Process; Rabies; Rabies virus; Research; Retina; Role; Sensory; Series; Signal Transduction; Slice; Source; Synapses; System; Testing; Tinnitus; Transgenic Mice; Trigeminal System; Vestibular ganglion; Vestibular nucleus structure; Viral; Visual; Work; body position; cell transformation; cell type; density; dorsal cochlear nucleus; excitatory neuron; fascinate; ganglion cell; granule cell; in vivo; innovation; insight; light gated; millisecond; mossy fiber; mouse genetics; multisensory; optogenetics; postsynaptic; presynaptic; response; skills; somatosensory; sound; source localization; spinal nerve posterior root; tool; transmission process

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 syn- apse 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 pre- sent 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 electro- physiology. Aim 3 during the R00 phase will combine the skills I have learned as a postdoc with my back- ground 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. Be- cause of UBCs’ potential role in the amplification of excitatory signals, this work may provide insights into an etiology of tinnitus.

项目摘要/摘要 单极刷状细胞(UBC)是一种位于耳蜗背核的兴奋性中间神经元细胞。 (DCN)和前庭小脑。UBC被放置在电路内以放大和延长信号 可能在多感官整合、声源定位和取消自我产生方面发挥重要作用 听起来。UBC有一种特征的大树枝状刷子，它减缓了谷氨酸从合成细胞中的扩散。 减少和延长兴奋性信号。多感官输入通过苔藓纤维传递到UBC。特鲁塞尔实验室 已经发现有两种类型的UBC-一种对从苔藓纤维中释放的谷氨酸产生反应 增加发射(在无人弹道上)，另一个以减少火力(关闭无人弹道)来回应。我最近有过 发现在前庭小脑，UBC接受来自前庭的直接初级传入输入 神经节细胞接受来自前庭核团的间接二次输入。UBC也是预制的 在耳蜗背核(DCN)发出，但它们的苔藓纤维输入未知。目标1将使用创新的 用于识别DCN中UBC亚型的输入源的工具和方法。目标2将测试UBC的突触 对这些投入的反应。目标3，R00阶段，将在体内测试脐带血干细胞的功能和电路。 这项提议在具有使用专业知识的导师和顾问的指导下，利用了尖端方法。在……里面 目标1，受我在前庭系统中的发现的启发，我将检验DCN初级感觉中的假设 苔藓纤维投射到UBC上，次生苔藓纤维投射到UBC上。这个目的是利用鼠标 针对UBC特异性打开或关闭的遗传学，以及伪型狂犬病病毒的单突触传播 确定突触前苔藓纤维来源。在目标2中，确定的途径将通过表达来验证 通道视紫红质在UBC投射来源和记录突触后电流的作用 生理学。在R00阶段的Aim 3将把我作为博士后所学的技能与我的背部结合起来- 地面使用活体电生理学。将通过记录来测试DCN电路中UBC的功能 来自主要输出(纺锤形)神经元在光发生激活的开或关的UBC。的作用 将通过光遗传学抑制UBC的开启或关闭来测试对DCN的多感觉输入门控的UBC。 这项研究将阐明这些令人着迷的兴奋性中间神经元在多感觉整合中的作用。就是- UBC在兴奋信号放大中的潜在作用，这项工作可能为深入了解 耳鸣的病因学。