Identification of factors underlying spiral ganglion neurons??? dynamic range
螺旋神经节神经元潜在因素的鉴定???
基本信息
- 批准号:8649806
- 负责人:
- 金额:$ 5.22万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-01-01 至 2016-12-31
- 项目状态:已结题
- 来源:
- 关键词:Action PotentialsAdultAffectAuditoryAuditory systemBindingCaliberCellsClinicalDetectionFiberFigs - dietaryFire - disastersGene ChipsGenerationsGenesHarvestHearingHeterogeneityInjection of therapeutic agentInner Hair CellsMeasuresMolecularMolecular ProfilingMusicNeuronsOrgan of CortiOutcomeOutputPeripheralPlayPopulationPositioning AttributePotassium ChannelProcessPropertyRattusRoleSCN1A proteinSideSodiumSolutionsSpeechStagingSubgroupSynapsesSynaptic PotentialsTestingTrainingVariantWaterbaseinterestmRNA Expressionneuronal cell bodyneurophysiologypostsynapticpublic health relevancerelating to nervous systemresearch studyresponsesoundspiral ganglionsrc-Family Kinasesvoltage
项目摘要
DESCRIPTION (provided by applicant): One astonishing feature of the auditory system is its broad dynamic range - the auditory system detects sounds from a water droplet to jet engine without causing damage. At the first neural processing stage of the auditory system, different groups of spiral ganglion neurons (SGNs) are thought to represent distinct dynamic ranges. Given that the dynamic range of inner hair cells is thought to be largely homogeneous, how afferent fibers acquire such heterogeneous dynamic ranges remains to be resolved. Recent studies provide evidence that the difference in dynamic range among afferent fibers originates, at least partially, at IHC/afferent synapses. Here, the proposed study hypothesizes an additional contributor to dynamic range by action potential (AP) generation mechanisms. In Specific Aim 1, we will determine whether the size of injected current required to fire an AP is variable among afferent fibers, thus testing for differences in postsynaptic threshold as a means of establishing dynamic range. For this, we will perform a current-clamp recording on single afferent fiber's bouton, and measure the minimum current injection required to fire an AP. A broad distribution of current threshold for AP firing would support that synaptic current may be differently propagated and integrated to fire AP among afferent fibers. In Specific Aim 2, we will determine whether AP generation mechanisms indeed contribute in creating heterogeneous dynamic range among afferent fiber. For this, excitatory post- synaptic currents (EPSCs) as well as APs from a single afferent fiber will be recorded while depolarizing the IHC contacted by the recorded fiber to a sequence of voltages. This experiment allows us to determine the afferent fiber's dynamic range at the level of EPSCs (output of pre- and post-synaptic mechanisms) as well as its dynamic range at the level of SGN output, AP firing rate. By comparing the lower and upper bounds of dynamic ranges by EPSC with those by AP firing rate, we will determine the respective contributions of synaptic and AP generation mechanisms in creating heterogeneous dynamic range among afferent fibers. In Specific Aim 3, we will determine whether there are variations in molecular profiles among afferent fibers. We are particularly interested in what specific molecules are involved in AP generation mechanisms that play a role in establishing heterogeneous dynamic range of SGNs. We will examine mRNA expression of candidate molecules at single-cell level by qRT-PCR. Candidates include voltage-gated sodium (Nav) channels, which are responsible for AP generation and one major determinant for setting the excitability of neurons as well as Nav channel ?-subunits ?1~3 and Src family kinases, which are known to modulate the property of Nav channels. We will use a gene chip array to compare spiral ganglia constituents in nonbiased manner focusing on those molecules that establish excitability. Outcome of the proposed study will advance our understanding in the field of auditory neurophysiology by providing input-output functions of SGNs. It will also reveal possible molecular players underlying heterogeneity of SGNs, which are important for proper auditory functions and for finding clinical solutions for hearing deficits.
描述(由申请人提供):听觉系统的一个令人惊讶的特征是其广泛的动态范围-听觉系统检测从水滴到喷气发动机的声音而不会造成损害。在听觉系统的第一个神经处理阶段,不同的螺旋神经节神经元(SGN)被认为代表不同的动态范围。鉴于内毛细胞的动态范围被认为是在很大程度上是均匀的,传入纤维如何获得这种异质性的动态范围仍然有待解决。最近的研究提供的证据表明,传入纤维之间的动态范围的差异起源于,至少部分地,在IHC/传入突触。在这里,拟议的研究假设了动作电位(AP)生成机制对动态范围的额外贡献。在具体目标1中,我们将确定激发AP所需的注入电流的大小是否在传入纤维之间是可变的,从而测试突触后阈值的差异作为建立动态范围的一种手段。为此,我们将在单个传入纤维的终扣上进行电流钳记录,并测量激发AP所需的最小电流注入。AP放电电流阈值的广泛分布将支持突触电流可以不同地传播和整合以在传入纤维之间放电AP。在具体目标2中,我们将确定AP生成机制是否确实有助于在传入纤维之间创建异质动态范围。为此,将记录来自单个传入纤维的兴奋性突触后电流(EPSC)以及AP,同时将与记录的纤维接触的IHC去极化为一系列电压。这个实验使我们能够确定传入纤维的动态范围在EPSC水平(突触前和突触后机制的输出),以及其动态范围在SGN输出水平,AP放电率。通过比较EPSC与AP放电率的动态范围的下限和上限,我们将确定突触和AP产生机制在传入纤维之间创建异质动态范围的各自贡献。在具体目标3中,我们将确定传入纤维之间的分子谱是否存在变化。我们特别感兴趣的是,哪些特定的分子参与AP生成机制,在建立SGNs的异质动态范围中发挥作用。我们将通过qRT-PCR在单细胞水平上检测候选分子的mRNA表达。候选者包括电压门控钠(Nav)通道,其负责AP的产生,并且是设置神经元兴奋性的主要决定因素,以及Nav通道?亚单位?1~3和Src家族激酶,它们已知调节Nav通道的性质。我们将使用基因芯片阵列比较螺旋神经节成分在无偏见的方式集中在那些分子,建立兴奋性。这项研究的结果将通过提供SGN的输入-输出功能来促进我们在听觉神经生理学领域的理解。它还将揭示SGN异质性的潜在分子参与者,这对于正确的听觉功能和寻找听力缺陷的临床解决方案至关重要。
项目成果
期刊论文数量(0)
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MAMIKO NIWA其他文献
MAMIKO NIWA的其他文献
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{{ truncateString('MAMIKO NIWA', 18)}}的其他基金
Single-unit response to AM sound in the auditory cortex.
听觉皮层对 AM 声音的单个单元反应。
- 批准号:
7409405 - 财政年份:2007
- 资助金额:
$ 5.22万 - 项目类别:
Single-unit response to AM sound in the auditory cortex.
听觉皮层对 AM 声音的单个单元反应。
- 批准号:
7495027 - 财政年份:2007
- 资助金额:
$ 5.22万 - 项目类别:
Single-unit response to AM sound in the auditory cortex.
听觉皮层对 AM 声音的单个单元反应。
- 批准号:
7676759 - 财政年份:2007
- 资助金额:
$ 5.22万 - 项目类别:
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