Molecular and Functional Mechanisms of the aging auditory neuron
衰老听觉神经元的分子和功能机制
基本信息
- 批准号:10496285
- 负责人:
- 金额:$ 46.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2028-08-31
- 项目状态:未结题
- 来源:
- 关键词:Action PotentialsAddressAffectAfferent NeuronsAgeAgingAnatomyAuditoryAuditory Brainstem ResponsesAuditory areaBackcrossingsBiological MarkersBrain StemCell NucleusCochleaCochlear nucleusComplexComputer AnalysisComputer ModelsCoupledDemyelinationsDependenceDevelopmentElderlyElectrophysiology (science)EnvironmentEtiologyEvaluationFrequenciesGenerationsHair CellsHumanIn SituInjectionsInjuryIon ChannelKineticsKnock-inKnock-in MouseLightMapsMeasuresMediatingMicroscopyMolecularMusNerve DegenerationNeuronsNoise-Induced Hearing LossPersonsPharmacogeneticsPharmacologyPhasePhenotypePhysiologicalPopulationPredispositionPresbycusisProcessPropertyReflex actionResolutionSensorySignal TransductionSpeedStimulusSynapsesSynaptic VesiclesVariantVisualizationWorkage effectage relatedagedbiophysical propertiescalbindincalretinindensityexcitotoxicityexperimental studyhearing impairmentinsightmouse modelneuralneuron lossneurosensoryoptogeneticsotoacoustic emissionpatch clamppostsynapticpressurepresynapticresponsesignal processingsoundspiral ganglionvectorvoltagevoltage clamp
项目摘要
Abstract
During development, cochlear hair cells (HCs) and neurons must be wired correctly, qualitatively, and
quantitatively. These include specific auditory afferent neurons (AN) wired to the brainstem cochlear nuclei (CN).
The activity of HCs maintains the number, size, and functions of ANs. Previous studies suggest that aging may
result in preferential loss of specific AN subtypes.
We hypothesize that ARHL arises from a loss of ultrafast afferent responses, accompanied by remodeling of
central auditory circuits and functions—changes that result in deficiencies in phase-locked response functions
in older adults.
We propose to examine age-related changes in distinct AN using three knockin mouse models: calretinin
(Calb2)-eGFP, calbindin (Calb1)-mCherry, Pou4f1 and (brn3a)-CFP, and optogenetic and pharmacogenetic
mouse models. The work will focus on longitudinal changes in:
1) structural (anatomic) projections from HCs to the brainstem nuclei (CN),
2) afferent neuron subtype distributions and functions, and
3) Identify the age dependence of ionic conductances in AN afferents
Aim 1 will trace afferent neuron subtype-specific projections from the cochlea to the CN and determine the age-
dependent changes to identify potential anatomic plasticity. We will measure age-dependent auditory function,
auditory brainstem responses (ABR), and distortion product otoacoustic emissions (DPOAE). We will evaluate
and perform these studies in parallel with changes in age-related auditory phenotype. For Aim 2, we will
determine regional and afferent neuron subtype variations in the response properties and the age-dependent
changes. We will evaluate the regularity of inter-spike intervals, synchronization parameters, including vector
strength (VS), winding ratio (k), and sensitivity to current injection, using experimental and physiological
stimulation. Finally, for Aim 3, we will identify the age dependence of ionic conductances in three groups of
afferent neurons. We will use patch-clamp analyses of the kinetics, voltage-dependence, pharmacology, and
conductance in young and aged neurons to determine the underlying mechanisms for the differences in response
properties of three neuronal subtypes, using computational analyses.
Thus, we will address the complexity of anatomic projections and signal processing and subsequent age-
dependent changes, which are necessary for developing a treatment for ARHL.
摘要
项目成果
期刊论文数量(0)
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{{ truncateString('EBENEZER N YAMOAH', 18)}}的其他基金
Determinants of age-induced hearing loss and reversal strategies
年龄引起的听力损失的决定因素和逆转策略
- 批准号:
10496280 - 财政年份:2023
- 资助金额:
$ 46.75万 - 项目类别:
Inner ear ion channels in healthy and diseased conditions
健康和患病条件下的内耳离子通道
- 批准号:
10745190 - 财政年份:2017
- 资助金额:
$ 46.75万 - 项目类别:
Inner ear ion channels in healthy and diseased conditions
健康和患病条件下的内耳离子通道
- 批准号:
9976492 - 财政年份:2017
- 资助金额:
$ 46.75万 - 项目类别:
Inner ear ion channels in healthy and diseased conditions
健康和患病条件下的内耳离子通道
- 批准号:
10194449 - 财政年份:2017
- 资助金额:
$ 46.75万 - 项目类别:
Determinants of age-induced hearing loss and reversal strategies
年龄引起的听力损失的决定因素和逆转策略
- 批准号:
9340057 - 财政年份:2016
- 资助金额:
$ 46.75万 - 项目类别:
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