Molecular and Functional Mechanisms of the aging auditory neuron

衰老听觉神经元的分子和功能机制

• 批准号: 10496285
• 负责人: EBENEZER N YAMOAH
• 金额: $ 46.75万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10496285
• 关键词: Action Potentials; Address; Affect; Afferent Neurons; Age; Aging; Anatomy; Auditory; Auditory Brainstem Responses; Auditory area; Backcrossings; Biological Markers; Brain Stem; Cell Nucleus; Cochlea; Cochlear nucleus; Complex; Computer Analysis; Computer Models; Coupled; Demyelinations; Dependence; Development; Elderly; Electrophysiology (science); Environment; Etiology; Evaluation; Frequencies; Generations; Hair Cells; Human; In Situ; Injections; Injury; Ion Channel; Kinetics; Knock-in; Knock-in Mouse; Light; Maps; Measures; Mediating; Microscopy; Molecular; Mus; Nerve Degeneration; Neurons; Noise-Induced Hearing Loss; Persons; Pharmacogenetics; Pharmacology; Phase; Phenotype; Physiological; Population; Predisposition; Presbycusis; Process; Property; Reflex action; Resolution; Sensory; Signal Transduction; Speed; Stimulus; Synapses; Synaptic Vesicles; Variant; Visualization; Work; age effect; age related; aged; biophysical properties; calbindin; calretinin; density; excitotoxicity; experimental study; hearing impairment; insight; mouse model; neural; neuron loss; neurosensory; optogenetics; otoacoustic emission; patch clamp; postsynaptic; pressure; presynaptic; response; signal processing; sound; spiral ganglion; vector; voltage; voltage clamp

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