Molecular and Functional Mechanisms of the aging auditory neuron

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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.