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.

Public Health Relevance

Hearing deficits affect 17% of the US adult population; limiting their abilities to communicate through speech and to enjoy music. The proposed study aims to understand electrophysiological mechanisms underlying proper functions of the peripheral auditory system. This study will potentially provide a basis for developing clinical remedies to restore auditory functions for people with hearing deficits.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZDC1-SRB-R (35))
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Sklare, Dan
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Stanford University
Schools of Medicine
United States
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