Cellular Mechanisms of Auditory Information Processing

NIH RePORTER · NIH · R01 · $513,490 · view on reporter.nih.gov ↗

Abstract

Hearing loss is a pervasive problem that can result from exposure to loud sounds, to drugs for treatment of cancer and infections, from aging, or from individual genetic factors. Noise-induce hearing loss (NIHL), from both occupational and recreational causes, is a growing issue that is currently is thought to affect more than 40 million Americans. Nearly 25% of adults have audiological signs consistent with causation by NIHL. Hearing loss leads to difficulties in communication, social isolation, and possibly to changes in cognition. Most causes of hearing loss are caused by dysfunctional changes in the cochlea and spiral ganglion cells, which in turn provided a degraded sensory representation to the cochlear nucleus (CN) where the axons of spiral ganglion cells, the auditory nerve fibers (ANFs), terminate. The consequences of cochlear NIHL then propagate throughout the central auditory system, engaging pathophysiological increases in excitability and altering synaptic function. The CN consists of networks of neurons with distinct patterns of synaptic innervation from ANFs, and these neurons create parallel, yet intertwined, pathways for upstream analysis. Although sensory processing in the CN has been well studied in animals with normal cochleae, how the mechanisms and functions of CN circuits change after hearing loss, and the consequences of those changes for sensory processing, is not as well understood. Many cellular mechanisms have only been studied in juvenile mice during a developmental sensitive period. There is an unmet need to understand the unique cellular mechanisms underlying NIHL that occur in adults. Here, we propose to use controlled NIHL to perturb the ANF inputs to the CN, and then to examine specific synapses and cellular excitability mechanisms related to sensory processing in noisy environments in the CN. First, we will examine the hypothesis that NIHL leads to increased excitability of three specific populations of CN neurons, two of which have not been studied, and one that has only been studied in very young animals, in brain slices in adult mice. We will determine which specific mechanisms and ion channels are causal to changes in excitability. Second, we will examine how the synaptic inputs to different neurons of the CN are affected by NIHL, testing the hypotheses that NIHL induces mechanisms that amplify residual dendritic excitatory synaptic inputs, and alter the functional organization and strength of inhibition at specific local connections. Third, we will examine how the detection of sounds in noise is affected by NIHL in these three populations of CN neurons, using an established acoustic paradigm, in both computational models and in vivo. Together the results from these studies will provide insights into how the early stage processing of sound is affected by hearing loss, and can contribute identifying approaches to optimize sensory discrimination after hearing loss.

Key facts

NIH application ID
10188497
Project number
5R01DC019053-02
Recipient
UNIV OF NORTH CAROLINA CHAPEL HILL
Principal Investigator
Paul B Manis
Activity code
R01
Funding institute
NIH
Fiscal year
2021
Award amount
$513,490
Award type
5
Project period
2020-06-15 → 2025-05-31