Auditory circuits in the mammalian CNS exhibit robust spontaneous activity before the onset of hearing. This activity originates within the developing cochlea and is dependent on excitation of inner hair cells (IHCs); however, little is known about the molecular mechanisms responsible for initiating spontaneous IHC activity or the consequences of this activity for development of auditory circuits in the brain. The studies outlined in this proposal will use in vivo genetic manipulations of key components of this pathway in combination with electrophysiological studies in isolated cochleae and in vivo imaging in unanesthetized mice to test the hypothesis that IHC activity is induced by the periodic release of ATP from inner supporting cells (ISCs). These studies will define the autoreceptor(s) responsible for detecting ATP and the mechanisms by which ISCs induce depolarization of nearby IHCs, events that ultimately trigger bursts of action potentials in spiral ganglion neurons (SGNs) and synchronous activity of neurons in central auditory circuits. The global activity patterns exhibited by auditory neurons before hearing onset will be defined in the inferior colliculus and primary auditory cortex (A1) during normal development and when sensory-independent activity from the cochlea is disrupted, providing fundamental new insight into the role of this cochlea-dependent activity in maturation of auditory circuits and the response of these circuits to deficits in activity during this crucial developmental stage. Changes in network activity in response to the loss of connexin 26, mutations of which are a major cause of non-syndromic deafness, will be examined to determine how disruption of gap junctional coupling among cochlear supporting cells alters the patterns of activity carried through nascent auditory circuits. In addition, the role of spontaneous activity in the refinement of dendritic and axonal projections of SGNs will be assessed through selective in vivo genetic manipulations of cells in the cochlea. These studies will provide greater insight into the fundamental mechanisms used to shape the circuits that process sound information.

Public Health Relevance

Spontaneous, sensory-independent neural activity occurs in the developing auditory system during early life, which may play a crucial role in the maturation of the circuits responsible for processing sound information. This proposal will define the molecular mechanisms responsible for initiating this activity within the inner ear and determine how disruptions of this activity influence the organization of sound processing centers in the brain. These studies may lead to a better understanding of how the auditory system adapts to loss of activity induced by genetic mutations, trauma or exposure to ototoxic drugs, and guide the development of new strategies for compensating for these deficits.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC008860-06
Application #
9444444
Study Section
Auditory System Study Section (AUD)
Program Officer
Cyr, Janet
Project Start
2007-12-01
Project End
2021-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
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Wang, Han Chin; Lin, Chun-Chieh; Cheung, Rocky et al. (2015) Spontaneous Activity of Cochlear Hair Cells Triggered by Fluid Secretion Mechanism in Adjacent Support Cells. Cell 163:1348-59
Tritsch, Nicolas X; Rodríguez-Contreras, Adrián; Crins, Tom T H et al. (2010) Calcium action potentials in hair cells pattern auditory neuron activity before hearing onset. Nat Neurosci 13:1050-2
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Tritsch, Nicolas X; Zhang, Ying-Xin; Ellis-Davies, Graham et al. (2010) ATP-induced morphological changes in supporting cells of the developing cochlea. Purinergic Signal 6:155-66