Central processing of the auditory environment begins with the generation of diverse, parallel, streams of information processing at the level of the first auditory center of the brain, the cochlear nucleus. These streams are created by populations of neurons with distinct patterns of synaptic inputs and projections. In order to accomplish their specific functions, the neurons in each stream utilize different cellular mechanisms, including ion channels that govern intrinsic excitability, and target-dependent synaptic inputs. Recent studies have shown that inhibition plays a much more important role in sculpting the responses of ventral cochlear nucleus (VCN) neurons to sound than previously appreciated. Inhibition can serve to enhance both the spectral and temporal processing of sound attributes that are important for sound identification and localization as well as speech processing. Our studies have revealed that the time course of inhibition, even from a single source, is different in the two principal cell types, the bushy and stellate cells.
The first aim of this proposal is to clarify the functional synaptic organization of two local inhibitory synaptic circuits in the VCN.
The second aim i s to test the hypothesis that the synaptic currents on different cell types are mediated by different glycine receptor subunits. We will also investigate the presynaptic mechanisms that regulate the time course of release during sustained activity.
The third aim i s to incorporate this information into a detailed computational model, which will be used to explore the importance of different aspects of inhibition in temporal and spectral processing in the VCN.
The fourth aim i s to determine how the function of these inhibitory circuits is affected by hearing loss. All of these experiments will be performed in brain slices of adult mice. Overall, our studies will identify critical mechanisms in early auditory information processing, and determine how those mechanisms contribute to the analysis of complex sounds. We will then determine how these mechanisms are affected by hearing loss, which will provide insights for alternative stimulation strategies for the hard-of-hearing and for cochlear implant users. The neural mechanisms of sensory processing in the brain underlie our normal perceptual abilities, including the identification of sound sources and the ability to communicate through sound. These mechanisms are changed by damage to the sensory organs, and consequently, residual perceptual abilities are often adversely affected. In this project, we seek to understand the functional synaptic organization and the underlying mechanisms that contribute to hearing at early stages of the auditory pathway. We will also determine how these basic mechanisms are affected by hearing loss, and how hearing loss affects higher-order sensory processing in the brain. These experiments will ultimately generate insights for alternative stimulation strategies for the hard-of-hearing, and for cochlear implant users.

Public Health Relevance

The neural mechanisms of sensory processing in the brain underlie our normal perceptual abilities, includ- ing the identification of sound sources and the ability to communicate through sound. These mechanisms are changed by damage to the sensory organs, and consequently, residual perceptual abilities are often adversely affected. In this project, we seek to understand the functional synaptic organization and the underlying mech- anisms that contribute to hearing at early stages of the auditory pathway. We will also determine how these basic mechanisms are affected by hearing loss, and how hearing loss affects higher-order sensory processing in the brain. These experiments will ultimately generate insights for alternative stimulation strategies for the hard-of-hearing, and for cochlear implant users.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC004551-13
Application #
8443852
Study Section
Auditory System Study Section (AUD)
Program Officer
Cyr, Janet
Project Start
2000-09-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
13
Fiscal Year
2013
Total Cost
$284,829
Indirect Cost
$91,368
Name
University of North Carolina Chapel Hill
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Liu, Qing; Manis, Paul B; Davis, Robin L (2014) I h and HCN channels in murine spiral ganglion neurons: tonotopic variation, local heterogeneity, and kinetic model. J Assoc Res Otolaryngol 15:585-99
Campagnola, Luke; Manis, Paul B (2014) A map of functional synaptic connectivity in the mouse anteroventral cochlear nucleus. J Neurosci 34:2214-30
Campagnola, Luke; Kratz, Megan B; Manis, Paul B (2014) ACQ4: an open-source software platform for data acquisition and analysis in neurophysiology research. Front Neuroinform 8:3
Xie, Ruili; Manis, Paul B (2014) GABAergic and glycinergic inhibitory synaptic transmission in the ventral cochlear nucleus studied in VGAT channelrhodopsin-2 mice. Front Neural Circuits 8:84
Xie, Ruili; Manis, Paul B (2013) Target-specific IPSC kinetics promote temporal processing in auditory parallel pathways. J Neurosci 33:1598-614
Xie, Ruili; Manis, Paul B (2013) Glycinergic synaptic transmission in the cochlear nucleus of mice with normal hearing and age-related hearing loss. J Neurophysiol 110:1848-59
Wang, Yong; O'Donohue, Heather; Manis, Paul (2011) Short-term plasticity and auditory processing in the ventral cochlear nucleus of normal and hearing-impaired animals. Hear Res 279:131-9
Rich, Alexander W; Xie, Ruili; Manis, Paul B (2010) Hearing loss alters quantal release at cochlear nucleus stellate cells. Laryngoscope 120:2047-53
Wang, Yong; Manis, Paul B (2008) Short-term synaptic depression and recovery at the mature mammalian endbulb of Held synapse in mice. J Neurophysiol 100:1255-64
Spirou, G A; Chirila, F V; von Gersdorff, H et al. (2008) Heterogeneous Ca2+ influx along the adult calyx of held: a structural and computational study. Neuroscience 154:171-85

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