The central auditory system exhibits a remarkable ability to extract information from a limited representation of the acoustic environment provided by the auditory nerve. Auditory information is first analyzed in the cochlear nucleus, where auditory nerve spike trains are transformed to create a set of parallel ascending pathways that emphasize different aspects of the acoustic environment. These transformations play essential roles in determining the source of a sound and in auditory communication. Recent studies have shown that the cellular mechanisms underlying neural integration in the cochlear nucleus are altered by hearing loss. In this proposal, we will investigate the integrative mechanisms of anterior ventral cochlear nucleus (AVCN) bushy neurons in normal animals, and in animals experiencing chronic hearing loss. We propose 3 aims. In the first aim, we will test explicit hypotheses about the subthreshold integrative mechanisms of AVCN bushy neurons using in vitro methods and dynamic clamp to apply realistic patterns of synaptic conductance changes that represent the activity expected with acoustic stimulation. We will test hypotheses about how the potassium conductances contribute to integration of synaptic inputs. We will also evaluate how tonotopic gradients of ion channel expression affect integration. In the second aim, we will test the hypothesis that the two primary sources of inhibition to bushy cells utilize synapses with different release properties and temporal dynamics. We will test whether inhibition is necessary to improve temporal fidelity of timing information, and whether inhibition helps to provide a sparse code to more central synapses. We will also document the organization of the functional circuitry within the AVCN through paired recordings between inhibitory interneurons and principal neurons. In the third aim, we will examine synaptic transmission at both excitatory and inhibitory synaptic inputs in a mouse model of hearing loss. We will test the hypothesis that hearing loss causes the postsynaptic receptors to return to an immature state. We will characterize the synaptic conductances and dynamics of neurons experiencing hearing loss. Finally, we will also investigate the more speculative hypothesis that there are compensatory changes in nicotinic cholinergic receptor function in the AVCN, since there is evidence that innervation of the cochlear nucleus by cholinergic afferents may be increased after profound hearing loss. These experiments will help us understand how information is processed in the central auditory system under normal hearing conditions, and will shed light on functional and cellular changes in central processing that occur in hearing loss and deafness. Understanding these dynamic changes is an essential step toward developing compensatory or corrective strategies to restore hearing and optimize auditory communication in the face of hair cell and ganglion cell loss ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC004551-07
Application #
7201637
Study Section
Auditory System Study Section (AUD)
Program Officer
Miller, Roger
Project Start
2000-09-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
7
Fiscal Year
2007
Total Cost
$304,150
Indirect Cost
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
Manis, Paul B; Campagnola, Luke (2018) A biophysical modelling platform of the cochlear nucleus and other auditory circuits: From channels to networks. Hear Res 360:76-91
Xie, Ruili; Manis, Paul B (2017) Synaptic transmission at the endbulb of Held deteriorates during age-related hearing loss. J Physiol 595:919-934
Xie, Ruili; Manis, Paul B (2017) Radiate and Planar Multipolar Neurons of the Mouse Anteroventral Cochlear Nucleus: Intrinsic Excitability and Characterization of their Auditory Nerve Input. Front Neural Circuits 11:77
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
Campagnola, Luke; Manis, Paul B (2014) A map of functional synaptic connectivity in the mouse anteroventral cochlear nucleus. J Neurosci 34:2214-30
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
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
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

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