Neurons and neural circuits in the cochlear nuclei are on the front line of auditory information processing. The CN receives a stereotyped representation of sound in the form of spike trains from the auditory nerve (AN), and produces highly modified parallel representations that drive the ascending auditory pathways. Traditionally, the cochlear nuclei are viewed as consisting of three major regions containing distinct populations of projection neurons that each emphasize different aspects of information about the acoustic environment in a parallel, but largely independent, fashion. However, coordinated spiking between output pathways can aid in the reconstruction of auditory objects and the detection of signals in noise by providing temporal cues that contribute to integration in higher auditory neurons. Our overarching hypothesis is that the relative spike timing between these pathways is coordinated not only by features in the acoustic stimulus, but importantly by shared local excitatory and inhibitory circuits, implying that the pathways are not independent. Coordinated activity may aid in the reconstruction of auditory objects and the detection of signals in noise by providing temporal coherence of activity across cells that can be integrated when these pathways converge onto higher auditory neurons. Yet, how the local circuits contribute to processing and their connectivity with other cells in the cochlear nuclei are only partially understood. In this proposal, we address how the output pathways of the cochlear nuclei can be coordinated through local circuits. The first stage of the work takes place in the context of normal hearing, and examines hypotheses about the functional synaptic connectivity of three cell types in the cochlear nuclei with the principal neurons and with each other, using optogenetic techniques and targeted patch clamp recording in brain slices form mice. The second stage incorporates the spatial structure of these circuits and the temporal dynamics of their synapses into a network model to evaluate how the activity between and within the output pathways is structured by the local circuits. We will then test predictions from the model with in vivo single unit studies. The finals stage considers the effects of a high-frequency noise-induced hearing loss on the functional organization of the CN circuit to determine how excitatory and inhibitory balance is altered. The rationale of the proposed research is that the successful restoration of function with cochlear implants or hearing aids depends on the ability to optimally engage the functional network architecture of the cochlear nucleus, which in turn requires an understanding of how information is integrated in the cochlear nuclei and how the output activity is coordinated by the local networks.

Public Health Relevance

The neural mechanisms of sensory processing in the brain underlie our normal perceptual abilities, which in hearing include the detection and identification of sound sources and the ability to communicate through sound. The central neural mechanisms change in response to damage to the sensory organs. Consequently residual perceptual abilities, which rely on delicate patterns of activity in the neurons, are often adversey affected. In this project, we seek to understand the functional neural circuits and their collaborative roles in processing sound in the 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.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Study Section
Auditory System Study Section (AUD)
Program Officer
Cyr, Janet
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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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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