Fast, time-varying features of sound are essential for humans and other mammals for localizing sound sources as well interpreting speech and communication calls. The broad goal of this research is both to understand how these features are processed in the brain, as well as to understand how neurons in auditory circuits acquire the appropriate biophysical properties during development to carry out these computations. This proposal focuses on the medial superior olive (MSO), the first and critical stage for processing interaural time differences (ITDs) from the two ears, cues that are used for localizing sounds along the horizontal plane. In the MSO, ITDs are computed and conveyed through the process of coincidence detection, by which excitatory inputs from the two ears are segregated onto different branches of a bipolar dendritic arbor and sum at the soma with submillisecond time resolution. Thus an understanding of how sound localization cues are processed in the MSO in turn requires knowledge of how the timing and strength of synaptic inputs are controlled in the two sets of dendrites. This proposal will investigate the hypothesis that the development of fast time-processing capabilities in MSO neurons is not preprogrammed, but is driven after hearing onset by synaptic and firing activity. We will explore this hypothesis by combining dendritic patch recordings, 2-photon and wide-field calcium imaging and anatomical techniques.
Aim 1 will examine the characteristics and role of the axon initial segment in shaping firing characteristics during development.
Aim 2 will examine how synaptic activity is translated into increasing intrinsic neuronal precision, via changes in hyperpolarization-activated cation channels, and Aim 3 will reveal the spatial pattern of excitatory synapse strength along MSO dendrites and whether this pattern is altered during the course of early auditory experience. The information from these experiments is important not only for understanding basic mechanisms of mammalian hearing but also for understanding how alterations of normal auditory development (e.g. via hearing deficits or deafness) shape the function of auditory circuits and how these circuits respond to the reintroduction of auditory activity via auditory prostheses.

Public Health Relevance

In the medial superior olive, the encoding of sound localization cues and speech signals depends critically on the development of intrinsic membrane properties that are both fast and precise. A mechanistic understanding of how these properties are governed by early auditory experience is thus important for understanding how the brain is affected by hearing loss, deafness, and the introduction of auditory prosthetic devices.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Auditory System Study Section (AUD)
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Platt, Christopher
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University of Texas Austin
Schools of Arts and Sciences
United States
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Winters, Bradley D; Jin, Shan-Xue; Ledford, Kenneth R et al. (2017) Amplitude Normalization of Dendritic EPSPs at the Soma of Binaural Coincidence Detector Neurons of the Medial Superior Olive. J Neurosci 37:3138-3149
Ko, Kwang Woo; Rasband, Matthew N; Meseguer, Victor et al. (2016) Serotonin modulates spike probability in the axon initial segment through HCN channels. Nat Neurosci 19:826-34
Franken, Tom P; Roberts, Michael T; Wei, Liting et al. (2015) In vivo coincidence detection in mammalian sound localization generates phase delays. Nat Neurosci 18:444-52
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van der Heijden, Marcel; Lorteije, Jeannette A M; Plauska, Andrius et al. (2013) Directional hearing by linear summation of binaural inputs at the medial superior olive. Neuron 78:936-48
Roberts, Michael T; Seeman, Stephanie C; Golding, Nace L (2013) A mechanistic understanding of the role of feedforward inhibition in the mammalian sound localization circuitry. Neuron 78:923-35
Khurana, Sukant; Liu, Zhiqiang; Lewis, Alan S et al. (2012) An essential role for modulation of hyperpolarization-activated current in the development of binaural temporal precision. J Neurosci 32:2814-23
Khurana, Sukant; Remme, Michiel W H; Rinzel, John et al. (2011) Dynamic interaction of Ih and IK-LVA during trains of synaptic potentials in principal neurons of the medial superior olive. J Neurosci 31:8936-47
Mathews, Paul J; Jercog, Pablo E; Rinzel, John et al. (2010) Control of submillisecond synaptic timing in binaural coincidence detectors by K(v)1 channels. Nat Neurosci 13:601-9
Scott, Luisa L; Mathews, Paul J; Golding, Nace L (2010) Perisomatic voltage-gated sodium channels actively maintain linear synaptic integration in principal neurons of the medial superior olive. J Neurosci 30:2039-50

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