The neurons of the lateral superior olive (LSO) in the auditory brainstem receive sound information from both ears. Inputs from the ipsilateral ear are via the cochlear nucleus, which gives rise to an excitatory, glutamatergic projection to the LSO. Inputs from the contralateral ear project to the contralateral cochlear nucleus, then through the medial nucleus of the trapezoid body (MNTB), a group of neurons that convert the glutamatergic signal to an inhibitory, glycinergic projection. The combination of inputs from the two ears determines the ability of LSO neurons to compute the location of sound in space around the head. Early in development the MNTB neurons also release the neurotransmitters GABA and glutamate. The purpose of these neurotransmitters in the proper structural development of neurons from the two ears is not very well understood. If glutamate is absent from the MNTB neurons, it has been shown that there is an improper refinement of patterns of neurons from the two ears that encode the same frequency onto a single LSO neuron. Less is known about the function of GABA in these synapses, but it has been shown that GABA release can cause a calcium rise in the LSO neurons, which may be important for formation of synapses between the neurons. This proposal aims to study the role of GABA in development of the projections from the MNTB to the LSO. Experiments will be performed in brain slices from mice containing both MNTB neurons and their projections to LSO neurons. Techniques will include whole-cell electrophysiology and 2-photon imaging to measure the patterns of activity in neurons when GABA signaling is altered pharmacologically. Tools including fluorescent dyes that measure changes in calcium signaling (indicative of cellular activity) and 'optogenetic'tools that allow stimulation of individual neurons using laser light will be used. The proposal also includes electron microscopy experiments to investigate the subcellular structures at the synapses between MNTB and LSO neurons in order to measure how GABA receptors are involved in the proper formation of synapses between the MNTB and LSO. This research will also have implications for investigation of GABA signaling in other brain regions. Research into the proper formation of neuronal circuits that encode sound localization is crucial for a greater understanding of hearing, both in animals and in humans. Understanding how neurons properly connect in developmental stages guides understanding of what can go wrong in situations in which normal hearing is compromised through aberrant development or through injury. A full understanding of the complexity of the perception of sound will guide refined therapies for treatment of hearing disorders.

Public Health Relevance

The neurons of the lateral superior olive (LSO) in the brainstem receive information from the two ears, which allows them to compute the location from which sound originates in space. This requires very precise patterning of inputs from neurons from the two ears. Study of the development of these patterns and the neurotransmitters involved is important for determining how normal hearing occurs, and in identification of potential targets for therapeutics in cases in which hearing is impaired due to genetics, disease, or injury.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZDC1-SRB-R (38))
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Sklare, Dan
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University of Pittsburgh
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Weisz, Catherine J C; Rubio, Maria E; Givens, Richard S et al. (2016) Excitation by Axon Terminal GABA Spillover in a Sound Localization Circuit. J Neurosci 36:911-25
Sturm, Joshua J; Weisz, Catherine J C (2015) Hyperactivity in the medial olivocochlear efferent system is a common feature of tinnitus and hyperacusis in humans. J Neurophysiol 114:2551-4