Hearing using 2 ears allows the extraction of sound timing information that animals, including humans, use to localize sounds in space and comprehend communication signals in complicated auditory environments. Understanding how the binaural hearing system develops is critical for implementing treatments for individuals with impairments. The medial superior olive (MSO) nucleus in the brainstem of mammals houses one of the first stages of processing combined information from both ears. MSO neurons enable detection of extremely minute timing differences between the arrivals of sounds at the 2 ears by responding maximally to binaural excitation at specific interaural time differences (ITDs). Glycinergic inhibitory inputs onto MSO neurons are critical for shaping their ITD responses. Prior to hearing onset, supernumerary inhibitory inputs are evenly distributed over the dendrites and soma of MSO neurons. After hearing onset, inhibition is dramatically refined. Most of the inhibitory inputs are pruned and those that remain are well timed with binaural excitation and concentrated onto the soma. Despite the relevance to the functioning of this important circuit, almost nothing is known about the cellular mechanisms that guide refinement of inhibition in the MSO. Synaptic plasticity is likely to be the key to maintaining a specific set of synapses in an experience-dependent process. The work proposed here seeks to understand inhibitory synaptic plasticity in the MSO and how it contributes to the development of inhibitory drive after hearing onset. This project utilizes electrophysiological and calcium imaging techniques in acute brain slices from Mongolian gerbils combined with in vivo manipulation of binaural auditory experience.
Aim 1 will reveal mechanisms of synaptic plasticity that guide the strengthening and synchronization of inhibitory drive with binaural excitation in the MSO. Preliminary results suggest a model of N-methyl D-aspartate receptor (NMDAR)- dependent inhibitory long-term potentiation (iLTP) in the MSO in which glutamate, either co-released with glycine or through spillover from adjacent excitatory inputs, binds NMDARs and action potential (AP)-driven depolarization from binaural excitatory drive relieves the magnesium block. The locus of NMDAR activation and source of glutamate will be determined.
Aim 2 seeks to understand what guides the developmental concentration of inhibitory inputs onto the soma of MSO neurons. Over the first 2 weeks of hearing, changes to intrinsic membrane properties of MSO neurons reduce the invasion of AP depolarization into the dendrites. My hypothesis is that inhibitory synapses in the dendrites progressively do not receive sufficient depolarization for iLTP and without this continued reinforcement are selectively pruned. To test this hypothesis, I will rear animals in omnidirectional noise, a manipulation known to disrupt binaural cues. Then I will determine whether iLTP, intrinsic changes, and somatic segregation of inhibition are retarded. Together, this work will give us a deeper understanding of the experience-dependent developmental refinement of inhibition in this important center for processing of binaural cues.
Humans and other mammals use the relative arrival time of sounds at the 2 ears to help us understand speech in complicated auditory environments and localize sounds in space. Inhibitory synaptic drive is a critical component of the system that extracts sound timing information, however, very little is known about how this inhibition is refined by auditory experience. This project seeks to reveal the cellular mechanisms of how experience- dependent inhibitory synaptic plasticity governs normal development of inhibitory drive in an important brainstem nucleus for the extraction of sound localization cues.
| Winters, Bradley D; Golding, Nace L (2018) Glycinergic Inhibitory Plasticity in Binaural Neurons Is Cumulative and Gated by Developmental Changes in Action Potential Backpropagation. Neuron 98:166-178.e2 |
| 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 |
