The dorsal cochlear nucleus (DCN) is a site for rapid and early processing of spectrally complex sounds, and is the first point in the auditory system where auditory and non-auditory information converges. Increased spontaneous activity in the DCN after hearing loss has also been associated with tinnitus. Increased electrical excitability or decreased inhibition could lead to increased activity of DCN neurons, are thus potential mechanisms for tinnitus. While the responses of DCN principal neurons (pyramidal cells) to sound are strongly molded by inhibition, little is known about the functional operation of the major inhibitory networks. The goals of this proposal are to investigate inhibitory circuits in the DCN, and to elucidate their roles in normal sensory processing as well as in auditory dysfunction. In the first aim, we will study the organization and synaptic dynamics of local inhibitory circuits in the DCN, using paired whole-cell recording. We will test whether the synaptic influence of the most populous inhibitory interneurons, the cartwheel cells, depends on the target cell type, and whether cartwheel cells can fire in a synchronized manner as predicted from their physiology and connections. We will test hypotheses about the spatial organization of cartwheel cell axons to determine whether this system, which receives non-tonotopic inputs, might operate in a tonotopic fashion. These experiments will include morphological reconstruction of cell pairs to elucidate the spatial organization of connections. In the second aim, we will investigate short and long-term synaptic plasticity at inhibitory synapses in the DCN. We will test whether cartwheel cells utilize glycine and GABA as co-transmitters onto the pyramidal cells and other cartwheel cells, and whether there is activity-dependent short-term modulation of inhibitory synapses. Long-term synaptic plasticity is present at the excitatory parallel fiber synapses onto pyramidal and cartwheel cells. We will test whether the inhibitory synapses from cartwheel to pyramidal cells, and between cartwheel cells, exhibit similar activity-dependent plastic changes. In the third aim, we will use our experimental data to create a biologically accurate circuit model of the DCN. We will use this model to test predictions about how changes in synaptic function associated with hearing loss can affect the output of the nucleus. In the fourth aim, we will test the hypotheses that central tinnitus produced by acoustic trauma is associated with decreases in inhibitory synaptic strength, or whether it is associated with increased intrinsic electrical excitability. Tinnitus is a phenomenon that affects nearly 20% of people in the U.S., and which is debilitating to nearly 2 million citizens. There is a significant unmet medical need for effective treatments. Our experiments will directly evaluate specific synaptic systems and receptors that can be targeted for pharmacological intervention for treatment and cure of this persistent problem. ? ? ?
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