The central auditory system exhibits a remarkable ability to extract information from a limited representation of the acoustic environment provided by the auditory nerve. Auditory information is first analyzed in the cochlear nucleus, where auditory nerve spike trains are transformed to create a set of parallel ascending pathways that emphasize different aspects of the acoustic environment. These transformations play essential roles in determining the source of a sound and in auditory communication. Recent studies have shown that the cellular mechanisms underlying neural integration in the cochlear nucleus are altered by hearing loss. In this proposal, we will investigate the integrative mechanisms of anterior ventral cochlear nucleus (AVCN) bushy neurons in normal animals, and in animals experiencing chronic hearing loss. We propose 3 aims. In the first aim, we will test explicit hypotheses about the subthreshold integrative mechanisms of AVCN bushy neurons using in vitro methods and dynamic clamp to apply realistic patterns of synaptic conductance changes that represent the activity expected with acoustic stimulation. We will test hypotheses about how the potassium conductances contribute to integration of synaptic inputs. We will also evaluate how tonotopic gradients of ion channel expression affect integration. In the second aim, we will test the hypothesis that the two primary sources of inhibition to bushy cells utilize synapses with different release properties and temporal dynamics. We will test whether inhibition is necessary to improve temporal fidelity of timing information, and whether inhibition helps to provide a sparse code to more central synapses. We will also document the organization of the functional circuitry within the AVCN through paired recordings between inhibitory interneurons and principal neurons. In the third aim, we will examine synaptic transmission at both excitatory and inhibitory synaptic inputs in a mouse model of hearing loss. We will test the hypothesis that hearing loss causes the postsynaptic receptors to return to an immature state. We will characterize the synaptic conductances and dynamics of neurons experiencing hearing loss. Finally, we will also investigate the more speculative hypothesis that there are compensatory changes in nicotinic cholinergic receptor function in the AVCN, since there is evidence that innervation of the cochlear nucleus by cholinergic afferents may be increased after profound hearing loss. These experiments will help us understand how information is processed in the central auditory system under normal hearing conditions, and will shed light on functional and cellular changes in central processing that occur in hearing loss and deafness. Understanding these dynamic changes is an essential step toward developing compensatory or corrective strategies to restore hearing and optimize auditory communication in the face of hair cell and ganglion cell loss ? ? ?
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