Our long-term goal is to understand the changes in the brain after an injury to the adult auditory system consisting of the ablation of one cochlea and sensorineural hearing loss. This injury initially destroyed the cochlear nerve, which carried cochlear excitation into the brain. Subsequently, the injury induced growth of new synapses, changes of synaptic strengths, and axonal and synaptic pruning in brain stem auditory nuclei. Since these plasticities may produce pathologic symptoms, such as tinnitus, rehabilitating the system after injury could depend on control of the mechanisms underlying plasticity. Because plastic changes and the mechanisms which generate them are poorly understood, we wish to identify more plastic changes, the signals that induce them, and the biochemical transduction pathways that link the signals to the plasticities. First, we will study synaptic rearrangements in the young adult guinea pig superior olive after cochlear ablation, using histological methods. Next, using neurochemical methods, we will study the auditory brain stem nuclei of adult guinea pigs, including the subdivisions of the cochlear nucleus, the nuclei of the superior olive, and the inferior colliculus. We will evaluate candidate signals, such as altered synaptic excitation, altered, neurotrophic support, and injury, each transduced through distinct second messenger pathways. We will determine if protein kinases, employed by second messenger pathways that transduce synaptic excitation and neuronal depolarization, can regulate synaptic activities in the brain stem auditory nuclei. We will also determine if protein kinases are involved in changes of synaptic strength after cochlear ablation. We will determine if neurotrophic support is available and can regulate synaptic activities in the brain stem auditory nuclei, if it is altered after cochlear ablation, and if it is involved in postlesion changes of synaptic strength. We will determine if transduction of altered neuronal excitation and neurotrophic support regulate nuclear factors that may induce plasticity through regulation of gene expression. Finally, we will determine if cochlear ablation activates second messenger pathways that transduce signals of injury to regulate nuclear factors that may change gene expression and induce degenerative pruning.
