Diagnosis of central hearing disorders is in a primitive state largely because of our limited understanding of the central auditory system. Probably many central auditory disorders have yet to even be described. Foundational for the function of any part of the brain is its chemistry. Both medical and illicit drug use have demonstrated that chemical imbalances can dramatically affect behavior. Chemical imbalances in the central auditory pathways would be expected to result in faulty processing of information about the sound environment and might manifest themselves, not as hearing loss, but as distorted hearing, including perception of sounds not actually present (e.g., tinnitus or hallucinations) or misinterpretation of environmental sounds. Many chemical imbalances that affect behavior involve communication between neurons, which has been found to involve chemical transmitters at virtually all synapses in mammals. This proposal is part of a long-range effort to understand the chemistry of the cochlear nucleus, the first brain center of the auditory system. Transmitter chemistry will be emphasized, especially that of acetylcholine, which is well-established in centrifugal, or efferent pathways, including that to the inner ear, and the amino acids aspartate, glutamate, glycine and gamma-aminobutyrate, which may be the most prominent transmitters in the brain. Our recent studies on the dorsal cochlear nucleus in brain slices have particularly implicated a neural circuit involving the granule cells in spontaneous activity of many neurons. Granule cells appear from anatomical studies to receive converging input from many sources. Their output projects as unmyelinated parallel fibers to the molecular layer of the dorsal cochlear nucleus, to especially influence cartwheel cells, which in turn influence the activity of the major output neurons of the dorsal cochlear nucleus, fusiform cells. We are able to study many aspects of this circuit in our brain slice preparation and propose experiments to further delineate its neurochemistry and pharmacology in slices from both control rats and from rats with lesions removing some of the inputs to circuit elements. Further studies are proposed to characterize the chemistry of the incubated slices and document the extent of differences from the in vivo state. We also want to apply what we have learned from slices to study the effects of cholinergic drugs on the physiology of fusiform and cartwheel cells in vivo. Proposed histochemical experiments are directed toward more detailed delineation of the cholinergic inputs to the cochlear nucleus, particularly its dorsal subdivision, using molecular biology and electron microscopy techniques.