The mechanisms responsible for chronic tinnitus are poorly understood. Currently there are no interventions that are effective in reducing or permanently eliminating tinnitus, a disorder that significantly degrades the quality of life for an estimated 7 million people. The goal of the proposed research is to identify the brain areas and pathological processes responsible for the development and persistence of chronic tinnitus, using an animal model. Recent work in our laboratory has shown that chronic tinnitus is associated with increased activity in the auditory brainstem and the cerebellum. Areas with significantly altered activity were the cochlear nucleus (CN), the inferior colliculus (IC), and the paraflocculus (PF) of the cerebellum. Particularly intriguing was that the enhanced activity in the PF was restricted to subjects with tinnitus, whereas enhanced activity in the CN and IC was also evident in normal subjects listening to an external source of a tinnitus-like sound. A working hypothesis for these observations is that peripheral auditory insults alter functional activity in focal brain areas and produce enhanced spontaneous activity that is perceived as tinnitus. Enhanced activity may emerge because ?-amino butyric acid (GABA)-mediated inhibition is downregulated, and this process may be driven by glutamate-mediated neuroplasticity. The proposed experiments will test these hypotheses by combining a functional imaging technique, manganese enhanced magnetic resonance imaging (MEMRI), with volume-localized proton magnetic resonance spectroscopy (1H-MRS). Psychophysical evidence of tinnitus will be established in rats using a method shown to be effective in discriminating animals with tinnitus from animals without tinnitus. The brains of rats, with and without tinnitus, will be compared using MEMRI. MEMRI will identify brain areas that have enhanced spontaneous activity, using high resolution imaging techniques. In the same animals, the identified areas will be examined using H-MRS. Spectra will be determined for the 1 inhibitory neurotransmitter GABA, and the excitatory neurotransmitter glutamic acid (Glu). The spectra will be used to determine tissue concentrations, enabling inferential conclusions regarding the up- and down- regulation of these transmitters. Comparison of transmitter function in each area of interest (AOI) will be used to confirm or modify the working hypotheses about the pathological processes at work. For example, elevated Glu and decreased GABA in an AOI would support the working hypothesis regarding pathological plasticity in the AOI. Since the preceding data are associational, follow-up ablation experiments will be used to determine the causal connection between an AOI and tinnitus. In these experiments, a specific AOI will be ablated either before or after tinnitus induction. Ablations before induction will enable conclusions to be drawn about tinnitus trigger zones while ablations after induction will enable conclusions to be drawn about tinnitus generator sites. AOI ablation should decrease tinnitus, if dysfunction in that area is necessary for tinnitus. Based on existing data, the dorsal cochlear nucleus and the PF will be targeted in initial ablation experiments. Relevance: Tinnitus is the perception of a sound when there is no external sound. Fifteen million adults in the U.S. describe their tinnitus as bothersome, and seven million have severe disabling tinnitus that degrades their quality of life and interferes with daily activities. Currently there are no interventions that are either generally effective or permanently eliminate tinnitus. The goal of the proposed research is to understand processes in the brain responsible for the development and persistence of chronic tinnitus, using an animal model and biomedical imaging technology. The benefit of the proposed studies is that they will identify brain areas and pathological processes that may then be targeted for therapeutic intervention.