Mice with behavioral evidence of tinnitus exhibit dorsal cochlear nucleus hyperactivity because of decreased GABAergic inhibition

TLDR

Tinnitus is linked to heightened spontaneous and evoked activity, increased neural synchrony, and tonotopic map reorganization, yet the neurotransmitter systems driving these changes remain poorly understood. We developed an in vitro assay to dissect how excitation and inhibition shape the neural correlates of tinnitus. Using flavoprotein autofluorescence imaging, we recorded evoked activity in dorsal cochlear nucleus slices after electrical stimulation of glutamatergic axons. Tinnitus mice exhibited larger, more spatially spread evoked responses, and GABAergic inhibition blockade amplified responses more in controls than tinnitus, indicating that reduced GABAergic inhibition underlies the heightened, distributed activity seen in tinnitus circuits.

Abstract

Tinnitus has been associated with increased spontaneous and evoked activity, increased neural synchrony, and reorganization of tonotopic maps of auditory nuclei. However, the neurotransmitter systems mediating these changes are poorly understood. Here, we developed an in vitro assay that allows us to evaluate the roles of excitation and inhibition in determining the neural correlates of tinnitus. To measure the magnitude and spatial spread of evoked circuit activity, we used flavoprotein autofluorescence (FA) imaging, a metabolic indicator of neuronal activity. We measured FA responses after electrical stimulation of glutamatergic axons in slices containing the dorsal cochlear nucleus, an auditory brainstem nucleus hypothesized to be crucial in the triggering and modulation of tinnitus. FA imaging in dorsal cochlear nucleus brain slices from mice with behavioral evidence of tinnitus (tinnitus mice) revealed enhanced evoked FA response at the site of stimulation and enhanced spatial propagation of FA response to surrounding sites. Blockers of GABAergic inhibition enhanced FA response to a greater extent in control mice than in tinnitus mice. Blockers of excitation decreased FA response to a similar extent in tinnitus and control mice. These findings indicate that auditory circuits in mice with behavioral evidence of tinnitus respond to stimuli in a more robust and spatially distributed manner because of a decrease in GABAergic inhibition.