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

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.

SUBMITTER: Middleton JW

PROVIDER: S-EPMC3088638 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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

Middleton Jason W JW Kiritani Taro T Pedersen Courtney C Turner Jeremy G JG Shepherd Gordon M G GM Tzounopoulos Thanos T

Proceedings of the National Academy of Sciences of the United States of America 20110418 18

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 autoflu ...[more]

PMID: 21502491

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Project description:One of the primary theories of the pathogenesis of tinnitus involves maladaptive auditory?somatosensory plasticity in the dorsal cochlear nucleus (DCN), which is assumed to be due to axonal sprouting. Although a disrupted balance between auditory and somatosensory inputs may occur following hearing damage and may induce tinnitus, examination of this phenomenon employed a model of hearing damage that does not account for the causal relationship between these changes and tinnitus. The present study aimed to investigate changes in auditory?somatosensory innervation and the role that axonal sprouting serves in this process by comparing results between animals with and without tinnitus. Rats were exposed to a noise?inducing temporary threshold shift and were subsequently divided into tinnitus and non?tinnitus groups based on the results of gap prepulse inhibition of the acoustic startle reflex. DCNs were collected from rats divided into three sub?groups according to the number of weeks (1, 2 or 3) following noise exposure, and the protein levels of vesicular glutamate transporter 1 (VGLUT1), which is associated with auditory input to the DCN, and VGLUT2, which is in turn primarily associated with somatosensory inputs, were assessed. In addition, factors related to axonal sprouting, including growth?associated protein 43 (GAP43), postsynaptic density protein 95, synaptophysin, ??thalassemia/mental retardation syndrome X?linked homolog (ATRX), growth differentiation factor 10 (GDF10), and leucine?rich repeat and immunoglobulin domain?containing 1, were measured by western blot analyses. Compared to the non?tinnitus group, the tinnitus group exhibited a significant decrease in VGLUT1 at 1 week and a significant increase in VGLUT2 at 3 weeks post?exposure. In addition, rats in the tinnitus group exhibited significant increases in GAP43 and GDF10 protein expression levels in their DCN at 3 weeks following noise exposure. Results from the present study provided further evidence that changes in the neural input distribution to the DCN may cause tinnitus and that axonal sprouting underlies these alterations.

Project description:In nonprimate mammals, the dorsal cochlear nucleus (DCN) is thought to play a role in the orientation of the head toward sounds of interest by integrating acoustic and somatosensory information. Humans and higher primates might not use this system because of reported phylogenetic changes in DCN cytoarchitecture [Moskowitz N (1969) Comparative aspects of some features of the central auditory system of primates. Ann N Y Acad Sci 167:357-369; Moore JK, Osen KK (1979) The cochlear nuclei in man. Am J Anat 154:393-418; Moore JK (1980) The primate cochlear nuclei: loss of lamination as a phylogenetic process. J Comp Neurol 193:609-629]. In this study, we re-evaluated this question from a comparative perspective and examined the rhesus monkey (cercopithecoid primate) using more sensitive probes and higher resolution imaging methods. We used electron microscopy to identify parallel fibers and their synapses, and molecular markers to determine that primates exhibit the main components of excitatory neurotransmission as other mammals. We observed that characteristics of the monkey molecular layer resembled what has been reported for nonprimates: (1) immunohistochemistry revealed many unmyelinated, thin axons and en passant glutamatergic synapses on dendritic spines; (2) immunohistochemistry for phosphodiesterase (PDE10A) showed the nuclei of granule cells distributed in the external molecular layer and the deep layers in the DCN; (3) antibodies for the inositol trisphosphate receptor (IP3r) and calbindin immunostained cartwheel cells; (4) postembedding immunogold labeling revealed synaptic expression of AMPA and delta glutamate receptor subunits on spines in parallel fiber endings; and (5) parallel fibers use vesicular glutamate transporter 1 (VGLUT1) to package glutamate into the synaptic vesicles and to mediate glutamate transport. These observations are consistent with the argument that the rhesus monkey DCN has neuronal features similar to those of other nonprimate mammals.

Project description:The dorsal cochlear nucleus (DCN) receives afferent input from the auditory nerve and is thus usually thought of as a monaural nucleus, but it also receives inputs from the contralateral cochlear nucleus as well as descending projections from binaural nuclei. Evidence suggests that some of these commissural and efferent projections are excitatory, whereas others are inhibitory. The goals of this study were to investigate the nature and effects of these inputs in the DCN by measuring DCN principal cell (type IV unit) responses to a variety of contralateral monaural and binaural stimuli. As expected, the results of contralateral stimulation demonstrate a mixture of excitatory and inhibitory influences, although inhibitory effects predominate. Most type IV units are weakly, if at all, inhibited by tones but are strongly inhibited by broadband noise (BBN). The inhibition evoked by BBN is also low threshold and short latency. This inhibition is abolished and excitation is revealed when strychnine, a glycine-receptor antagonist, is applied to the DCN; application of bicuculline, a GABAA-receptor antagonist, has similar effects but does not block the onset of inhibition. Manipulations of discrete fiber bundles suggest that the inhibitory, but not excitatory, inputs to DCN principal cells enter the DCN via its output pathway, and that the short latency inhibition is carried by commissural axons. Consistent with their respective monaural effects, responses to binaural tones as a function of interaural level difference are essentially the same as responses to ipsilateral tones, whereas binaural BBN responses decrease with increasing contralateral level. In comparison to monaural responses, binaural responses to virtual space stimuli show enhanced sensitivity to the elevation of a sound source in ipsilateral space but reduced sensitivity in contralateral space. These results show that the contralateral inputs to the DCN are functionally relevant in natural listening conditions, and that one role of these inputs is to enhance DCN processing of spectral sound localization cues produced by the pinna.

Dataset Information

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

Publications

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

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