Short communicationGlutamic acid decarboxylase levels in the cochlear nucleus of rats with acoustic trauma-induced chronic tinnitus
Introduction
Tinnitus is the perception of phantom sound, often described as a “ringing in the ears” [2]. Although many people experience tinnitus transiently, it can also become a chronic condition that has a severe negative impact on the quality of life. Symptoms of tinnitus persisting beyond a 6 month period define it as a chronic condition, and approximately 10–15% of the population is affected, requiring medical intervention [9], [10]. Aging, exposure to loud noise and certain drugs have the potential to cause auditory damage and tinnitus, and there is an urgent need for a more standardised clinical management and effective therapies [10]. However, a prerequisite for more effective treatment is a better understanding of the pathophysiology of the condition.
Increased spontaneous activity and tonotopic map reorganisation in the auditory brain regions have been correlated with tinnitus, yet the mechanisms underlying these changes are not well understood [2]. One of the hypotheses is that a down-regulation of inhibitory neurotransmission might be responsible for the neuronal hyperactivity and tinnitus generation [13], [15]. This was supported by evidence that pharmacological manipulations enhancing brain GABAergic transmission reduced behavioural signs of tinnitus in animals [6], [16], [20]. It has been shown that a hearing loss-induced decrease in inhibitory synaptic transmission occurs in the auditory cortical area corresponding to the tinnitus frequency and this decrease in inhibitory synaptic transmission is also correlated with a reduced level of glutamic acid decarboxylase (GAD), the enzyme responsible for the synthesis of GABA, in the same area [16]. Time-dependent changes in GAD levels following acoustic trauma have also been reported in the rat inferior colliculus (IC) [12]. In addition, evidence of reduced GABAergic inhibition and increased spontaneous activity has also been found in the dorsal cochlear nucleus (DCN) of mice with behaviour signs of tinnitus [11]. Since the CN is the first region of the CNS to receive and process auditory information, it occupies an pivotal role in the generation of tinnitus [3]. The dorsal cochlear nucleus (DCN), especially, has been proposed as a tinnitus trigger site [7]. Therefore, changes in GABAergic inhibition in the DCN would alter the balance of excitation and inhibition, resulting in disruption of responses in the higher auditory pathways [11]. The aim of this study, therefore, was to further investigate tinnitus-related long-term changes in GABAergic inhibition in the CN by comparing the expression of GAD in rats exposed to acoustic trauma that induced tinnitus with that in rats that were not exposed to acoustic trauma, using immunohistochemistry. In addition, GAD expression was also compared between rats that received l-baclofen, a GABAB receptor agonist and those that did not, in order to test the hypothesis that increasing GABAergic inhibition by administering l-baclofen alters GAD levels associated with tinnitus.
Section snippets
Experimental design
Data were obtained from the brains of 20 male Wistar rats (200–300 g) that were part of a larger study investigating the effects of l-baclofen on tinnitus perception [19]. In the original study, the animals were divided into several groups: exposed (acoustic trauma) + vehicle, sham control + vehicle, exposed-baclofen and sham-baclofen with n = 8 in each group [19]. For the purpose of this study, i.e. to investigate tinnitus-related changes in GAD levels, only the brains from animals with confirmed
Results
There was a significant elevation of ABR thresholds immediately after noise exposure (F(1, 47.14) = 62.99, P ≤ 0.001; see Fig. 1A and B in [19]); however, the ABR thresholds had returned to normal by 22 weeks when they were measured prior to sacrifice (see Fig. 1C in [19]). At 2 weeks after the acoustic trauma and the first vehicle or drug treatment, the animals were tested in the conditioned behavioural paradigm for indications of tinnitus [19]. In response to either broad band noise (BBN) or 32
Discussion
The results of this study showed that there was no significant difference between the intensity of GAD immunolabelling in the VCN or DCN of exposed rats confirmed to have tinnitus at 17.5 weeks following exposure, compared to sham rats, when the DCN and VCN were analysed at 22 weeks post-exposure. There was also no difference between the rats treated with l-baclofen and vehicle. This result suggests that GAD levels in the CN are not altered at 22 weeks post-exposure or correlated with the
Acknowledgements
This research was supported by grants from the Jean Cathie Estate and the New Zealand Neurological Foundation. KM was supported by a University of Otago MSc Scholarship and SD by a Beswick Summer Scholarship.
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Cited by (10)
Can GABAkines quiet the noise? The GABA<inf>A</inf> receptor neurobiology and pharmacology of tinnitus
2022, Biochemical PharmacologyCitation Excerpt :Exposure to high intensity sound induces an increase in spontaneous activity in the dorsal cochlear nucleus (DCN) and may present a possible neural correlate of tinnitus [144]. Decreased levels of glutamic decarboxylase in response to acoustic trauma have been reported [84]. Further, studies in animal models have confirmed the link between DCN hyperactivity and behavioral evidence of tinnitus [108,145,146] in animal models.
Acute high-intensity noise induces rapid Arc protein expression but fails to rapidly change GAD expression in amygdala and hippocampus of rats: Effects of treatment with D-cycloserine
2016, Hearing ResearchCitation Excerpt :Many authors, including Møller (2011a) hypothesize that tinnitus results from abnormal neural plasticity high-jacking many of the mechanisms used routinely for formation of memories. In tinnitus, consolidation of such memories can occur over a long time course, as rats exposed to acute high-intensity noise exposure can often take several weeks to develop behavioral evidence of tinnitus (Engineer et al., 2011; Mohankumar et al., 2015; Zheng et al., 2015). Given the necessary time constraints to capture changes in Arc protein expression (rapid transcription, transport, translation, and subsequent degradation; Guzowski et al., 1999), the presence of tinnitus in experimental animals used in this study could not be tested; however, the consistent early up-regulation of Arc expression is indicative of early neuronal activity within these limbic regions resulting from exposure to acute traumatic noise.
Cell proliferation in the cochlear nucleus following acoustic trauma in rat
2015, NeuroscienceCitation Excerpt :We cannot exclude this possibility since we measured ABRs only on the exposed side. However, any such effect is likely to be minimal since in our previous studies, using the same stimulus, we have found no significant changes in ABR thresholds in the contralateral, non-exposed, ear (Zheng et al., 2014a, 2015a,b). It is possible that the BrdU labeling of these cells in the CN represented cells with damaged DNA rather than true cell proliferation, since BrdU can be incorporated into damaged DNA during the process of DNA repair (Landgren and Curtis, 2011).