A Conditioned Behavioral Paradigm for Assessing Onset and Lasting Tinnitus in Rats

Abstract

Numerous behavioral paradigms have been developed to assess tinnitus-like behavior in animals. Nevertheless, they are often limited by prolonged training requirements, as well as an inability to simultaneously assess onset and lasting tinnitus behavior, tinnitus pitch or duration, or tinnitus presence without grouping data from multiple animals or testing sessions. To enhance behavioral testing of tinnitus, we developed a conditioned licking suppression paradigm to determine the pitch(s) of both onset and lasting tinnitus-like behavior within individual animals. Rats learned to lick water during broadband or narrowband noises, and to suppress licking to avoid footshocks during silence. After noise exposure, rats significantly increased licking during silent trials, suggesting onset tinnitus-like behavior. Lasting tinnitus-behavior, however, was exhibited in about half of noise-exposed rats through 7 weeks post-exposure tested. Licking activity during narrowband sound trials remained unchanged following noise exposure, while ABR hearing thresholds fully recovered and were comparable between tinnitus(+) and tinnitus(-) rats. To assess another tinnitus inducer, rats were injected with sodium salicylate. They demonstrated high pitch tinnitus-like behavior, but later recovered by 5 days post-injection. Further control studies showed that 1): sham noise-exposed rats tested with footshock did not exhibit tinnitus-like behavior, and 2): noise-exposed or sham rats tested without footshocks showed no fundamental changes in behavior compared to those tested with shocks. Together, these results demonstrate that this paradigm can efficiently test the development of noise- and salicylate-induced tinnitus behavior. The ability to assess tinnitus individually, over time, and without averaging data enables us to realistically address tinnitus in a clinically relevant way. Thus, we believe that this optimized behavioral paradigm will facilitate investigations into the mechanisms of tinnitus and development of effective treatments.

Neuroinflammation mediates noise-induced synaptic imbalance and tinnitus in rodent models

“…To verify the role of neuroinflammation in noise-induced tinnitus, we used a different rodent model of tinnitus and our newly developed conditioning-based behavioral test [66]. Awake rats were binaurally exposed to loud band-limited noise to induce tinnitus.…”

“…However, some have argued that, instead of tinnitus, impairment in gap detection may reflect a temporal processing deficit [89–95], a central auditory processing deficit that contributes to dyslexia [96–98]. To disambiguate the role of neuroinflammation in tinnitus, we performed a conditioning-based test for tinnitus [66]. We found that blocking TNF-α expression by dTT significantly reduced behavioral evidence of tinnitus in the conditioning-based test, confirming that neuroinflammation contributes to tinnitus etiology.…”

“…The behavioral test and experimental procedures were the same as previously reported [66]. Briefly, to induce tinnitus, awake adult male Sprague Dawley rats were binaurally exposed to an intense band-limited noise (8–16 kHz, 105 dB SPL, 2 hours) twice separated by 1 week.…”

Exposing Pathological Sensory Predictions in Tinnitus Using Auditory Intensity Deviant Evoked Responses

“…Numerous methods have been developed to determine this and broadly fall into two categories. Conditioned behavior models (Rüttiger et al, 2003;Brozoski and Bauer, 2016;Pace et al, 2016) are often regarded as the more accurate, and require lengthy prior training of animals to perform or refrain from certain behaviors, such as licking, during the presence of an ongoing sound. Automatic response methods (Turner et al, 2006;Lobarinas et al, 2013) have the advantage of requiring no training, and exploit involuntary responses, such as the acoustic startle response, in conjunction with stimuli related to the possible tinnitus (e.g., a short gap in an ongoing pure tone) to modify this depending on tinnitus status, but are subject to caveats and controversies (Campolo et al, 2013;Lobarinas et al, 2013), and show inconsistent replicability in humans (Fournier and Hébert, 2013;Shadwick and Sun, 2014;Boyen et al, 2015).…”

Pathophysiology of Subjective Tinnitus: Triggers and Maintenance

“…The majority of research done with help of animal models points to noise-induced hearing loss and tinnitus as an adequate model for the development of chronic tinnitus ( Bauer and Brozoski, 2001 ; Turner and Larsen, 2016 ). The report of Pace et al (2016) focuses on a novel experimental paradigm and makes distinction between the salicylate-induced tinnitus (tinnitus duration 5 days) and noise-induced tinnitus (tinnitus duration 7 weeks). An attempt to define such criteria has already been made using clinical studies ( Leaver et al, 2016a ).…”