Differential pathologies resulting from sound exposure: Tinnitus vs hearing loss

The first step in identifying the mechanism(s) responsible for tinnitus development would be to discover a neural correlate that is differentially expressed in tinnitus-positive compared to tinnitus negative animals. Previous research has identified several neural correlates of tinnitus in animals that have tested positive for tinnitus. However it is unknown whether all or some of these correlates are linked to tinnitus or if they are a byproduct of hearing loss, a common outcome of tinnitus induction. Abnormally high spontaneous activity has frequently been linked to tinnitus. However, while some studies demonstrate that hyperactivity positively correlates with behavioral evidence of tinnitus, others show that when all animals develop hyperactivity to sound exposure, not all exposed animals show evidence of tinnitus. My working hypothesis is that certain aspects of hyperactivity are linked to tinnitus while other aspects are linked to hearing loss. The first specific aim utilized the gap induced prepulse inhibition of the acoustic startle reflex (GIPAS) to monitor the development of tinnitus in CBA/CaJ mice during one year following sound exposure. Immediately after sound exposure, GIPAS testing revealed widespread gap detection deficits across all frequencies, which was likely due to temporary threshold shifts. However, three months after sound exposure these deficits were limited to a narrow frequency band and were consistently detected up to one year after exposure. This suggests the development of chronic tinnitus is a long lasting and highly dynamic process. The second specific aim assessed hearing loss in sound exposed mice using several techniques. Acoustic brainstem responses recorded initially after sound exposure reveal large magnitude deficits in all exposed mice. However, at the three month period, thresholds return to control levels in all mice suggesting that ABRs are not a reliable tool for assessing permanent hearing loss. Input/output functions of the acoustic startle reflex show that after sound exposure the magnitude of startle responses decrease in most mice, to varying degrees. Lastly, PPI audiometry was able to detect specific behavioral threshold deficits for each mouse after sound exposure. These deficits persist past initial threshold shifts and are able to detect frequency specific permanent threshold shifts. The third specific aim examined hyperactivity and increased bursting activity in the inferior colliculus after sound exposure in relation to tinnitus and hearing loss. Spontaneous firing rates were increased in all mice after sound exposure regardless of behavioral evidence of tinnitus. However, abnormal increased bursting activity was not found in the animals identified with tinnitus but was exhibited in a mouse with broad-band severe threshold deficits. CBA/CaJ mice are a good model for both tinnitus development and noise-induced hearing loss studies. Hyperactivity which was evident in all exposed animals does not seem to be well correlated with behavioral evidence of tinnitus but more likely to be a general result of acoustic over exposure. Data from one animal strongly suggest that wide-spread severe threshold deficits are linked to an elevation of bursting activity predominantly ipsilateral to the side of sound exposure. This result is intriguing and should be followed up in further studies. Data obtained in this study provide new insights into underlying neural pathologies following sound exposure and have possible clinical applications for development of effective treatments and diagnostic tools for tinnitus and hearing loss.