Evidence of Key Tinnitus-Related Brain Regions Documented by a Unique Combination of Manganese-Enhanced MRI and Acoustic Startle Reflex Testing

Abstract

Animal models continue to improve our understanding of tinnitus pathogenesis and aid in development of new treatments. However, there are no diagnostic biomarkers for tinnitus-related pathophysiology for use in awake, freely moving animals. To address this disparity, two complementary methods were combined to examine reliable tinnitus models (rats repeatedly administered salicylate or exposed to a single noise event): inhibition of acoustic startle and manganese-enhanced MRI. Salicylate-induced tinnitus resulted in wide spread supernormal manganese uptake compared to noise-induced tinnitus. Neither model demonstrated significant differences in the auditory cortex. Only in the dorsal cortex of the inferior colliculus (DCIC) did both models exhibit supernormal uptake. Therefore, abnormal membrane depolarization in the DCIC appears to be important in tinnitus-mediated activity. Our results provide the foundation for future studies correlating the severity and longevity of tinnitus with hearing loss and neuronal activity in specific brain regions and tools for evaluating treatment efficacy across paradigms.

Isoflurane blocks temporary tinnitus

“…Isoflurane also significantly reduced this startle response amplitude in 5/10 animals. Increased startle response amplitudes following a tinnitus inducer (such as acoustic trauma or salicylate) are consistent with previous studies, and have been suggested as a possible behavioral correlate of hyperacusis (Ison et al, 2007;Holt et al, 2010;Turner and Parrish, 2008;Sun et al, 2009).…”

“…The reversibility of temporary tinnitus offers practical experimental advantages, such as the ability to compare brain activity when the animal is or is not experiencing tinnitus. For example, temporary tinnitus produced by high doses of salicylate alters both driven and spontaneous activity levels and inhibitory function at multiple levels of the auditory system, including dorsal cochlear nucleus, inferior colliculus, and auditory cortex (Bauer et al, 2000;Holt et al, 2010;Ralli et al, 2010;Stolzberg et al, 2011;Zhang et al, 2011). However, because drug-induced tinnitus and noise-induced tinnitus may arise from distinct brain mechanisms (Eggermont, 2008;Sun et al, 2009;Norena et al, 2010), a method for inducing temporary noiseinduced tinnitus is likely to be useful.…”

“…This could block temporary tinnitus by preventing noise-induced hearing loss. Some experimental studies of chronic tinnitus have used anesthesia during exposure (isoflurane: Kraus et al, 2010;ketamine-xylazine: Bauer and Brozoski, 2001;Turner et al, 2006), but some do not (Milbrandt et al, 2000;Norena and Eggermont, 2005;Holt et al, 2010;Norena et al, 2003). Whether isoflurane anesthesia during acoustic trauma prevents temporary tinnitus therefore remains an open question that directly affects experimental design in tinnitus studies.…”

Chronic tinnitus and unipolar brush cell alterations in the cerebellum and dorsal cochlear nucleus

“…System-level tinnitus alterations have been extensively investigated in the dorsal cochlear nucleus (DCN) (Kaltenbach, 2006; Kaltenbach et al, 2008), inferior colliculus (Bauer et al, 2008; Holt et al, 2010; Jastreboff et al, 1986; Melcher et al, 2000), auditory thalamus (Kalappa et al, 2014; Richardson et al, 2011), and auditory cortex (Deng et al, 2015; Engineer et al, 2011; Langers et al, 2012; Norena et al, 2006; Tan et al, 2007; Zhang et al, 2011). Nevertheless specific cellular mechanisms remain unclear.…”

Molecular Mechanism of Tinnitus

“…Following the hypothesis that subcortical hyperactivity during tinnitus may occur in the DCN independently of the cochlea (Kaltenbach, 2011 ) , a selective activation of nonlemniscal pathways may be a likely consequence. This would explain recent fi ndings of hyperactivity in the dorsal cortex of the inferior colliculus (DCIC) rather than in the central nucleus of the inferior colliculus (CIC) (Holt et al, 2010 ) . The major sources of input to the dorsal part of the MGB are from nonlemniscal parts of the IC, the DCIC and external cortex of the inferior colliculus (ECIC) that in turn receive ascending information from the (dorsal nucleus of the lateral lemniscus [DNLL]) (Malmierca & Merchán, 2004 ) .…”