Effects of Furosemide on Cochlear Neural Activity, Central Hyperactivity and Behavioural Tinnitus after Cochlear Trauma in Guinea Pig

Abstract

Cochlear trauma causes increased spontaneous activity (hyperactivity) to develop in central auditory structures, and this has been suggested as a neural substrate for tinnitus. Using a guinea pig model we have previously demonstrated that for some time after cochlear trauma, central hyperactivity is dependent on peripheral afferent drive and only later becomes generated intrinsically within central structures. Furosemide, a loop diuretic, reduces spontaneous firing of auditory afferents. We investigated in our guinea pig model the efficacy of furosemide in reducing 1) spontaneous firing of auditory afferents, using the spectrum of neural noise (SNN) from round window recording, 2) hyperactivity in inferior colliculus, using extracellular single neuron recordings and 3) tinnitus at early time-points after cochlear trauma. Tinnitus was assessed using gap prepulse inhibition of acoustic startle (GPIAS). Intraperitoneal furosemide, but not saline, caused a marked decrease in both SNN and central hyperactivity. Intracochlear perfusion with furosemide similarly reversed central hyperactivity. In animals in which GPIAS measurements suggested the presence of tinnitus (reduced GPIAS), this could be reversed with an intraperitoneal injection with furosemide but not saline. The results are consistent with furosemide reducing central hyperactivity and behavioural signs of tinnitus by acting peripherally to decrease spontaneous firing of auditory afferents. The data support the notion that hyperactivity may be involved in the generation of tinnitus and further suggest that there may be a therapeutic window after cochlear trauma using drug treatments that target peripheral spontaneous activity.

Maladaptive plasticity in tinnitus — triggers, mechanisms and treatment

“…Several studies at the next auditory center of the brain stem, the inferior colliculus (IC), have demonstrated increased SFRs just below, within and just above the noise-damaged region of the cochlea, which correlated with presence of tinnitus using GPIAS [48, 49], but in some studies [50, 51] the increased spontaneous activity was not dependent on the presence of tinnitus. Nonetheless, increases in IC spontaneous activity appear to be dependent on that transmitted from the DCN since DCN ablation prior to noise damage prevents IC hyperactivity as well as tinnitus development [52].…”

Development of the head, pinnae, and acoustical cues to sound location in a precocial species, the guinea pig ( Cavia porcellus )

“…Guinea pigs are a common model for anatomical (Dong et al, 2010; Schofield et al, 2006), physiological (Koehler and Shore, 2013; Shackleton et al, 2009; Zohar et al, 2011), behavioral (Berger et al, 2013; Dehmel et al, 2012; Mulders et al, 2014) and developmental (Withington-Wray et al, 1990; Withington et al, 1994) studies of the auditory system. They are also popular models for studies of middle (Guan and Gan, 2011; Lee et al, 2014) and inner (Chen et al, 2014) ear mechanics likely because the guinea pig is audiometrically similar to humans in that they hear sounds over comparable ranges of frequencies (Heffner et al, 1971; Syka et al, 2000).…”

Suppression of putative tinnitus-related activity by extra-cochlear electrical stimulation

“…This increase in central neural activity occurs despite the reduction of spontaneous and stimulusevoked cochlear nerve activity after cochlear lesions (Hartmann et al 1984;Heinz and Young 2004;Kujawa and Liberman 2009;Liberman and Dodds 1984;Shepherd and Javel 1997). The spontaneous central hyperactivity triggered by hearing loss has been suggested to represent tinnitus-related activity (Bauer et al 2008;Brozoski et al 2007;Kaltenbach et al 2004;Mulders et al 2014;Mulders and Robertson 2009;Norena 2011;Schaette and Kempter 2012).…”