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.
Highlights
A common side-effect of hearing loss is tinnitus, a phantom hearing sensation described as hissing or ringing in the ears [1]
(black bars) and at 10 weeks post-acoustic trauma. The fact that these animals continued to pass gap prepulse inhibition of acoustic startle (GPIAS) testing suggests they did not develop tinnitus throughout this 10 week period and in addition supports the notion that GPIAS is a robust and consistent phenomenon
This paper provides for the first time, direct evidence in a single animal model that a drug treatment that reduces spontaneous firing rates in the auditory nerve, eliminates the hyperactivity in the central nucleus of the inferior colliculus (CNIC) caused by acoustic trauma, and eliminates the behavioural signs of tinnitus
Summary
A common side-effect of hearing loss is tinnitus, a phantom hearing sensation described as hissing or ringing in the ears [1]. Many human studies have described abnormal activity within auditory pathways of tinnitus sufferers [12,13,14,15], the exact neural substrate is unknown. Animal models of hearing loss have shown increased spontaneous firing rates in central auditory structures (hyperactivity), alterations in neural synchrony, as well as reorganization [16,17,18,19,20,21], but exactly how these changes contribute to the development of tinnitus is still debated. GPIAS consisted of a narrowband noise centred at either 8 or 14 kHz (3dB bandwidths = 1 kHz). These two frequency bands were chosen to fall within the centre of peripheral hearing loss (14 kHz) and just below the region of hearing loss (8 kHz). Animals had to pass GPIAS and PPI twice before a cochlear trauma was performed
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