Nitric oxide increases gain in the ventral cochlear nucleus of guinea pigs with tinnitus

Abstract

Previous work has led to the hypothesis that, during the production of noise‐induced tinnitus, higher levels of nitric oxide (NO), in the ventral cochlear nucleus (VCN), increase the gain applied to a reduced input from the cochlea. To test this hypothesis, we noise‐exposed 26 guinea pigs, identified evidence of tinnitus in 12 of them and then compared the effects of an iontophoretically applied NO donor or production inhibitor on VCN single unit activity. We confirmed that the mean driven firing rate for the tinnitus and control groups was the same while it had fallen in the non‐tinnitus group. By contrast, the mean spontaneous rate had increased for the tinnitus group relative to the control group, while it remained the same for the non‐tinnitus group. A greater proportion of units responded to exogenously applied NO in the tinnitus (56%) and non‐tinnitus groups (71%) than a control population (24%). In the tinnitus group, endogenous NO facilitated the driven firing rate in 37% (7/19) of neurons and appeared to bring the mean driven rate back up to control levels by a mechanism involving N‐methyl‐D‐aspartic acid (NMDA) receptors. By contrast, in the non‐tinnitus group, endogenous NO only facilitated the driven firing rate in 5% (1/22) of neurons and there was no facilitation of driven rate in the control group. The effects of endogenous NO on spontaneous activity were unclear. These results suggest that NO is involved in increasing the gain applied to driven activity, but other factors are also involved in the increase in spontaneous activity.

Nitric oxide signalling underlies salicylate-induced increases in neuronal firing in the inferior colliculus: a central mechanism of tinnitus?

“…Upregulation of nNOS in the ventral cochlear nucleus has been reported in animals in which tinnitus was confirmed behaviourally after either salicylate treatment (Zheng et al, 2006) or noise exposure (Coomber et al, 2014;Coomber et al, 2015). Furthermore, evidence for nitric oxide-dependent effects on firing in ventral cochlear nucleus neurons have been reported in animals with tinnitus (Hockley et al, 2020a). At the level of the auditory midbrain, we have reported increased nNOS expression in the dorsal cortex of the IC in rats with tinnitus (Maxwell et al, 2019).…”

“…Increased membrane expression of both nNOS and the NR1 NMDA receptor subunit has been reported in the ventral cochlear nucleus following cochlear ablation (Chen et al, 2004). Interestingly, recent evidence also reveals an increased neuronal modulation by nitric oxide in the ventral cochlear nucleus in animals with behavioural evidence of tinnitus following noise exposure (Hockley et al, 2020a;Hockley et al, 2020b).…”

Nitric Oxide Signaling in the Auditory Pathway

“…The interaction of nNOS with activity-dependent calcium increases might be a component of the feedback in protecting inner hair cells from noise over-exposure ( Shen et al, 2003 ; Mohrle et al, 2017 ). Application of nNOS inhibitors or NO donors in vivo , differentially affected spontaneous and sound-evoked firing rates in different cell types, which may contribute to increased gain during tinnitus ( Coomber et al, 2015 ; Hockley et al, 2019 , 2020 ).…”

“…The auditory pathway provides a system in which many of these issues can be explored. In fact, the generation of cGMP, NO-induced intrinsic plasticity, synaptic plasticity and changes in in vivo firing rates have been clearly demonstrated in the auditory brainstem: cochlear nucleus: (Cao et al, 2019;Hockley et al, 2019Hockley et al, , 2020, Superior Olivary Complex: (Steinert et al, 2008(Steinert et al, , 2011Tozer et al, 2012;Yassin et al, 2014;Kopp-Scheinpflug et al, 2015), and Inferior Colliculus: (Olthof et al, 2019) and in an animal model of tinnitus (Coomber et al, 2014(Coomber et al, , 2015.…”

Strain Comparison in Rats Differentiates Strain-Specific from More General Correlates of Noise-Induced Hearing Loss and Tinnitus

“…Almost all experimental approaches investigating tinnitus mechanisms involve rodent animal models. Among them are mice (Hickox and Liberman 2014 ; Liberman and Liberman 2015 ; Nowotny et al 2017 ; Park et al 2020 ), gerbils (Nowotny et al 2011 ; Kiefer et al 2015 ; Schilling et al 2017 ; Jeschke et al 2021 ), hamsters (Chen et al 2013 ; Manzoor et al 2013 ), guinea pigs (Mulders et al 2014 ; Hockley et al 2020 ), and rats (Turner et al 2006 ; Caspary et al 2008 ; Lobarinas et al 2013 ; Möhrle et al 2019 ; van Zwieten et al 2021 ).…”