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.
Highlights
Tinnitus is characterised by the perception of sound, independent of external stimuli
The enzyme synthesising nitric oxide (NO) exists in three main forms, but it is the neuronal form that is mainly relevant to this study
The localised signalling sometimes involves a postsynaptic complex where its synthesising enzyme neuronal NO synthase is bound directly to N-methyl-D-aspartate (NMDA) receptors (Christopherson, Hillier, Lim, & Bredt, 1999; OlthofBakker, Gartside, & Rees, 2019). This means that the calcium entering through the NMDA channels is directly available for activating the calcium-dependent, neuronal form of NOS
Summary
Tinnitus is characterised by the perception of sound, independent of external stimuli. The ventral cochlear nucleus (VCN) is one of the first nuclei in the auditory pathway, receiving most of its input from the auditory nerve, and it is thought to have a role in the development of tinnitus (Gu, Herrmann, Levine, & Melcher, 2012) It contains relatively high levels of neuronal nitric oxide synthase (Vincent & Kimura, 1992; Zheng, Seung Lee, Smith, & Darlington, 2006), the enzyme responsible for NO synthesis in a calcium-dependent manner (Knowles & Moncada, 1994). Iontophoresis was combined with these recordings to determine the physiological role of NO in the VCN following the development of tinnitus This allowed us to test the hypothesis that the increases in NO production are responsible for maintaining driven firing rates at a normal healthy level despite the reduced afferent input associated with hearing loss in the tinnitus animals. If NMDA channels are involved in mediating the increased firing rates of T animals, blocking endogenous NO production should reduce the effect of NMDA application, as it does in some neurons of the cat visual cortex (Cudeiro et al, 1997), rather than increasing the NMDA response, which is its more common action
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