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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., (© 2020 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

The gaseous free radical, nitric oxide (NO) acts as a ubiquitous neuromodulator, contributing to synaptic plasticity in a complex way that can involve either long term potentiation or depression. It is produced by neuronal nitric oxide synthase (nNOS) which is presynaptically expressed and also located postsynaptically in the membrane and cytoplasm of a subpopulation of each major neuronal type in the ventral cochlear nucleus (VCN). We have used iontophoresis in vivo to study the effect of the NOS inhibitor L-NAME (L-NG-Nitroarginine methyl ester) and the NO donors SIN-1 (3-Morpholinosydnonimine hydrochloride) and SNOG (S-Nitrosoglutathione) on VCN units under urethane anaesthesia. Collectively, both donors produced increases and decreases in driven and spontaneous firing rates of some neurones. Inhibition of endogenous NO production with L-NAME evoked a consistent increase in driven firing rates in 18% of units without much effect on spontaneous rate. This reduction of gain produced by endogenous NO was mirrored when studying the effect of L-NAME on NMDA(N-Methyl-D-aspartic acid)-evoked excitation, with 30% of units showing enhanced NMDA-evoked excitation during L-NAME application (reduced NO levels). Approximately 25% of neurones contain nNOS and the NO produced can modulate the firing rate of the main principal cells: medium stellates (choppers), large stellates (onset responses) and bushy cells (primary-like responses). The main endogenous role of NO seems to be to partly suppress driven firing rates associated with NMDA channel activity but there is scope for it to increase neural gain if there were a pathological increase in its production following hearing loss., (© 2019 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Tinnitus chronically affects between 10-15% of the population but, despite its prevalence, the underlying mechanisms are still not properly understood. One experimental model involves administration of high doses of sodium salicylate, as this is known to reliably induce tinnitus in both humans and animals. Guinea pigs were implanted with chronic electrocorticography (ECoG) electrode arrays, with silver-ball electrodes placed on the dura over left and right auditory cortex. Two more electrodes were positioned over the cerebellum to monitor auditory brainstem responses (ABRs). We recorded resting-state and auditory evoked neural activity from awake animals before and 2 h following salicylate administration (350 mg/kg; i.p.). Large increases in click-evoked responses (> 100%) were evident across the whole auditory cortex, despite significant reductions in wave I ABR amplitudes (in response to 20 kHz tones), which are indicative of auditory nerve activity. In the same animals, significant decreases in 6-10 Hz spontaneous oscillations (alpha waves) were evident over dorsocaudal auditory cortex. We were also able to demonstrate for the first time that cortical evoked potentials can be inhibited by a preceding gap in background noise [gap-induced pre-pulse inhibition (PPI)], in a similar fashion to the gap-induced inhibition of the acoustic startle reflex that is used as a behavioural test for tinnitus. Furthermore, 2 h following salicylate administration, we observed significant deficits in PPI of cortical responses that were closely aligned with significant deficits in behavioural responses to the same stimuli. Together, these data are suggestive of neural correlates of tinnitus and oversensitivity to sound (hyperacusis)., (© 2016 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Animal models of tinnitus allow us to study the relationship between changes in neural activity and the tinnitus percept. Here, guinea pigs were subjected to unilateral noise trauma and tested behaviourally for tinnitus 8 weeks later. By comparing animals with tinnitus with those without, all of which were noise-exposed, we were able to identify changes unique to the tinnitus group. Three physiological markers known to change following noise exposure were examined: spontaneous firing rates (SFRs) and burst firing in the inferior colliculus (IC), evoked auditory brainstem responses (ABRs), and the number of neurons in the cochlear nucleus containing nitric oxide synthase (NOS). We obtained behavioural evidence of tinnitus in 12 of 16 (75%) animals. Both SFRs and incidences of burst firing were elevated in the IC of all noise-exposed animals, but there were no differences between tinnitus and no-tinnitus animals. There were significant decreases in ipsilateral ABR latencies in tinnitus animals, contrary to what might be expected with a small hearing loss. Furthermore, there was an ipsilateral-contralateral asymmetry in NOS staining in the ventral cochlear nucleus (VCN) that was only apparent in tinnitus animals. Tinnitus animals had a significantly greater number of NOS-containing neurons on the noise-exposed side, whereas no-tinnitus animals did not. These data suggest that measuring NOS in the VCN and recording ABRs supplement behavioural methods for confirming tinnitus in animals, and that nitric oxide is involved in plastic neural changes associated with tinnitus., (© 2014 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

The ferret (Mustela putorius) is a medium-sized, carnivorous mammal with good low-frequency hearing; it is relatively easy to train, and there is therefore a good body of behavioural data detailing its detection thresholds and localization abilities. However, despite extensive studies of the physiology of the central nervous system of the ferret, even extending to the prefrontal cortex, little is known of the functioning of the auditory periphery. Here, we provide an insight into this peripheral function by detailing responses of single auditory nerve fibres. Our expectation was that the ferret auditory nerve responsiveness would be similar that of its near relative, the cat. However, by comparing a range of variables (the frequency tuning, the variation of rate-level functions with spontaneous rate, and the high-frequency cut-off of phase locking) across several species, we show that the auditory nerve (and hence cochlea) in the ferret is more similar to that of the guinea-pig and chinchilla than to that of the cat. Animal models of hearing are often chosen on the basis of the similarity of their audiogram to that of the human, particularly in the low-frequency region. We show here that whereas the ferret hears well at low frequencies, this is likely to occur via fibres with higher characteristic frequencies. These qualitative differences in response characteristics in auditory nerve fibres are important in interpreting data across all of auditory science, as it has been argued recently that tuning in animals is broader than in humans., (© 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)

We investigated how physiologically observed forward suppression interacts with stimulus frequency in neuronal responses in the guinea pig auditory cortex. The temporal order and frequency proximity of sounds influence both their perception and neuronal responses. Psychophysically, preceding sounds (conditioners) can make successive sounds (probes) harder to hear. These effects are larger when the two sounds are spectrally similar. Physiological forward suppression is usually maximal for conditioner tones near to a unit's characteristic frequency (CF), the frequency to which a neuron is most sensitive. However, in most physiological studies, the frequency of the probe tone and CF are identical, so the role of unit CF and probe frequency cannot be distinguished. Here, we systemically varied the frequency of the probe tone, and found that the tuning of suppression was often more closely related to the frequency of the probe tone than to the unit's CF, i.e. suppressed tuning was specific to probe frequency. This relationship was maintained for all measured gaps between the conditioner and the probe tones. However, when the probe frequency and CF were similar, CF tended to determine suppressed tuning. In addition, the bandwidth of suppression was slightly wider for off-CF probes. Changes in tuning were also reflected in the firing rate in response to probe tones, which was maximally reduced when probe and conditioner tones were matched in frequency. These data are consistent with the idea that cortical neurons receive convergent inputs with a wide range of tuning properties that can adapt independently., (© 2011 Medical Research Council. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)

The auditory thalamus (medial geniculate body, MGB) receives its main ascending input from the inferior colliculus (IC), which was considered to be an obligatory relay for all auditory inputs to the MGB. However, recent anatomical evidence in the rat [ (Malmierca et al. 2002) J. Neurosci., 22, 10891-10897] has confirmed the presence of a direct pathway from the dorsal cochlear nucleus (DCN) to the medial MGB, bypassing the IC, as previously suggested in the chimpanzee [ (Strominger et al. 1977) J. Comp. Neurol., 172, 349-366]. We show that this direct pathway is also present in the guinea pig and apparently results in short latency responses in the thalamus. Injection of anterograde tracer into the DCN of five adult guinea pigs revealed terminal boutons and axonal swellings distributed throughout the medial MGB, but absent from all other MGB subdivisions. Electrophysiological recordings made from 39 adult guinea pigs (24 male & 15 female) showed neurons in the medial MGB responded with significantly shorter latencies to acoustic clicks (7.8 ms) than those from the ventral (11.0 ms), dorsal (14.4 ms), or shell (16.5 ms) MGB, consistent with the direct pathway from the DCN. The function of the direct pathway is not known but may be related to the fast responses and the role of the medial MGB in integrating combined somatosensory and auditory inputs. Short latency responses may be important in priming the auditory cortex to prepare it for rapid analysis and in recruiting the amygdala for rapid emotional responses such as fear.

Evidence for population-level right-handedness in nonhuman primates seems inconsistent and contradictory, and many hypotheses have been advanced to account for this volatility. Funnel plots (scatter plots of percent right-hand use vs. sample size) offer a straightforward graphical technique for assessing: 1) the strength and consistency of handedness, 2) whether variability is consistent with normal sampling variation, and 3) how likely reports of statistically significant handedness might have arisen due to chance (i.e., type I error). They are informative for both within- and among-population variation. Reexamination of within-population variation from a detailed and widely cited study reporting significant population-level right-handedness in 140 individual captive chimpanzees (Hopkins [1994] Dev. Psychobiol. 27:395-407) revealed several puzzling patterns: 1) funnel plots showed higher percent right-hand use among individuals for which fewer observations were recorded, 2) when individuals with fewer than 25 observations were excluded, statistical support for population-level right-handedness either became marginal (P = 0.043, when computed as average percent use of the right hand) or disappeared (P = 0.62, when computed as proportion of individuals using the right hand more than the left, whether they did so significantly or not), and 3) the proportion of statistically ambilateral chimpanzees actually increased with increasing number of observations per individual, rather than decreased as would be expected for true population-level right-handedness. In addition, funnel plots of among-population variation from an earlier meta-analysis (McGrew and Marchant [1997] Yrbk. Phys. Anthropol. 40:201-232) suggested that the four reports of significant right-handedness, out of 37 estimates from 14 studies, were likely those that achieved statistical significance simply due to chance. Funnel plots, and the more refined statistical tests they suggest, confirm that the current evidence for population-level right-handedness in chimpanzees remains equivocal., (Copyright 2002 Wiley-Liss, Inc.)