Attenuation of noise-induced hyperactivity in the dorsal cochlear nucleus by pre-treatment with MK-801

Abstract

It has previously been hypothesized that hyperactivity of central auditory neurons following exposure to intense noise is a consequence of synaptic alterations. Recent studies suggest the involvement of NMDA receptors in the induction of this hyperactive state. NMDA receptors can mediate long term changes in the excitability of neurons through their involvement in excitotoxic injury and long term potentiation and depression. In this study, we examined the effect of administering an NMDA receptor blocker on the induction of hyperactivity in the dorsal cochlear nucleus (DCN) following intense sound exposure. Our prediction was that if hyperactivity induced by intense sound exposure is dependent on NMDA receptors, then blocking these receptors by administering an NMDA receptor antagonist just before animals are exposed to intense sound should reduce the degree of hyperactivity that subsequently emerges. We compared the levels of hyperactivity that develop in the DCN after intense sound exposure to activity recorded in control animals that were not sound exposed. One group of animals to be sound exposed received intraperitoneal injection of MK-801 twenty minutes preceding the sound exposure, while the other group received injection of saline. Recordings performed in the DCN 26-28 days post-exposure revealed increased response thresholds and widespread increases in spontaneous activity in the saline-treated animals that had been sound exposed, consistent with earlier studies. The animals treated with MK-801 preceding sound exposure showed similarly elevated thresholds but an attenuation of hyperactivity in the DCN; the attenuation was most robust in the high frequency half of the DCN, but lower levels of hyperactivity were also found in the low frequency half. These findings suggest that NMDA receptors are an important component of the hyperactivity-inducing mechanism following intense sound exposure. They further suggest that blockade of NMDA receptors may offer a useful therapeutic approach to preventing induction of noise-induced hyperactivity-related hearing disorders, such as tinnitus and hyperacusis.

Keywords: Auditory; Excitotoxicity; Hearing; Long term potentiation; Neuroprotection; Tinnitus.

Fig. 1

Image of the left DCN of one of the animals in the control group, viewed from a dorsal perspective, showing the locations of the different recording sites used to map spontaneous activity. Points are spaced 100 μm apart both horizontally and vertically. Locations at which recordings of spontaneous activity were preceded by recordings of frequency tuning are shown by points surrounded by circles. The outline of the DCN is demarcated by the dark line. The oval highlights 3 points that were averaged to contribute to the point in Fig. 3A for the mean activity at 1.2 mm. Scale bar = 200 μm.

Fig. 2

Comparison of neural response thresholds in control and the two groups of tone-exposed animals (MK-801-treated and saline-treated). Each point represents the mean CF threshold + SEM for all tuning curves that were recorded in a bin whose center is indicated on the abscissa. Tuning curve sample sizes ranged from 3–5 for control saline-treated animals (except for locus 0.55, which was based on a sample of 2 tuning curves), 5–8 for exposed saline treated (except for locus 1.4, which was based on a single tuning curve), and 7–12 for exposed MK-801 treated animals (except for loci 0.85 and 1.05, which were based on 4 and 3 tuning curves, respectively). Distance is relative to the lateral edge of the DCN. CF is defined as the frequency at which the response occurred at the lowest intensity.

Fig. 3

A. Comparison of spontaneous activity profiles in control and intense-tone-exposed animals. B. Mean spontaneous rates in the three animal groups based on data pooled across all 15 medial-lateral locations and across all animals in each group. C,D. Similar comparisons as in B but for lateral (0.1–0.7 mm, representing frequencies below 10 kHz) and medial (0.8–1.5 mm, representing frequencies above about 10 kHz) halves of the DCN, respectively. Error bars show SEM in each case. Frequency equivalents of the topographic locations are indicated by the bottom scale. Statistical significances of differences are indicated by * p < 0.05, ** p <0.005, *** p < 0.0005, **** p < 0.00005.