Choline acetyltransferase activity in the hamster central auditory system and long-term effects of intense tone exposure.

Acoustic trauma often leads to loss of hearing of environmental sounds, tinnitus, in which a monotonous sound not actually present is heard, and/or hyperacusis, in which there is an abnormal sensitivity to sound. Research on hamsters has documented physiological effects of exposure to intense tones, including increased spontaneous neural activity in the dorsal cochlear nucleus. Such physiological changes should be accompanied by chemical changes, and those chemical changes associated with chronic effects should be present at long times after the intense sound exposure. Using a microdissection mapping procedure combined with a radiometric microassay, we have measured activities of choline acetyltransferase (ChAT), the enzyme responsible for synthesis of the neurotransmitter acetylcholine, in the cochlear nucleus, superior olive, inferior colliculus, and auditory cortex of hamsters 5 months after exposure to an intense tone compared with control hamsters of the same age. In control hamsters, ChAT activities in auditory regions were never more than one-tenth of the ChAT activity in the facial nerve root, a bundle of myelinated cholinergic axons, in agreement with a modulatory rather than a dominant role of acetylcholine in hearing. Within auditory regions, relatively higher activities were found in granular regions of the cochlear nucleus, dorsal parts of the superior olive, and auditory cortex. In intense-tone-exposed hamsters, ChAT activities were significantly increased in the anteroventral cochlear nucleus granular region and the lateral superior olivary nucleus. This is consistent with some chronic upregulation of the cholinergic olivocochlear system influence on the cochlear nucleus after acoustic trauma.

Amino acid concentrations in the hamster central auditory system and long-term effects of intense tone exposure.

Exposure to intense sounds often leads to loss of hearing of environmental sounds and hearing of a monotonous tonal sound not actually present, a condition known as tinnitus. Chronic physiological effects of exposure to intense tones have been reported for animals and should be accompanied by chemical changes present at long times after the intense sound exposure. By using a microdissection mapping procedure combined with high-performance liquid chromatography (HPLC), we have measured concentrations of nine amino acids, including those used as neurotransmitters, in the cochlear nucleus, inferior colliculus, medial geniculate, and auditory cortex of hamsters 5 months after exposure to an intense tone, compared with control hamsters of the same age. No very large differences in amino acid concentrations were found between exposed and control hamsters. However, increases of glutamate and γ-aminobutyrate (GABA) in some parts of the inferior colliculus of exposed hamsters were statistically significant. The most consistent differences between exposed and control hamsters were higher aspartate and lower taurine concentrations in virtually all regions of exposed hamsters, which reached statistical significance in many cases. Although these amino acids are not considered likely neurotransmitters, they indirectly have roles in excitatory and inhibitory neurotransmission, respectively. Thus, there is evidence for small, widespread, long-term increases in excitatory transmission and decreases in inhibitory transmission after a level of acoustic trauma previously shown to produce hearing loss and tinnitus.

Ringing ears: the neuroscience of tinnitus.

Tinnitus is a phantom sound (ringing of the ears) that affects quality of life for millions around the world and is associated in most cases with hearing impairment. This symposium will consider evidence that deafferentation of tonotopically organized central auditory structures leads to increased neuron spontaneous firing rates and neural synchrony in the hearing loss region. This region covers the frequency spectrum of tinnitus sounds, which are optimally suppressed following exposure to band-limited noise covering the same frequencies. Cross-modal compensations in subcortical structures may contribute to tinnitus and its modulation by jaw-clenching and eye movements. Yet many older individuals with impaired hearing do not have tinnitus, possibly because age-related changes in inhibitory circuits are better preserved. A brain network involving limbic and other nonauditory regions is active in tinnitus and may be driven when spectrotemporal information conveyed by the damaged ear does not match that predicted by central auditory processing.

Amino acid and acetylcholine chemistry in mountain beaver cochlear nucleus and comparisons to pocket gopher, other rodents, and cat.

The mountain beaver and pocket gopher are two rodents that live mostly underground in tunnel systems. Previous studies have suggested that their cochlear nucleus structure, particularly that of the dorsal cochlear nucleus (DCN), differs significantly from that of other mammals, that the hearing ability of the pocket gopher is deficient compared to that of other rodents, and that the DCN of the mountain beaver is more responsive to slow oscillations of air pressure than to sounds. We conducted some electrophysiological recordings from mountain beaver DCN and then used microchemical methods to map in mountain beaver cochlear nuclei the distributions of amino acids, including the major neurotransmitters of the brain, and enzyme activities related to the metabolism of the neurotransmitter acetylcholine, which functions in centrifugal pathways to the cochlear nucleus. Similar measurements were made for a pocket gopher cochlear nucleus. Responses to tonal stimuli were found in mountain beaver DCN. Distributions and magnitudes of neurotransmitter and related amino acids within mountain beaver and pocket gopher cochlear nuclei were not very different from those of other rodents and cat. However, the enzyme of synthesis for acetylcholine, choline acetyltransferase, had only low activities in the DCN of both mountain beaver and pocket gopher. The chemical distributions in the mountain beaver DCN support a conclusion that it corresponds to just the superficial DCN portion of other mammals. High correlations between the concentrations of γ-aminobutyrate (GABA) and glycine were found for both mountain beaver and pocket gopher cochlear nuclei, suggesting that their co-localization in cochlear nucleus synapses may be especially prominent in these animals. Previous evidence suggests convergence of somatosensory and auditory information in the DCN, and this may be especially true in animals spending most of their time underground. Our results suggest that the enlarged DCN of the mountain beaver and that of the pocket gopher are not very different from those of other rodents with respect to involvement of amino acid neurotransmitters, but they appear to have reduced cholinergic innervation.

The Role of the Brainstem in Generating and Modulating Tinnitus.

Purpose The purpose of this work is to present a perspective article summarizing ideas pertaining to the brainstem's role in generating and modulating tinnitus. It is organized in 4 sections: Part 1, the role of the brainstem as a tinnitus generator; Part 2, the role of the brainstem in modulating tinnitus; Part 3, the role of the brainstem in nonauditory comorbid conditions associated with tinnitus; and Part 4, clinical implications. In Part 1, well-established neurophysiological models are discussed providing the framework of evidence that auditory brainstem nuclei play a role in generating tinnitus. In Part 2, ideas are presented explaining modulatory effects on tinnitus related to underlying pathways originating from or projecting to brainstem auditory and nonauditory nuclei. This section addresses multiple phenomena including somatic-related, attention-mediated, and emotion-mediated changes in the tinnitus percept. In Part 3, the role of the brainstem in common nonauditory comorbidities that occur in patients with tinnitus is discussed. Part 4 presents clinical implications of these new ideas related to the brainstem's involvement in generating and modulating tinnitus. Impact Knowledge of the brainstem's involvement in generating and modulating tinnitus provides a context for health care professionals to understand the temporal relationship between tinnitus and common nonauditory comorbid conditions.

Dorsal cochlear nucleus hyperactivity and tinnitus: are they related?

PURPOSE: Eight lines of evidence implicating the dorsal cochlear nucleus (DCN) as a tinnitus contributing site are reviewed. We now expand the presentation of this model, elaborate on its essential details, and provide answers to commonly asked questions regarding its validity. CONCLUSIONS: Over the past decade, numerous studies have converged to support the hypothesis that the DCN may be an important brain center in the generation and modulation of tinnitus. Although other auditory centers have been similarly implicated, the DCN deserves special emphasis because, as a primary acoustic nucleus, it occupies a potentially pivotal position in the hierarchy of functional processes leading to the emergence of tinnitus percepts. Moreover, because a great deal is known about the underlying cellular categories and the details of synaptic circuitry within the DCN, this brain center offers a potentially powerful model for probing mechanisms underlying tinnitus.

Effects of AUT00063, a Kv3.1 channel modulator, on noise-induced hyperactivity in the dorsal cochlear nucleus.

The purpose of this study was to test whether a Kv3 potassium channel modulator, AUT00063, has therapeutic potential for reversing noise-induced increases in spontaneous neural activity, a state that is widely believed to underlie noise-induced tinnitus. Recordings were conducted in noise exposed and control hamsters from dorsal cochlear nucleus (DCN) fusiform cells before and following intraperitoneal administration of AUT00063 (30 mg/kg). Fusiform cell spontaneous activity was increased in sound-exposed animals, approximating levels that were nearly 50% above those of controls. Administration of AUT00063 resulted in a powerful suppression of this hyperactivity. The first signs of this suppression began 13 min after AUT00063 administration, but activity continued to decline gradually until reaching a floor level which was approximately 60% of pre-drug baseline by 25 min after drug treatment. A similar suppressive effect of AUT00063 was observed in control animals, with onset of suppression first apparent at 13 min post-treatment, but continuing to decline toward a floor level that was 54% of pre-drug baseline and was reached 28 min after drug treatment. In contrast, no suppression of spontaneous activity was observed in animals given similar injections of vehicle (control) solution. The suppressive effect of AUT00063 was achieved without significantly altering heart rate and with minimal effects on response thresholds, supporting the interpretation that the reductions of hyperactivity were not a secondary consequence of a more general physiological suppression of the brain or auditory system. These findings suggest that Kv3 channel modulation may be an effective approach to suppressing spontaneous activity in the auditory system and may provide a future avenue for treatment of tinnitus resulting from exposure to intense sound.

Solenoidal Micromagnetic Stimulation Enables Activation of Axons With Specific Orientation.

Electrical stimulation of the central and peripheral nervous systems - such as deep brain stimulation, spinal cord stimulation, and epidural cortical stimulation are common therapeutic options increasingly used to treat a large variety of neurological and psychiatric conditions. Despite their remarkable success, there are limitations which if overcome, could enhance outcomes and potentially reduce common side-effects. Micromagnetic stimulation (µMS) was introduced to address some of these limitations. One of the most remarkable properties is that µMS is theoretically capable of activating neurons with specific axonal orientations. Here, we used computational electromagnetic models of the µMS coils adjacent to neuronal tissue combined with axon cable models to investigate µMS orientation-specific properties. We found a 20-fold reduction in the stimulation threshold of the preferred axonal orientation compared to the orthogonal direction. We also studied the directional specificity of µMS coils by recording the responses evoked in the inferior colliculus of rodents when a pulsed magnetic stimulus was applied to the surface of the dorsal cochlear nucleus. The results confirmed that the neuronal responses were highly sensitive to changes in the µMS coil orientation. Accordingly, our results suggest that µMS has the potential of stimulating target nuclei in the brain without affecting the surrounding white matter tracts.

The dorsal cochlear nucleus as a contributor to tinnitus: mechanisms underlying the induction of hyperactivity.

It has been hypothesized that tinnitus percepts may arise, in part, from increases in spontaneous neural activity in the central auditory system. The DCN is the lowest central auditory nucleus where this hyperactivity is observed, and it is most prominent following exposure to intense sound or ototoxic insult. Efforts to develop effective treatments for tinnitus will probably benefit from a better understanding of the mechanisms underlying the induction of hyperactivity in the DCN. This chapter will summarize the evidence linking tinnitus to altered activity in the DCN and review some of the likely mechanisms underlying the induction of hyperactivity following injury to the ear.

Intense sound-induced plasticity in the dorsal cochlear nucleus of rats: evidence for cholinergic receptor upregulation.

Previous studies in a number of species have demonstrated that spontaneous activity in the dorsal cochlear nucleus (DCN) becomes elevated following exposure to intense sound. This condition of hyperactivity has aroused considerable interest because it may represent an important neural correlate of tinnitus. There is some evidence that neurons in the superficial DCN, such as cartwheel, stellate and fusiform cells, may contribute to the level of hyperactivity induced by intense sound, although the relative importance of these different cell types is unknown. In the present study, we sought to determine the effect of intense sound exposure on multiunit spontaneous activity both at the DCN surface and in the fusiform cell layer and to examine the influence of cholinergic input to DCN circuits on the level of activity in the fusiform cell layer. Rats were studied in two groups, one of which had been exposed to a continuous intense sound (10 kHz 127 dB SPL) for 4h while the other group served as unexposed controls. Between 30 and 52 days post-exposure, recordings of multiunit activity were performed at the DCN surface as well as in the middle of the fusiform cell layer. Changes in fusiform cell layer activity were also studied in response to superficial applications of the cholinergic agonist, carbachol, either alone or following pre-application of the cholinergic antagonist, atropine. The results demonstrated that multiunit spontaneous activity in the rat DCN was generally much higher in both control and exposed animals relative to that which has been observed in other species. This activity was significantly higher at the DCN surface of sound-exposed animals than that of controls. In contrast, hyperactivity could not be demonstrated in the fusiform cell layer of sound-exposed animals. Carbachol administration most commonly caused suppression of fusiform cell layer activity. However, this suppression was considerably stronger in the DCN of sound-exposed animals than in controls. These findings suggest that, hyperactivity at the DCN surface of exposed rats may arise as a consequence of more highly activated neurons in the molecular layer, such as cartwheel and/or stellate cells, and that the lack of hyperactivity in the fusiform cell layer may be the result of inhibition of fusiform cells by these inhibitory interneurons. Although this finding does not rule out fusiform cells as possible sources of hyperactivity in other species, or even in the rat after short post-exposure recovery periods, the enhanced sensitivity of the fusiform cell layer to cholinergic stimulation suggests that in the rat, at least after prolonged post-exposure recovery periods, increased inhibition of activity in this layer by more superficially located neurons may result from an upregulation of receptors for cholinergic input. This upregulation may be greater in rats than in other species due to the relatively heavy cholinergic input that exists in the cochlear nucleus of this species.

Differentiation of simple spike waveforms in the hamster dorsal cochlear nucleus.

The dorsal cochlear nucleus (DCN) consists of many cell types with different morphologies and properties. DCN cells belonging to different morphological classes are distinguished by differences in their physiological characteristics such as their spectral and temporal response patterns, their levels of spontaneous activity, and certain biophysical properties. Recent studies suggest that they may also exhibit different action potentials, such as simple and complex spikes. In the present study, we systematically examined the spike waveforms of spontaneously active DCN neurons using extracellular recording methods. Neurons were found to exhibit simple spikes consisting of trains of individual action potentials. Spikes fell into two discrete groups of opposite polarity, those with M-shaped and those with W-shaped waveforms. The shapes of these waveforms recorded from a given unit remained constant, despite large changes in amplitude that occurred as the electrode was moved along its axis of penetration. A quantitative analysis of the fine details of the waveforms demonstrated that, although the durations of W- and M-shaped spikes exhibited considerable variation, the variants within each category fell along a continuous gradient rather than into discrete subgroups. Both M- and W-shaped waveforms were found predominantly in the fusiform cell and deep layers, with smaller numbers found in the dorsal acoustic stria. Consideration of their depths of occurrence, their response properties, and levels of spontaneous activity of the recorded neurons suggests that W-shaped waveforms probably are associated with fusiform cells, whereas M-shaped spikes likely originate from more than one cell type.

The dorsal cochlear nucleus as a participant in the auditory, attentional and emotional components of tinnitus.

The dorsal cochlear nucleus (DCN) has been modeled in numerous studies as a possible source of tinnitus-generating signals. This hypothesis was originally developed on the basis of evidence that the DCN becomes hyperactive following exposure to intense noise. Since these early observations, evidence that the DCN is an important contributor to tinnitus has grown considerably. In this paper, the available evidence to date will be summarized. In addition, the DCN hypothesis of tinnitus can now be expanded to include possible involvement in other, non-auditory components of tinnitus. It will be shown by way of literature review that the DCN has direct connections with non-auditory brainstem structures, such as the locus coeruleus, reticular formation and raphe nuclei, that are implicated in the control of attention and emotional responses. The hypothesis will be presented that attentional and emotional disorders, such as anxiety and depression, which are commonly associated with tinnitus, may result from an interplay between these non-auditory brainstem structures and the DCN. Implicit in this hypothesis is that attempts to develop effective anti-tinnitus therapies are likely to benefit from a greater understanding of how the levels of activity in the DCN are influenced by different states of activation of these non-auditory brainstem structures and vice versa.

Effects of intense tone exposure on choline acetyltransferase activity in the hamster cochlear nucleus.

Choline acetyltransferase (ChAT) activity has been mapped in the cochlear nucleus (CN) of control hamsters and hamsters that had been exposed to an intense tone. ChAT activity in most CN regions of hamsters was only a third or less of the activity in rat CN, but in granular regions ChAT activity was similar in both species. Eight days after intense tone exposure, average ChAT activity increased on the tone-exposed side as compared to the opposite side, by 74% in the anteroventral CN (AVCN), by 55% in the granular region dorsolateral to it, and by 74% in the deep layer of the dorsal CN (DCN). In addition, average ChAT activity in the exposed-side AVCN and fusiform soma layer of DCN was higher than in controls, by 152% and 67%, respectively. Two months after exposure, average ChAT activity was still 53% higher in the exposed-side deep layer of DCN as compared to the opposite side. Increased ChAT activity after intense tone exposure may indicate that this exposure leads to plasticity of descending cholinergic innervation to the CN, which might affect spontaneous activity in the DCN that has been associated with tinnitus.

Tinnitus as a plastic phenomenon and its possible neural underpinnings in the dorsal cochlear nucleus.

Tinnitus displays many features suggestive of plastic changes in the nervous system. These can be categorized based on the types of manipulations that induce them. We have categorized the various forms of plasticity that characterize tinnitus and searched for their neural underpinnings in the dorsal cochlear nucleus (DCN). This structure has been implicated as a possible site for the generation of tinnitus-producing signals owing to its tendency to become hyperactive following exposure to tinnitus inducing agents such as intense sound and cisplatin. In this paper, we review the many forms of plasticity that have been uncovered in anatomical, physiological and neurochemical studies of the DCN. Some of these plastic changes have been observed as consequences of peripheral injury or as fluctuations in the behavior and chemical activities of DCN neurons, while others can be induced by stimulation of auditory or even non-auditory structures. We show that many parallels can be drawn between the various forms of plasticity displayed by tinnitus and the various forms of neural plasticity which have been defined in the DCN. These parallels lend further support to the hypothesis that the DCN is an important site for the generation and modulation of tinnitus-producing signals.

Oncologic and Functional Outcomes of Surgical and Nonsurgical Treatment of Advanced Squamous Cell Carcinoma of the Supraglottic Larynx.

IMPORTANCE: Nonsurgical treatment of advanced supraglottic laryngeal cancer is widely used as part of a larynx preservation protocol. However, recent studies have suggested that nonsurgical treatment may be associated with inferior survival. Furthermore, it is not clear whether preservation of the larynx provides superior voice or swallowing function in the long term. OBJECTIVE: To test the hypothesis that surgical treatment of advanced-stage squamous cell carcinoma of the supraglottic larynx is associated with superior overall survival (OS), freedom from recurrence (FFR), and noninferior voice and swallowing function. DESIGN, SETTING, AND PARTICIPANTS: Retrospective medical record review of patients treated for stage III or IV squamous cell carcinoma of the supraglottic larynx between January 1990 and June 2013 at a tertiary referral center: 97 patients underwent surgical treatment and 138, nonsurgical treatment. Exclusion criteria included prior definitive treatment for laryngeal cancer or evidence of distant metastatic disease at presentation. The median follow-up for all 235 patients was 63 months. INTERVENTIONS: Surgical or nonsurgical therapy. MAIN OUTCOMES AND MEASURES: Freedom from recurrence (FFR), OS, larynx preservation, voice graded from 1 to 5, and swallowing graded from 1 to 6 using our voice and swallowing function scales. RESULTS: Surgical treatment was associated with superior FFR (5-year FFR: 75% vs 55%; P = .006) but not OS (5-year OS: 52% vs 52%; P = .61). The larynx was preserved in 83% of patients in the nonsurgical group vs 42% of patients in the surgical group (P < .001). Voice function was superior in the nonsurgical group at all time points through 5 years after treatment (mean voice score, 3.8 vs 2.6; P < .001). Swallowing function was comparable between surgical and nonsurgical groups. Multivariable analysis revealed that advanced age (hazard ratio [HR], 1.43 per 10-year increment; 95% CI, 1.19-1.72) and clinical N stage (HR, 1.17 per 1-level increment; 95% CI, 1.05-1.30) were associated with worse OS, while treatment with chemotherapy was associated with superior OS (HR, 0.61; 95% CI, 0.41-0.92). CONCLUSIONS AND RELEVANCE: Compared with surgical treatment, nonsurgical treatment as part of a larynx preservation protocol is associated with a higher likelihood of recurrence but has similar OS and should continue to be viewed as a viable alternative for the treatment of advanced supraglottic laryngeal cancer.

Activity in the dorsal cochlear nucleus of hamsters previously tested for tinnitus following intense tone exposure.

Chronic increases in spontaneous multiunit activity can be induced in the dorsal cochlear nucleus (DCN) of hamsters by intense sound exposure (Kaltenbach and McCaslin, 1996). It has been hypothesized that this hyperactivity may represent a neural code that could underlie the sound percepts of tinnitus. The goal of the present study was to determine whether hyperactivity could be demonstrated in animals that had previously been tested for tinnitus, and, if so, whether animals differing in their behavioral evidence for tinnitus also differ in their levels of spontaneous activity. The results showed not only that levels of activity in exposed animals were higher than those in control animals, but the degree to which the activity was increased was related to the strength of the behavioral evidence for tinnitus. These findings are consistent with the hypothesis that hyperactivity in the DCN may be a physiological correlate of noise-induced tinnitus.

Increases in spontaneous neural activity in the hamster dorsal cochlear nucleus following cisplatin treatment: a possible basis for cisplatin-induced tinnitus.

Recent investigations in the hamster have implicated increased spontaneous activity (SA) in the dorsal cochlear nucleus (DCN) as a contributing factor in the etiology of tinnitus induced by intense sound exposure. It might therefore be expected that increased SA would also develop in the DCN of hamsters treated with cisplatin, another cause of tinnitus. We tested this hypothesis by measuring the effects of cisplatin on SA in the DCN. Adult hamsters were divided into three groups, each receiving five injections of cisplatin at one of the following doses: 3 mg/kg, 2.25 mg/kg, or 1.5 mg/kg. Each group had corresponding controls receiving injections of isotonic saline. The effects of cisplatin were studied electrophysiologically 1 month after treatment by recording multiunit SA on the surface of the DCN. Measurements of SA were obtained in three rows of 13-15 locations spaced roughly 100 microm apart and spanning the length of the DCN along the tonotopic axis. Effects of cisplatin were evaluated by comparing plots of mean SA vs. tonotopic locus for cisplatin-treated groups with those of their corresponding untreated control groups. The results demonstrated a consistently higher level of SA in cisplatin-treated groups than in untreated controls. Whereas the highest rates of mean SA in control groups were between 10 and 15 events/s, the highest mean spontaneous rates in cisplatin-treated groups were between 25 and 38 events/s. The cisplatin-induced hyperactivity was greatest in the medial half of the DCN corresponding to the high frequency portion of the tonotopic range. These results suggest that cisplatin treatment is an effective inducer of hyperactivity in the DCN. This hyperactivity may be an important neural correlate of cisplatin-induced tinnitus.

Effects of cochlear ablation on noise induced hyperactivity in the hamster dorsal cochlear nucleus: implications for the origin of noise induced tinnitus.

Chronic increases in multiunit spontaneous activity are induced in the dorsal cochlear nucleus (DCN) following exposures to intense sound. This hyperactivity has been implicated as a neurophysiological correlate of noise induced tinnitus. However, it is not known whether this hyperactivity originates centrally, or instead, reflects an increase in the level of spontaneous input from the auditory nerve. In the present study we addressed this issue by testing whether hyperactivity, induced in the DCN by previous exposure to intense sound, persists after ipsilateral cochlear input to the DCN has been removed. To induce hyperactivity, Syrian golden hamsters were exposed under anesthesia to an intense pure tone (122-127 dB SPL at 10 kHz) for 4 h. Additional hamsters, which were anesthetized for 4 h, but not tone exposed, served as controls. Electrophysiological recordings of spontaneous activity were performed on the surface of the left DCN in animals in which the ipsilateral cochlea was either intact or ablated. The degree of cochlear removal was determined by microdissection and histologic evaluation of the cochlea after completion of each recording session. Comparisons between the levels of activity recorded in animals with and without intact cochleas revealed that the induced hyperactivity in the DCN persisted after both partial and complete cochlear ablations. These results indicate that the maintenance of hyperactivity is not dependent on input from the ipsilateral cochlea, implying that hyperactivity originates centrally.

Effects of acoustic trauma on dorsal cochlear nucleus neuron activity in slices.

Previous studies found increased multi-unit spontaneous activity in the dorsal cochlear nucleus (DCN) of animals that had been exposed to intense sound. Such activity may be related to tinnitus. Our study examined effects of previous exposure to intense sound on single neurons in the DCN, by measuring spontaneous activities and sensitivities to acetylcholine, an important neurotransmitter of centrifugal pathways to the cochlear nucleus, in brain slices. Spontaneous discharges were recorded extracellularly in the DCN portion of brain slices from control and intense-tone-exposed rats. Slices from exposed rats showed increased prevalence of bursting and decreased regular spontaneous activity. Since regular neurons include fusiform cells, and bursting neurons include cartwheel cells, intense tone exposure may lead to increased activity of DCN cartwheel cells and decreased activity of fusiform cells. Alternatively, the activity of some fusiform cells might change to bursting. Intense tone exposure also appeared to increase bursting neuron sensitivity to carbachol. This suggests that changes in DCN cartwheel cell spontaneous activity may reflect changes in effects of cholinergic centrifugal pathways following intense tone exposure. We conclude that acoustic trauma may lead to changes in the physiology and pharmacology of DCN neurons. These changes may be related to underlying mechanisms of central tinnitus.

Induction of enhanced acoustic startle response by noise exposure: dependence on exposure conditions and testing parameters and possible relevance to hyperacusis.

There has been a recent surge of interest in the development of animal models of hyperacusis, a condition in which tolerance to sounds of moderate and high intensities is diminished. The reasons for this decreased tolerance are likely multifactorial, but some major factors that contribute to hyperacusis are increased loudness perception and heightened sensitivity and/or responsiveness to sound. Increased sound sensitivity is a symptom that sometimes develops in human subjects after acoustic insult and has recently been demonstrated in animals as evidenced by enhancement of the acoustic startle reflex following acoustic over-exposure. However, different laboratories have obtained conflicting results in this regard, with some studies reporting enhanced startle, others reporting weakened startle, and still others reporting little, if any, change in the amplitude of the acoustic startle reflex following noise exposure. In an effort to gain insight into these discrepancies, we conducted measures of acoustic startle responses (ASR) in animals exposed to different levels of sound, and repeated such measures on consecutive days using a range of different startle stimuli. Since many studies combine measures of acoustic startle with measures of gap detection, we also tested ASR in two different acoustic contexts, one in which the startle amplitudes were tested in isolation, the other in which startle amplitudes were measured in the context of the gap detection test. The results reveal that the emergence of chronic hyperacusis-like enhancements of startle following noise exposure is highly reproducible but is dependent on the post-exposure thresholds, the time when the measures are performed and the context in which the ASR measures are obtained. These findings could explain many of the discrepancies that exist across studies and suggest guidelines for inducing in animals enhancements of the startle reflex that may be related to hyperacusis.