Elsevier

Hearing Research

Volume 212, Issues 1–2, February 2006, Pages 9-21
Hearing Research

Research paper
Spontaneous activity in the inferior colliculus of CBA/J mice after manipulations that induce tinnitus

https://doi.org/10.1016/j.heares.2005.10.003Get rights and content

Abstract

Several physiological studies have linked experimentally induced tinnitus to increases in the spontaneous activity of auditory neurons. These results have led to the proposal of hyperactivity models of tinnitus in which elevated neural activity in the absence of auditory stimulation is perceived as phantom sound. Such models are appealing in their simplicity but remain controversial because a generalized elevation of spontaneous rates may not be observed after treatments that induce tinnitus in humans and experimental animals. Our study addressed these issues by characterizing the effects of common methods of tinnitus induction on spontaneous activity in the central nucleus of the inferior colliculus (ICC). The ICC is an interesting structure in tinnitus research because its diverse inputs include putative generator sites in the dorsal cochlear nucleus, as well as brainstem sources that appear to remain normal after tinnitus induction. Groups of CBA/J mice were subjected to one of three induction methods: bilateral or unilateral sound exposure, and acute salicylate intoxication. Relative to normal baselines, bilaterally exposed mice showed increases in the spontaneous rates of neurons with tuning near the exposure frequency. When the sample was separated into physiologically defined response classes, exposure effects were strongest among neurons with broad excitatory bandwidths. By contrast, salicylate decreased the spontaneous rates of low-frequency neurons with transient sound-evoked activity. Our results suggest that the disordered processes of hearing that give rise to tinnitus do not involve a pervasive elevation of spontaneous activity or a single mode of induction.

Introduction

Subjective tinnitus is broadly defined as a sound percept in the absence of an acoustic event. The phantom sound may range from a subtle pitch to a debilitating roar. In most cases, the etiology of the condition is unknown and clinical interventions are symptomatic.

Direct investigations of the neurophysiological basis of tinnitus have been made possible by the refinement of behavioral approaches that allow objective assessments of tinnitus percepts in animal models (Jastreboff et al., 1988). Ensuing laboratory studies have related tinnitus behaviors to physiological changes in auditory structures ranging from the cochlea (Guitton et al., 2003) to cortex (Komiya and Eggermont, 2000, Norena and Eggermont, 2003, Seki and Eggermont, 2003). It is widely assumed that the induction of tinnitus is manifested by an elevation of spontaneous rates (SRs) in these diverse structures. The brain interprets the hyperactivity as sound stimulation.

Tinnitus may be induced in experimental animals by treatment with salicylate or acoustic overexposure. Both methods have been linked to hyperactivity. Evans et al. (1981) were the first to show that high doses of sodium salicylate increased the SRs of auditory-nerve fibers in cats. Their observations were soon extended to the central auditory system by salicylate studies of the inferior colliculus (Jastreboff and Sasaki, 1986) and sound-exposure studies of the dorsal cochlear nucleus (DCN) (Kaltenbach and McCaslin, 1996). In particular, the results from Kaltenbach and McCaslin suggest that the DCN serves as a primary tinnitus generator site because sound-induced hyperactivity is not observed in the auditory nerve (Liberman and Kiang, 1978) or ventral cochlear nucleus (VCN) (Salvi et al., 1978).

Subsequent research has added complexity to early physiological descriptions of tinnitus. Average SRs are not changed in the auditory nerve when toxicity is controlled with lower doses of salicylate (Stypulkowski, 1990). In fact, significant decreases are noted when fibers are subdivided according to SR or BF (Muller et al., 2003). Similar observations have been made in auditory cortex (Eggermont and Kenmochi, 1998, Ochi and Eggermont, 1996). Like salicylate, the effects of sound exposure on SR may target some neural populations and not others in the same structure. For example, cortical hyperactivity is found in the reorganized cortical areas of exposed animals but not in areas remote to the acoustic trauma (Komiya and Eggermont, 2000).

The inconsistencies of average SR measures have shifted the focus of tinnitus studies to the temporal patterns of spontaneous activity. Initial applications of these time-based measures have supported the hyperactivity model of tinnitus. In the external cortex of the IC, salicylate intoxication produces a shortening of interspike intervals (ISIs) and escalation of bursting activity (Chen and Jastreboff, 1995). The changes are prominent at frequencies that match the pitch of tinnitus in animal behavioral studies (Jastreboff et al., 1988). When the same analysis is applied to primary auditory cortex (Ochi and Eggermont, 1996), no change is observed in the percentage of bursting neurons, the statistics of their interspike intervals, or the strength of correlation between simultaneously recorded neurons. Other aspects of cortical timing may be sensitive to tinnitus induction. For example, the degree of synchronized responding between neurons is enhanced in reorganized cortical areas following acoustic trauma (Komiya and Eggermont, 2000).

The goal of the present study was to evaluate the most widely cited physiological correlates of tinnitus using the same species, induction method, recording site, physiological measure, and anesthetic state. Three common methods of tinnitus induction were compared: bilateral sound exposure, unilateral sound exposure, and salicylate treatment. Comparisons of single-unit responses in untreated and treated mice were performed in conjunction with physiological classification to assess the importance of frequency tuning and response type. The recordings were made after minimal surgical preparation to reduce the need for anesthesia. The central nucleus of the inferior colliculus (ICC) was selected as the recording site because this structure integrates inputs from a variety of auditory nuclei, including putative generator sites in the dorsal cochlear nucleus (DCN).

Section snippets

Subjects

All procedures were reviewed and approved by the Institutional Animal Care and Use Committee of The Johns Hopkins School of Medicine.

Male and female CBA/J mice (n = 86) were obtained from Jackson Labs at an approximate age of 8–16 weeks. The mice were maintained in institutional facilities before being studied in a single acute electrophysiological experiment. Auditory-brainstem responses (ABRs) confirmed normal hearing thresholds prior to experimental treatments. Our methods for deriving

Results

The presentation of results begins with global statistical comparisons of the spontaneous rates in untreated and treated mice. This method of analysis fails to demonstrate generalized physiological effects in most instances but conforms to descriptions from previous studies of the inferior colliculus (e.g., Jastreboff and Sasaki, 1986). Our subsequent analyses suggest that significant rate changes may be isolated in the ICC of treated subjects by focusing on discrete neural populations. Each

Discussion

The major finding of this study was a significant increase of SRs in the inferior colliculus of mice after sound exposure and a significance decrease after acute salicylate treatment. In both contexts, the physiological correlates of tinnitus induction were best expressed by restricted tonotopic regions and isolated neural response classes.

Acknowledgements

Tinnitus measures were funded by a Grant-in-Aid from the Tinnitus Research Consortium. Physiological classification systems for the mouse inferior colliculus were developed through NIDCD grant DC04841. Diana Ma was supported by NIDCD training grant DC00023. Hiroshi Hidaka was sponsored by a fellowship from the Department of Otolaryngology, Tohoku University Graduate School of Medicine. Technical support was provided by NIDCD CORE grant DC05211.

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