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.

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.

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.

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.

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.

Mapping and morphometric analysis of synapses and spines on fusiform cells in the dorsal cochlear nucleus.

Fusiform cells are the main integrative units of the mammalian dorsal cochlear nucleus (DCN), collecting and processing inputs from auditory and other sources before transmitting information to higher levels of the auditory system. Despite much previous work describing these cells and the sources and pharmacological identity of their synaptic inputs, information on the three-dimensional organization and utltrastructure of synapses on these cells is currently very limited. This information is essential since an understanding of synaptic plasticity and remodeling and pathologies underlying disease states and hearing disorders must begin with knowledge of the normal characteristics of synapses on these cells, particularly those features that determine the strength of their influence on the various compartments of the cell. Here, we employed serial block face scanning electron microscopy (SBFSEM) followed by 3D reconstructions to map and quantitatively characterize synaptic features on DCN fusiform cells. Our results reveal a relative sparseness of synapses on the somata of fusiform cells but a dense distribution of synapses on apical and basal dendrites. Synapses on apical dendrites were smaller and more numerous than on basal dendrites. The vast majority of axosomatic terminals were found to be linked to other terminals connected by the same axon or different branches of the same axon, suggesting a high degree of divergent input to fusiform cells. The size of terminals was correlated with the number of mitochondria and with the number of active zones, which was highly correlated with the number of postsynaptic densities, suggesting that larger terminals exert more powerful influence on the cell than smaller terminals. These size differences suggest that the input to basal dendrites, most likely those from the auditory nerve, provide the most powerful sources of input to fusiform cells, while those to apical dendrites (e.g., parallel fiber) are weaker but more numerous.

Activation of the central nervous system induced by micro-magnetic stimulation.

Electrical and transcranial magnetic stimulations have proven to be therapeutically beneficial for patients suffering from neurological disorders. Moreover, these stimulation technologies have provided invaluable tools for investigating nervous system functions. Despite this success, these technologies have technical and practical limitations impeding the maximization of their full clinical and preclinical potential. Recently, micro-magnetic stimulation, which may offer advantages over electrical and transcranial magnetic stimulation, has proven effective in activating the neuronal circuitry of the retina in vitro. Here we demonstrate that this technology is also capable of activating neuronal circuitry on a systems level using an in vivo preparation. Specifically, the application of micro-magnetic fields to the dorsal cochlear nucleus activates inferior colliculus neurons. Additionally, we demonstrate the efficacy and characteristics of activation using different magnetic stimulation parameters. These findings provide a rationale for further exploration of micro-magnetic stimulation as a prospective tool for clinical and preclinical applications.

Improving tinnitus with mechanical treatment of the cervical spine and jaw.

BACKGROUND: Tinnitus affects approximately 30-50 million Americans. In approximately 0.5-1.0% of the population, tinnitus has a moderate to severe impact on their quality of life. Musculature and joint pathologies of the head and neck are frequently associated with tinnitus and have been hypothesized to play a contributing role in its etiology. However, specific physical therapy interventions to assist in improving tinnitus have not yet been reported. PURPOSE: To describe the examination and treatment intervention of a patient with subjective tinnitus. PATIENT DESCRIPTION: The patient was a 42-yr-old male experiencing intermittent bilateral tinnitus, headaches, blurred vision, and neck tightness. His occupation required long-term positioning into neck protraction. Examination found limitations in cervical extension, bilateral rotation, and side bending. Asymmetry was also noted with temporomandibular joint (TMJ) movements. Upon initial evaluation the patient demonstrated functional, physical, and emotional deficits per neck, headache, and dizziness self-report scales and a score on the Tinnitus Handicap Inventory (THI) of 62. Resisted muscle contractions of the cervical spine in flexion, extension, and rotation increased his tinnitus. INTERVENTION: Treatment focused on normalizing cervical spine mobility through repetitive movements, joint mobilization, and soft tissue massage. RESULTS: At 2.5 mo, the patient demonstrated a complete reversal of his tinnitus after 10 physical therapy sessions as noted by his score of 0 on the THI upon discharge. He also demonstrated objective improvements in his cervical motion. This case reflected treatment targeted at cervical and TMJ impairments and notable improvements to tinnitus. Future studies should further explore the direct and indirect treatment of tinnitus by physical therapists through clinical trials.

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.

Facial nerve neurorrhaphy and the effects of glucocorticoids in a rat model.

OBJECTIVE: After nerve injury, an exaggerated neuroinflammatory process may hinder neuron regeneration and recovery. Immunomodulation using glucocorticoids may therefore improve facial nerve injury outcomes. This study aims to examine the effect of both local and systemic dexamethasone administration on facial nerve functional recovery after axotomy in a rat model. STUDY DESIGN: Randomized, placebo-controlled, blinded animal study. Setting Animal laboratory. SUBJECTS AND METHODS: Seventy-four Wistar rats underwent facial nerve axotomy with immediate neurorrhaphy. Rats were randomly assigned a postoperative group: control (no therapy); systemic dexamethasone 0.5, 1, 5, or 10 mg/kg for 3 administrations; or topically applied dexamethasone at 2 or 4 mg/mL. Blinded, standardized facial assessments and nerve conduction studies (NCS) were performed. Gross facial motion assessments were corroborated with vibrissae frequency video analysis. RESULTS: At 8 weeks, rats receiving systemic dexamethasone at 5 mg/kg attained greater eye blink closure (P = .004) and vibrissae motion (P = .012) compared with controls. Systemic dexamethasone at 0.5, 1, and 10 mg/kg and intraoperative topical application of dexamethasone at 2 or 4 mg/mL did not produce a significant improvement in facial motion compared with controls. Nerve conduction studies show a trend of increased return of compound muscle action potential amplitude levels compared with baseline among rats that received systemic dexamethasone 5 mg/kg but do not achieve statistical significance. CONCLUSION: In a rat facial nerve axotomy model, high-dose systemic dexamethasone therapy may improve functional recovery when administered in the immediate period following neurorrhaphy.

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.

Tinnitus: Models and mechanisms.

Over the past decade, there has been a burgeoning of scientific interest in the neurobiological origins of tinnitus. During this period, numerous behavioral and physiological animal models have been developed which have yielded major clues concerning the likely neural correlates of acute and chronic forms of tinnitus and the processes leading to their induction. The data increasingly converge on the view that tinnitus is a systemic problem stemming from imbalances in the excitatory and inhibitory inputs to auditory neurons. Such changes occur at multiple levels of the auditory system and involve a combination of interacting phenomena that are triggered by loss of normal input from the inner ear. This loss sets in motion a number of plastic readjustments in the central auditory system and sometimes beyond the auditory system that culminate in the induction of aberrant states of activation that include hyperactivity, bursting discharges and increases in neural synchrony. This article will review was has been learned about the biological origins of these alterations, summarize where they occur and examine the cellular and molecular mechanisms that are most likely to underlie them.

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.

Alterations in the spontaneous discharge patterns of single units in the dorsal cochlear nucleus following intense sound exposure.

Electrophysiological recordings in the dorsal cochlear nucleus (DCN) were conducted to determine the nature of changes in single unit activity following intense sound exposure and how they relate to changes in multiunit activity. Single and multiunit spontaneous discharge rates and auditory response properties were recorded from the left DCN of tone exposed and control hamsters. The exposure condition consisted of a 10 kHz tone presented in the free-field at a level of 115 dB for 4h. Recordings conducted at 5-6 days post-exposure revealed several important changes. Increases in multiunit spontaneous neural activity were observed at surface and subsurface levels of the DCN of exposed animals, reaching a peak at intermediate depths corresponding to the fusiform cell layer and upper level of the deep layer. Extracellular spikes from single units in the DCN of both control and exposed animals characteristically displayed either M- or W-shaped waveforms, although the proportion of units with M-shaped spikes was higher in exposed animals than in controls. W-shaped spikes showed significant increases in the duration of their major peaks after exposure, suggestive of changes in the intrinsic membrane properties of neurons. Spike amplitudes were not found to be significantly increased in exposed animals. Spontaneous discharge rates of single units increased significantly from 8.7 spikes/s in controls to 15.9 spikes/s after exposure. Units with the highest activity in exposed animals displayed type III electrophysiological responses patterns, properties usually attributed to fusiform cells. Increases in spontaneous discharge rate were significantly larger when the comparison was limited to a subset of units having type III frequency response patterns. There was an increase in the incidence of simple spiking activity as well as in the incidence of spontaneous bursting activity, although the incidence of spikes occurring in bursts was low in both animal groups (i.e., <30%). Despite this low incidence, approximately half of the increase in spontaneous activity in exposed animals was accounted for by an increase in bursting activity. Finally, we found no evidence of an increase in the mean number of spontaneously active units in electrode penetrations of exposed animals compared to those in controls. Overall our results indicate that the increase in multiunit activity observed at the DCN surface reflects primarily an increase in the spontaneous discharge rates of single units below the DCN surface, of which approximately half was contributed by spikes in bursts. The highest level of hyperactivity was observed among units having the response properties most commonly attributed to fusiform cells.

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.

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.

Summary of evidence pointing to a role of the dorsal cochlear nucleus in the etiology of tinnitus.

Evidence has accumulated in the last decade that the dorsal cochlear nucleus (DCN) may be an important site in the etiology of tinnitus. This evidence comes from a combination of studies conducted in animals and humans. This paper will review the key findings, as follows. 1) Direct electrical stimulation of the DCN leads to changes in the loudness of tinnitus. This suggests that the loudness of tinnitus may be linked to changes in the level of neural activity in the DCN. 2) Exposure to tinnitus inducers, such as intense sound or cisplatin, causes neural activity in the DCN to become chronically elevated, a condition known as neuronal hyperactivity. 3) This hyperactivity is very similar to the activity that is evoked in the DCN by sound stimulation, suggesting that the hyperactivity represents a code that signals the presence of sound, even when there is no longer any sound stimulus. 4) Noise-induced hyperactivity in the DCN is correlated with tinnitus. Behavioral studies have demonstrated that animals exposed to the same intense sound that causes hyperactivity in the DCN develop tinnitus-like percepts. The correlation between the level of hyperactivity and the behavioral index of tinnitus was found to be statistically significant. 5) The DCN is a polysensory integration center, and electrophysiological studies have shown that both spontaneous activity and hyperactivity of neurons in the DCN can be modulated by stimulation of certain ipsilateral cranial nerves, such as the sensory branch of the trigeminal nerve. This ipsilateral modulation of DCN activity offers a plausible explanation of how tinnitus, when perceived on one side, can be modulated by certain manipulations of the head and neck on the side ipsilateral to the tinnitus, but rarely on the contralateral side. 6) The DCN exhibits various forms of neuronal plasticity that parallel the various forms of plasticity that characterize tinnitus. These findings collectively strengthen the view that the DCN may be a key structure that should be included as a target of anti-tinnitus treatment.

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.