Single-unit data for sensory neuroscience: Responses from the auditory nerve of young-adult and aging gerbils.

This dataset was collected to study the functional consequences of age-related hearing loss for the auditory nerve, which carries acoustic information from the periphery to the central auditory system. Using high-impedance glass electrodes, raw voltage traces and spike times were recorded from more than one thousand single fibres of the auditory nerve of young-adult, middle-aged, and old Mongolian gerbils raised in a quiet environment. The dataset contains not only responses to simple acoustic stimuli to characterize the fibres, but also to more complex stimuli, such as speech logatomes in background noise and Schroeder-phase stimuli. A software toolbox is provided to search through the dataset, to plot various analysed outcomes, and to give insight into the analyses. This dataset may serve as a valuable resource to test further hypotheses about age-related hearing loss. Additionally, it can aid in optimizing available computational models of the auditory system, which can contribute to, or eventually even fully replace, animal experiments.

Pulsed Radiofrequency of the Auricular Branch of the Vagal Nerve in Tinnitus Patients.

INTRODUCTION: Pulsed radiofrequency of the auricular branch of the vagal nerve has strongly reduced tinnitus in a person with violent tinnitus and severe cervical pain. OBJECTIVES: The objective of our study was to study the long-term effects of pulsed radiofrequency of the auricular branch of the vagal nerve in a large group of tinnitus sufferers and to find predictors for a prosperous result. DESIGN: A monocenter backward-looking group study. RESULTS: 48% of tinnitus sufferers who undertook pulsed radiofrequency of the auricular branch of the vagal nerve reported a reduced loudness of their tinnitus, which was qualified as being moderate to good in 87% of these patients. The reduction exceeded mostly 1 year. An angle smaller than 3 degrees between the 2nd and 3rd cervical vertebrae on lateral radiograph predicted a better outcome of this therapy. CONCLUSION: Neuromodulation of the auricular branch of the vagal nerve is an uncomplicated remedy for tinnitus, especially for tinnitus patients with a pathologically small C2-C3 angle.

Altered neural encoding of vowels in noise does not affect behavioral vowel discrimination in gerbils with age-related hearing loss.

Introduction: Understanding speech in a noisy environment, as opposed to speech in quiet, becomes increasingly more difficult with increasing age. Using the quiet-aged gerbil, we studied the effects of aging on speech-in-noise processing. Specifically, behavioral vowel discrimination and the encoding of these vowels by single auditory-nerve fibers were compared, to elucidate some of the underlying mechanisms of age-related speech-in-noise perception deficits. Methods: Young-adult and quiet-aged Mongolian gerbils, of either sex, were trained to discriminate a deviant naturally-spoken vowel in a sequence of vowel standards against a speech-like background noise. In addition, we recorded responses from single auditory-nerve fibers of young-adult and quiet-aged gerbils while presenting the same speech stimuli. Results: Behavioral vowel discrimination was not significantly affected by aging. For both young-adult and quiet-aged gerbils, the behavioral discrimination between /eː/ and /iː/ was more difficult to make than /eː/ vs. /aː/ or /iː/ vs. /aː/, as evidenced by longer response times and lower d' values. In young-adults, spike timing-based vowel discrimination agreed with the behavioral vowel discrimination, while in quiet-aged gerbils it did not. Paradoxically, discrimination between vowels based on temporal responses was enhanced in aged gerbils for all vowel comparisons. Representation schemes, based on the spectrum of the inter-spike interval histogram, revealed stronger encoding of both the fundamental and the lower formant frequencies in fibers of quiet-aged gerbils, but no qualitative changes in vowel encoding. Elevated thresholds in combination with a fixed stimulus level, i.e., lower sensation levels of the stimuli for old individuals, can explain the enhanced temporal coding of the vowels in noise. Discussion: These results suggest that the altered auditory-nerve discrimination metrics in old gerbils may mask age-related deterioration in the central (auditory) system to the extent that behavioral vowel discrimination matches that of the young adults.

Cochlear aging disrupts the correlation between spontaneous rate- and sound-level coding in auditory nerve fibers.

The spiking activity of auditory nerve fibers (ANFs) transmits information about the acoustic environment from the cochlea to the central auditory system. Increasing age leads to degeneration of cochlear tissues, including the sensory hair cells and stria vascularis. Here, we aim to identify the functional effects of such age-related cochlear pathologies of ANFs. Rate-level functions (RLFs) were recorded from single-unit ANFs of young adult (n = 52, 3-12 months) and quiet-aged (n = 24, >36 months) Mongolian gerbils of either sex. RLFs were used to determine sensitivity and spontaneous rates (SRs) and were classified into flat-saturating, sloping-saturating, and straight categories, as previously established. A physiologically based cochlear model, adapted for the gerbil, was used to simulate the effects of cochlear degeneration on ANF physiology. In ANFs tuned to low frequencies (<3.5 kHz), SR was lower in those of aged gerbils, while an age-related loss of low-SR fibers was evident in ANFs tuned to high frequencies. These changes in SR distribution did not affect the typical SR versus sensitivity correlation. The distribution of RLF types among low-SR fibers, however, shifted toward that of high-SR fibers, specifically showing more fast-saturating and fewer sloping-saturating RLFs. A modeled striatal degeneration, which affects the combined inner hair cell and synaptic output, reduced SR but left RLF type unchanged. An additional reduced basilar membrane gain, which decreased sensitivity, explained the changed RLF types. Overall, the data indicated age-related changes in the characteristics of single ANFs that blurred the established relationships between SR and RLF types.NEW & NOTEWORTHY Auditory nerve fibers, which connect the cochlea to the central auditory system, change their encoding of sound level in aged gerbils. In addition to a general shift to higher levels, indicative of decreased sensitivity, level coding was also differentially affected in fibers with low- and high-spontaneous rates. Loss of low-spontaneous rate fibers, combined with a general decrease of spontaneous rate, further blurs the categorization of auditory nerve fiber types in the aged gerbil.

Auditory Nerve Fiber Discrimination and Representation of Naturally-Spoken Vowels in Noise.

To understand how vowels are encoded by auditory nerve (AN) fibers, a number of representation schemes have been suggested that extract the vowel's formant frequencies from AN-fiber spiking patterns. The current study aims to apply and compare these schemes for AN-fiber responses to naturally-spoken vowels in a speech-shaped background noise. Responses to three vowels were evaluated; based on behavioral experiments in the same species, two of these were perceptually difficult to discriminate from each other (/e/ vs /i/), and one was perceptually easy to discriminate from the other two (/a:/). Single-unit AN fibers were recorded from ketamine/xylazine-anesthetized Mongolian gerbils of either sex (n = 8). First, single-unit discrimination between the three vowels was studied. Compared with the perceptually easy discriminations, the average spike timing-based discrimination values were significantly lower for the perceptually difficult vowel discrimination. This was not true for an average rate-based discrimination metric, the rate d-prime (d'). Consistently, spike timing-based representation schemes, plotting the temporal responses of all recorded units as a function of their best frequency (BF), i.e., dominant component schemes, average localized interval rate, and fluctuation profiles, revealed representation of the vowel's formant frequencies, whereas no such representation was apparent in the rate-based excitation pattern. Making use of perceptual discrimination data, this study reveals that discrimination difficulties of naturally-spoken vowels in speech-shaped noise originate peripherally and can be studied in the spike timing patterns of single AN fibers.

Age-related decline in cochlear ribbon synapses and its relation to different metrics of auditory-nerve activity.

Loss of inner hair cell-auditory nerve fiber synapses is considered to be an important early stage of neural presbyacusis. Mass potentials, recorded at the cochlear round window, can be used to derive the neural index (NI), a sensitive measure for pharmacologically-induced synapse loss. Here, we investigate the applicability of the NI for measuring age-related auditory synapse loss in young-adult, middle-aged, and old Mongolian gerbils. Synapse loss, which was progressively evident in the 2 aged groups, correlated weakly with NI when measured at a fixed sound level of 60 dB SPL. However, the NI was confounded by decreases in single-unit firing rates at 60 dB SPL. NI at 30 dB above threshold, when firing rates were similar between age groups, did not correlate with synapse loss. Our results show that synapse loss is poorly reflected in the NI of aged gerbils, particularly if further peripheral pathologies are present. The NI may therefore not be a reliable clinical tool to assess synapse loss in aged humans with peripheral hearing loss.

Temporal Coding of Single Auditory Nerve Fibers Is Not Degraded in Aging Gerbils.

People suffering from age-related hearing loss typically present with deficits in temporal processing tasks. Temporal processing deficits have also been shown in single-unit studies at the level of the auditory brainstem, midbrain, and cortex of aged animals. In this study, we explored whether temporal coding is already affected at the level of the input to the central auditory system. Single-unit auditory nerve fiber recordings were obtained from 41 Mongolian gerbils of either sex, divided between young, middle-aged, and old gerbils. Temporal coding quality was evaluated as vector strength in response to tones at best frequency, and by constructing shuffled and cross-stimulus autocorrelograms, and reverse correlations, from responses to 1 s noise bursts at 10-30 dB sensation level (dB above threshold). At comparable sensation levels, all measures showed that temporal coding was not altered in auditory nerve fibers of aging gerbils. Furthermore, both temporal fine structure and envelope coding remained unaffected. However, spontaneous rates were decreased in aging gerbils. Importantly, despite elevated pure tone thresholds, the frequency tuning of auditory nerve fibers was not affected. These results suggest that age-related temporal coding deficits arise more centrally, possibly due to a loss of auditory nerve fibers (or their peripheral synapses) but not due to qualitative changes in the responses of remaining auditory nerve fibers. The reduced spontaneous rate and elevated thresholds, but normal frequency tuning, of aged auditory nerve fibers can be explained by the well known reduction of endocochlear potential due to strial dysfunction in aged gerbils.SIGNIFICANCE STATEMENT As our society ages, age-related hearing deficits become ever more prevalent. Apart from decreased hearing sensitivity, elderly people often suffer from a reduced ability to communicate in daily settings, which is thought to be caused by known age-related deficits in auditory temporal processing. The current study demonstrated, using several different stimuli and analysis techniques, that these putative temporal processing deficits are not apparent in responses of single-unit auditory nerve fibers of quiet-aged gerbils. This suggests that age-related temporal processing deficits may develop more central to the auditory nerve, possibly due to a reduced population of active auditory nerve fibers, which will be of importance for the development of treatments for age-related hearing disorders.

The aging cochlea: Towards unraveling the functional contributions of strial dysfunction and synaptopathy.

Strial dysfunction is commonly observed as a key consequence of aging in the cochlea. A large body of animal research, especially in the quiet-aged Mongolian gerbil, shows specific histopathological changes in the cochlear stria vascularis and the putatively corresponding effects on endocochlear potential and auditory nerve responses. However, recent work suggests that synaptopathy, or the loss of inner hair cell-auditory nerve fiber synapses, also presents as a consequence of aging. It is now believed that the loss of synapses is the earliest age-related degenerative event. The present review aims to integrate classic and novel research on age-related pathologies of the inner ear. First, we summarize current knowledge on age-related strial dysfunction and synaptopathy. We describe how these cochlear pathologies fit into the categories for presbyacusis, as first defined by Schuknecht in the '70s. Further, we discuss how strial dysfunction and synaptopathy affect sound coding by the auditory nerve and how they can be experimentally induced to study their specific contributions to age-related hearing deficits. As such, we aim to give an overview of the current literature on age-related cochlear pathologies and hope to inspire further research on the role of cochlear aging in age-related hearing deficits.

Neural coding of the sound envelope is changed in the inferior colliculus immediately following acoustic trauma.

Sensorineural hearing loss is often accompanied by difficulties with understanding speech in fluctuating backgrounds, suggesting that neural coding of complex sound features, such as the sound envelope, is impaired. Here, we studied how temporal and rate coding of the envelope is affected in the inferior colliculus immediately after acoustic trauma. Neural activity in response to amplitude-modulated noise was recorded from the inferior colliculus of the guinea pig, before and immediately after a 1-hr 11-kHz acoustic trauma. Units with a characteristic frequency (CF) below the trauma frequency (<11 kHz) showed increased response gains, a measure for temporal coding of the sound envelope, especially at low modulation frequencies (≤128 Hz). Units with a CF > 11 kHz, which had large acoustic trauma-induced threshold shifts, had decreased response gains to amplitude-modulated noise. Shapes of temporal modulation transfer functions shifted toward a higher proportion of low-pass shapes in low-CF units, and to less band-pass shapes in high-CF units. Furthermore, driven firing rates decreased, especially at high modulation frequencies for high-CF units. The observed changes occurred immediately following trauma and were thus a result of the immediate trauma-induced damage to the auditory system. If also present in human subjects, reduced response gains in high-frequency units could disrupt coding of consonants and consequently impair speech understanding in noisy environments. Moreover, the enhanced temporal coding by low-CF units of the low modulation frequencies could overly amplify responses to low-frequency noise, further deteriorating listening in noise.

Glutamatergic Projections to the Cochlear Nucleus are Redistributed in Tinnitus.

Tinnitus alters auditory-somatosensory plasticity in the cochlear nucleus (CN). Correspondingly, bimodal auditory-somatosensory stimulation treatment attenuates tinnitus, both in animals and humans (Marks et al., 2018). Therefore, we hypothesized that tinnitus is associated with altered somatosensory innervation of the CN. Here, we studied the expression of vesicular glutamate transporters 1 and 2 (VGLUT1 and VGLUT2) in the CN, which reveals glutamatergic projections from the cochlea as well as somatosensory systems to this brainstem auditory center. Guinea pigs were unilaterally exposed to narrowband noise and behaviorally tested for tinnitus using gap-prepulse inhibition of the acoustic startle. Following physiological and behavioral measures, brain sections were immunohistochemically stained for VGLUT1 or VGLUT2. Puncta density was determined for each region of the ipsilateral and contralateral CN. Tinnitus was associated with an ipsilateral upregulation of VGLUT2 puncta density in the granule cell domain (GCD) and anteroventral CN (AVCN). Furthermore, there was a tinnitus-associated interaural asymmetry for VGLUT1 expression in the AVCN and deep layer of the dorsal CN (DCN3), due to contralateral downregulation of VGLUT1 expression. These tinnitus-related glutamatergic imbalances were reversed upon bimodal stimulation treatment. Tinnitus-associated ipsilateral upregulation of VGLUT2-positive projections likely derives from somatosensory projections to the GCD and AVCN. This upregulation may underlie the neurophysiological hallmarks of tinnitus in the CN. Reversing the increased ipsilateral glutamatergic innervation in the CN is likely a key mechanism in treating tinnitus.

Multisensory Integration Enhances Temporal Coding in Ventral Cochlear Nucleus Bushy Cells.

Temporal coding of auditory stimuli is critical for understanding communication signals. The bushy cell, a major output neuron of the ventral cochlear nucleus, can "phase-lock" precisely to pure tones and the envelopes of complex stimuli. Bushy cells are also putative recipients of brainstem somatosensory projections and could therefore play a role in perception of communication signals because multisensory integration is required for such complex sound processing. Here, we examine the role of multisensory integration in temporal coding in bushy cells by activating the spinal trigeminal nucleus (Sp5) while recording responses from bushy cells. In normal-hearing guinea pigs of either sex, bushy cell single unit responses to amplitude-modulated (AM) broadband noise were compared with those in the presence of preceding Sp5 electrical stimulation (i.e., bimodal stimuli). Responses to the AM stimuli were also compared with those obtained 45 min after the bimodal stimulation. Bimodal auditory-Sp5 stimulation resulted in enhanced envelope coding for low modulation frequencies, which persisted for up to 45 min. AM detection thresholds were significantly improved 45 min after bimodal auditory-Sp5 stimulation, but not during bimodal auditory-Sp5 stimulation. Anterograde labeling of Sp5 projections was found within the dendritic fields of bushy cells and their inhibitory interneurons, D-stellate cells. Therefore, enhanced AM responses and improved AM sensitivity of bushy cells were likely facilitated by Sp5 neurons through monosynaptic excitatory projections and indirect inhibitory projections. These somatosensory projections may be involved in the improved perception of communication stimuli with multisensory stimulation, consistent with psychophysical studies in humans.SIGNIFICANCE STATEMENT Multisensory integration is crucial for sensory coding because it improves sensitivity to unimodal stimuli and enhances responses to external stimuli. Although multisensory integration has typically been described in the cerebral cortex, the cochlear nucleus in the brainstem is also innervated by multiple sensory systems, including the somatosensory and auditory systems. Here, we showed that convergence of these two sensory systems in the cochlear nucleus results in improved temporal coding in bushy cells, principal output neurons that send projections to higher auditory structures. The improved temporal coding instilled by bimodal auditory-Sp5 stimulation may be important in priming the neurons for coding biologically relevant sounds such as communication signals.

Selective hair cell ablation and noise exposure lead to different patterns of changes in the cochlea and the cochlear nucleus.

In experimental animal models of auditory hair cell (HC) loss, insults such as noise or ototoxic drugs often lead to secondary changes or degeneration in non-sensory cells and neural components, including reduced density of spiral ganglion neurons, demyelination of auditory nerve fibers and altered cell numbers and innervation patterns in the cochlear nucleus (CN). However, it is not clear whether loss of HCs alone leads to secondary degeneration in these neural components of the auditory pathway. To elucidate this issue, we investigated changes of central components after cochlear insults specific to HCs using diphtheria toxin receptor (DTR) mice expressing DTR only in HCs and exhibiting complete HC loss when injected with diphtheria toxin (DT). We showed that DT-induced HC ablation has no significant impacts on the survival of auditory neurons, central synaptic terminals, and myelin, despite complete HC loss and profound deafness. In contrast, noise exposure induced significant changes in synapses, myelin and CN organization even without loss of inner HCs. We observed a decrease of neuronal size in the auditory pathway, including peripheral axons, spiral ganglion neurons, and CN neurons, likely due to loss of input from the cochlea. Taken together, selective HC ablation and noise exposure showed different patterns of pathology in the auditory pathway and the presence of HCs is not essential for the maintenance of central synaptic connectivity and myelination.

Spontaneous behavior in noise and silence: a possible new measure to assess tinnitus in Guinea pigs.

This study describes two experiments that were conducted in search for a behavioral paradigm to test for tinnitus in guinea pigs. Conditioning paradigms are available to determine the presence of tinnitus in animals and are based on the assumption that tinnitus impairs their ability to detect silent intervals in continuous noise. Guinea pigs have not been subjected to these paradigms yet; therefore, we investigated whether guinea pigs could be conditioned in the two-way shuttle-box paradigm to respond to silent intervals in noise. Even though guinea pigs could be trained relatively easy to respond to the presence of a noise interval, training guinea pigs to silent intervals in noise was unsuccessful. Instead, it appeared that they became immobile when the continuous stimulus was suddenly stopped. This was confirmed by the next experiment, in which we subjected guinea pigs to alternating intervals of noise and silence with a random duration between 30 and 120 s. Indeed, guinea pigs were significantly longer immobile during silence compared to during noise. By interpreting immobility as a signature of perceiving silence, we hypothesized that the presence of tinnitus would reduce immobility in silence. Therefore, we unilaterally exposed one group of guinea pigs to an 11-kHz tone of 124 dB sound pressure level for 1 h. A subset of the exposed animals was significantly more active in silence, but also more active in noise, as compared to the control group. The increased mobility during silent intervals might represent tinnitus. However, the increased mobility in noise of this group implies that the observed behavior could have derived from, e.g., an overall increase in activity. Therefore, conducting validation experiments is very important before implementing this method as a new screening tool for tinnitus. Follow-up experiments are discussed to further elucidate the origin of the increased mobility in both silence and noise.

A time for learning and a time for sleep: the effect of sleep deprivation on contextual fear conditioning at different times of the day.

STUDY OBJECTIVES: Sleep deprivation negatively affects memory consolidation, especially in the case of hippocampus-dependent memories. Studies in rodents have shown that 5 hours of sleep deprivation immediately following footshock exposure selectively impairs the formation of a contextual fear memory. In these studies, both acquisition and subsequent sleep deprivation were performed in the animals' main resting phase. However, in everyday life, subjects most often learn during their active phase. DESIGN: Here we examined the effects of sleep deprivation on memory consolidation for contextual fear in rats when the task was performed at different times of the day, particularly, at the beginning of the resting phase or right before the onset of the active phase. MEASUREMENTS AND RESULTS: Results show that sleep deprivation immediately following training affects consolidation of contextual fear, independent of time of training. However, in the resting phase memory consolidation was impaired by 6 hours of posttraining sleep deprivation, whereas, in the active phase, the impairment was only seen after 12 hours of sleep deprivation. Since rats sleep at least twice as much during the resting phase compared with the active phase, these data suggest that the effect of sleep deprivation depends on the amount of sleep that was lost. Also, control experiments show that effects of sleep deprivation were not related to the amount of stimulation the animals received and were therefore not likely an indirect effect of the sleep-deprivation method. CONCLUSION: These results support the notion that sleep immediately following acquisition, independent of time of day, promotes memory consolidation and that sleep deprivation may disrupt this process depending on the amount of sleep that is lost.