Publications using TDT

Fragile X Syndrome (FXS), a neurodevelopmental disorder, is the most prevalent single-gene cause of autism spectrum disorder. Autism has been associated with impaired auditory processing, abnormalities in the auditory brainstem response (ABR), and reduced cell number and size in the auditory brainstem nuclei. FXS is characterized by elevated cortical responses to sound stimuli, with some evidence for aberrant ABRs. Here, we assessed ABRs and auditory brainstem anatomy in Fmr1-/- mice, an animal model of FXS. We found that Fmr1-/- mice showed elevated response thresholds to both click and tone stimuli. Amplitudes of ABR responses were reduced in Fmr1-/- mice for early peaks of the ABR. The growth of the peak I response with sound intensity was less steep in mutants that in wild type mice. In contrast, amplitudes and response growth in peaks IV and V did not differ between these groups. We did not observe differences in peak latencies or in interpeak latencies. Cell size was reduced in Fmr1-/- mice in the ventral cochlear nucleus (VCN) and in the medial nucleus of the trapezoid body (MNTB). We quantified levels of inhibitory and excitatory synaptic inputs in these nuclei using markers for presynaptic proteins. We measured VGAT and VGLUT immunolabeling in VCN, MNTB, and the lateral superior olive (LSO). VGAT expression in MNTB was significantly greater in the Fmr1-/- mouse than in wild type mice. Together, these observations demonstrate that FXS affects peripheral and central aspects of hearing and alters the balance of excitation and inhibition in the auditory brainstem.

So far, most studies of core auditory cortex (AC) have characterized the spectral and temporal tuning properties of cells in non-awake, anesthetized preparations. As experiments in awake animals are scarce, we here used dynamic spectral-temporal broadband ripples to study the properties of the spectrotemporal receptive fields (STRFs) of AC cells in awake monkeys. We show that AC neurons were typically most sensitive to low ripple densities (spectral) and low velocities (temporal), and that most cells were not selective for a particular spectrotemporal sweep direction. A substantial proportion of neurons preferred amplitude-modulated sounds (at zero ripple density) to dynamic ripples (at non-zero densities). The vast majority (>93%) of modulation transfer functions were separable with respect to spectral and temporal modulations, indicating that time and spectrum are independently processed in AC neurons. We also analyzed the linear predictability of AC responses to natural vocalizations on the basis of the STRF. We discuss our findings in the light of results obtained from the monkey midbrain inferior colliculus by comparing the spectrotemporal tuning properties and linear predictability of these two important auditory stages.

Sound categorization is essential for auditory behaviors like acoustic communication, but its genesis within the auditory pathway is not well understood—especially for learned natural categories like vocalizations, which often share overlapping acoustic features that must be distinguished (e.g., speech). We use electrophysiological mapping and single-unit recordings in mice to investigate how representations of natural vocal categories within core auditory cortex are modulated when one category acquires enhanced behavioral relevance. Taking advantage of a maternal mouse model of acoustic communication, we found no long-term auditory cortical map expansion to represent a behaviorally relevant pup vocalization category—contrary to expectations from the cortical plasticity literature on conditioning with pure tones. Instead, we observed plasticity that improved the separation between acoustically similar pup and adult vocalization categories among a physiologically defined subset of late-onset, putative pyramidal neurons, but not among putative interneurons. Additionally, a larger proportion of these putative pyramidal neurons in maternal animals compared with nonmaternal animals responded to the individual pup call exemplars having combinations of acoustic features most typical of that category. Together, these data suggest that higher-order representations of acoustic categories arise from a subset of core auditory cortical pyramidal neurons that become biased toward the combination of acoustic features statistically predictive of membership to a behaviorally relevant sound category.

Critical periods are developmental windows during which the stimuli an animal encounters can reshape response properties in the affected system to a profound degree. Despite this window's importance, the neural mechanisms that regulate it are not completely understood. Pioneering studies in visual cortex initially indicated that norepinephrine (NE) permits ocular dominance column plasticity during the critical period, but later research has suggested otherwise. More recent work implicating NE in experience-dependent plasticity in the adult auditory cortex led us to re-examine the role of NE in critical period plasticity. Here, we exposed dopamine β-hydroxylase knock-out ( Dbh −/− ) mice, which lack NE completely from birth, to a biased acoustic environment during the auditory cortical critical period. This manipulation led to a redistribution of best frequencies (BFs) across auditory cortex in our control mice, consistent with prior work. By contrast, Dbh −/− mice failed to exhibit the expected redistribution of BFs, even though NE-deficient and NE-competent mice showed comparable auditory cortical organization when reared in a quiet colony environment. These data suggest that while intrinsic tonotopic patterning of auditory cortical circuitry occurs independently from NE, NE is required for critical period plasticity in auditory cortex.

In mammals, efferent projections to the cochlear receptor are constituted by olivocochlear (OC) fibers that originate in the superior olivary complex. Medial and lateral OC neurons make synapses with outer hair cells and with auditory nerve fibers, respectively. In addition to the OC system, there are also descending projections from the auditory cortex that are directed towards the thalamus, inferior colliculus, cochlear nucleus, and superior olivary complex. Olivocochlear function can be assessed by measuring a brainstem reflex mediated by auditory nerve fibers, cochlear nucleus neurons, and OC fibers. Although it is known that the OC reflex is activated by contralateral acoustic stimulation and produces a suppression of cochlear responses, the influence of cortical descending pathways in the OC reflex is largely unknown. Here, we used auditory cortex electrical microstimulation in chinchillas to study a possible cortical modulation of cochlear and auditory nerve responses to tones in the absence and presence of contralateral noise. We found that cortical microstimulation produces two different peripheral modulations: (i) changes in cochlear sensitivity evidenced by amplitude modulation of cochlear microphonics and auditory nerve compound action potentials and (ii) enhancement or suppression of the OC reflex strength as measured by auditory nerve responses, which depended on the intersubject variability of the OC reflex. Moreover, both corticofugal effects were not correlated, suggesting the presence of two functionally different efferent pathways. These results demonstrate that auditory cortex electrical microstimulation independently modulates the OC reflex strength and cochlear sensitivity.

In noisy settings, listening is aided by correlated dynamic visual cues gleaned from a talker's face—an improvement often attributed to visually reinforced linguistic information. In this study, we aimed to test the effect of audio–visual temporal coherence alone on selective listening, free of linguistic confounds. We presented listeners with competing auditory streams whose amplitude varied independently and a visual stimulus with varying radius, while manipulating the cross-modal temporal relationships. Performance improved when the auditory target's timecourse matched that of the visual stimulus. The fact that the coherence was between task-irrelevant stimulus features suggests that the observed improvement stemmed from the integration of auditory and visual streams into cross-modal objects, enabling listeners to better attend the target. These findings suggest that in everyday conditions, where listeners can often see the source of a sound, temporal cues provided by vision can help listeners to select one sound source from a mixture.

Clinical audiometry has long focused on determining the detection thresholds for pure tones, which depend on intact cochlear mechanics and hair cell function. Yet many listeners with normal hearing thresholds complain of communication difficulties, and the causes for such problems are not well understood. Here, we explore whether normal-hearing listeners exhibit such suprathreshold deficits, affecting the fidelity with which subcortical areas encode the temporal structure of clearly audible sound. Using an array of measures, we evaluated a cohort of young adults with thresholds in the normal range to assess both cochlear mechanical function and temporal coding of suprathreshold sounds. Listeners differed widely in both electrophysiological and behavioral measures of temporal coding fidelity. These measures correlated significantly with each other. Conversely, these differences were unrelated to the modest variation in otoacoustic emissions, cochlear tuning, or the residual differences in hearing threshold present in our cohort. Electroencephalography revealed that listeners with poor subcortical encoding had poor cortical sensitivity to changes in interaural time differences, which are critical for localizing sound sources and analyzing complex scenes. These listeners also performed poorly when asked to direct selective attention to one of two competing speech streams, a task that mimics the challenges of many everyday listening environments. Together with previous animal and computational models, our results suggest that hidden hearing deficits, likely originating at the level of the cochlear nerve, are part of “normal hearing.”

In the diverse mechanosensory systems that animals evolved, the waveform of stimuli can be encoded by phase locking in spike trains of primary afferents. Coding of the fine structure of sounds via phase locking is thought to be critical for hearing. The upper frequency limit of phase locking varies across species and is unknown in humans. We applied a method developed previously, which is based on neural adaptation evoked by forward masking, to analyze mass potentials recorded on the cochlea and auditory nerve in the cat. The method allows us to separate neural phase locking from receptor potentials. We find that the frequency limit of neural phase locking obtained from mass potentials was very similar to that reported for individual auditory nerve fibers. The results suggest that this is a promising approach to examine neural phase locking in humans with normal or impaired hearing or in other species for which direct recordings from primary afferents are not feasible.

Hearing loss resulting from hair cell degeneration is a common disease that affects millions of people worldwide. Strategies to overcome the apparent irreversible hair cell loss in mammals become paramount for hearing protection. Here we reported that, by using a well-established gentamicin-induced hair cell loss model in vitro, adjudin, a multi-functional small molecule drug, protected cochlear hair cells from gentamicin damage. Immunohistochemistry, Western blotting and quantitative RT-PCR analyses revealed that adjudin exerted its otoprotective effects by up-regulating the level of Sirt3, a member of Sirtuin family protein located in mitochondria, which regulates reactive oxygen species (ROS) production in cochlear cells and inhibits the production of ROS and apoptotic cells induced by gentamicin. Sirt3 silencing experiments confirmed that Sirt3-ROS signaling axis mediated hair cell protection against gentamicin by adjudin, at least in part. Furthermore, adjudin's otoprotection effects were also observed in an in vivo gentamicin-injured animal model. Taken together, these findings identify adjudin as a novel otoprotective small molecule via elevating Sirt3 levels and Sirt3 may be of therapeutic value in hair cell protection from ototoxic insults.

When competing speech sounds are spatially separated, listeners can make use of the ear with the better target-to-masker ratio. Recent studies showed that listeners with normal hearing are able to efficiently make use of this “better-ear,” even when it alternates between left and right ears at different times in different frequency bands, which may contribute to the ability to listen in spatialized speech mixtures. In the present study, better-ear glimpsing in listeners with bilateral sensorineural hearing impairment, who perform poorly in spatialized speech mixtures, was investigated. The results suggest that this deficit is not related to better-ear glimpsing.

Short-time spectral changes in the speech signal are important for understanding noise-vocoded sentences. These information-bearing acoustic changes, measured using cochlea-scaled entropy in cochlear implant simulations [CSECI; Stilp et al. (2013). J. Acoust. Soc. Am. 133(2), EL136–EL141; Stilp (2014). J. Acoust. Soc. Am. 135(3), 1518–1529], may offer better understanding of speech perception by cochlear implant (CI) users. However, perceptual importance of CSECI for normal-hearing listeners was tested at only one spectral resolution and one temporal resolution, limiting generalizability of results to CI users. Here, experiments investigated the importance of these informational changes for understanding noise-vocoded sentences at different spectral resolutions (4–24 spectral channels; Experiment 1), temporal resolutions (4–64 Hz cutoff for low-pass filters that extracted amplitude envelopes; Experiment 2), or when both parameters varied (6–12 channels, 8–32 Hz; Experiment 3). Sentence intelligibility was reduced more by replacing high-CSECI intervals with noise than replacing low-CSECI intervals, but only when sentences had sufficient spectral and/or temporal resolution. High-CSECI intervals were more important for speech understanding as spectral resolution worsened and temporal resolution improved. Trade-offs between CSECI and intermediate spectral and temporal resolutions were minimal. These results suggest that signal processing strategies that emphasize information-bearing acoustic changes in speech may improve speech perception for CI users.

Tinnitus has been associated with enhanced central gain manifested by increased spontaneous activity and sound-evoked firing rates of principal neurons at various stations of the auditory pathway. Yet, the mechanisms leading to these modifications are not well understood. In a recent in vivo study, we demonstrated that stimulus-timing-dependent bimodal plasticity mediates modifications of spontaneous and tone-evoked responses of fusiform cells in the dorsal cochlear nucleus (DCN) of the guinea pig. Fusiform cells from sham animals showed primarily Hebbian learning rules while noise-exposed animals showed primarily anti-Hebbian rules, with broadened profiles for the animals with behaviorally verified tinnitus (Koehler SD, Shore SE. J Neurosci 33: 19647–19656, 2013a). In the present study we show that well-timed bimodal stimulation induces alterations in the rate-level functions (RLFs) of fusiform cells. The RLF gains and maximum amplitudes show Hebbian modifications in sham and no-tinnitus animals but anti-Hebbian modifications in noise-exposed animals with evidence for tinnitus. These findings suggest that stimulus-timing bimodal plasticity produced by the DCN circuitry is a contributing mechanism to enhanced central gain associated with tinnitus.

Selective attention enhances cortical activity representing an attended sound stream in human posterolateral superior temporal gyrus (PLST). It is unclear, however, what mechanisms are associated with a target detection task that necessitates sustained attention (vigilance) to a sound stream. We compared responses elicited by target and non-target sounds, and to sounds presented in a passive-listening paradigm. Subjects were neurosurgical patients undergoing invasive monitoring for medically refractory epilepsy. Stimuli were complex tones, band-limited noise bursts and speech syllables. High gamma cortical activity (70-150 Hz) was examined in all subjects using subdural grid electrodes implanted over PLST. Additionally, responses were measured from depth electrodes implanted within Heschl's gyrus (HG) in one subject. Responses to target sounds recorded from PLST were increased when compared to responses elicited by the same sounds when they were not-targets, and when they were presented during passive listening. Increases in high gamma activity to target sounds occurred during later portions (after 250 ms) of the response. These increases were related to the task and not to detailed stimulus characteristics. In contrast, earlier activity that did not vary across conditions did represent stimulus acoustic characteristics. Effects observed on PLST were not noted in HG. No consistent effects were noted in the averaged evoked potentials in either cortical region. We conclude that task dependence modulates later activity in PLST during vigilance. Later activity may represent feedback from higher cortical areas. Study of concurrently recorded activity from frontoparietal areas is necessary to further clarify task-related modulation of activity on PLST.

Objective: By attaching a transducer to the aural cartilage, a relatively loud sound is audible even with a negligibly small fixation force. Previous study has identified several pathways for sound transmission by means of cartilage conduction. This investigation focused on the relative contribution of direct vibration of the aural cartilage to sound transmission in an open and in an occluded ear. Methods: Thresholds with and without an earplug were compared for three experimental conditions: the transducer being placed on the tragus, pretragus, and mastoid. Eight volunteers with normal hearing participated. Results: The thresholds increased with distance of the transducer from the ear canal (tragus, pretragus, mastoid, in that order). The differences were statistically significant for all conditions except for the occluded ear at 4 kHz. With the earplug inserted, the thresholds for the tragus condition were most sensitive below 2 kHz, indicating a significant contribution of direct vibration of the aural cartilage. Conclusion: Direct vibration of the aural cartilage can enhance sound transmission. At low frequencies, cartilage conduction can deliver sound efficiently across a blockage in the ear canal. Stray airborne sound radiating from the transducer dominates cartilage conduction in the open ear at high frequencies.

Objective: The Brazilian-Portuguese hearing in noise test (HINT) was used to investigate the benefit to speech recognition of listening in a fluctuating background. The goal was to determine whether modulation masking release varied as a function of the speech-to-masker ratio at threshold. Speech-to-masker ratio at threshold was manipulated using the novel approach of adjusting the time-compression of the speech. Design: Experiment 1 measured performance-intensity functions in both a steady speech-shaped noise masker and a 10-Hz square-wave modulated masker. Experiment 2 measured speech-to-masker ratios at threshold as a function of time-compression of the speech (0, 33, and 50%) in both maskers. Study sample: Participants were normal-hearing adults who were native speakers of Brazilian Portuguese (Experiment 1: N = 10; Experiment 2: N = 30). Results: The slope of the performance-intensity function was shallower in the modulated masker than in the steady masker for both words and sentences. Thresholds increased with increasing time-compression in both maskers, but more markedly in the modulated masker, resulting in reduced modulation masking release with increasing time-compression. Conclusions: Speech-to-masker ratio at threshold varies with time-compression of speech. The results are relevant to the issue of whether degree of masker modulation benefit depends on speech-to-masker ratio at threshold.

Human sound localization abilities rely on binaural and spectral cues. Spectral cues arise from interactions between the sound wave and the listener's body (head-related transfer function, HRTF). Large individual differences were reported in localization abilities, even in young normal-hearing adults. Several studies have attempted to determine whether localization abilities depend mostly on acoustical cues or on perceptual processes involved in the analysis of these cues. These studies have yielded inconsistent findings, which could result from methodological issues. In this study, we measured sound localization performance with normal and modified acoustical cues (i.e., with individual and non-individual HRTFs, respectively) in 20 naïve listeners. Test conditions were chosen to address most methodological issues from past studies. Procedural training was provided prior to sound localization tests. The results showed no direct relationship between behavioral results and an acoustical metrics (spectral-shape prominence of individual HRTFs). Despite uncertainties due to technical issues with the normalization of the HRTFs, large acoustical differences between individual and non-individual HRTFs appeared to be needed to produce behavioral effects. A subset of 15 listeners then trained in the sound localization task with individual HRTFs. Training included either visual correct-answer feedback (for the test group) or no feedback (for the control group), and was assumed to elicit perceptual learning for the test group only. Few listeners from the control group, but most listeners from the test group, showed significant training-induced learning. For the test group, learning was related to pre-training performance (i.e., the poorer the pre-training performance, the greater the learning amount) and was retained after 1 month. The results are interpreted as being in favor of a larger contribution of perceptual factors than of acoustical factors to sound localization abilities with virtual sources.

Objective: Age-related hearing loss (AHL), or presbycusis, is the most common sensory disorder among the elderly. We used C57BL/6J mice as an AHL model to determine a possible association between AHL and a high-fat diet (HFD). Methods: Forty C57BL/6J mice were randomly assigned to a control or HFD group. Each group was divided into the following subgroups: 1-, 3-, 5- and 12-month groups (HFD, n = 5/subgroup; control, n = 5/subgroup). Nine CBA/N-slc mice were also used as a 12-month control (n = 5) or 12-month HFD (n = 4) group. The mice were fed a HFD or normal (control) diet throughout this study. Hearing function was evaluated at 1, 3, 5 and 12 months using auditory evoked brainstem responses (ABRs). Spiral ganglion cells (SGCs) were also counted. Results: The elevation of ABR thresholds (at 4 and 32 kHz) at 3 and 5 months was significantly suppressed in the HFD group compared with the control groups for C57BL/6J mice. After 12 months, the elevation of ABR thresholds was significantly suppressed in the HFD group at all frequencies for C57BL/6J mice. In contrast, CBA/N-slc mice displayed opposite outcomes, as ABR thresholds at all frequencies at 12 months were significantly elevated in the HFD group compared with the control group. For the C57BL/6J mice at 12 months, SGC numbers significantly decreased in all parts of the cochleae in the control group compared with the HFD groups. In contrast, for the CBA/N-slc mice, SGC numbers significantly decreased, particularly in the upper parts of the cochleae in the HFD group compared with the control groups. Conclusions: The elevation in ABR thresholds and SGC loss associated with aging in the HFD-fed C57BL/6J mice were significantly suppressed compared with those in the normal diet-fed mice. These results suggest that HFD delays AHL progression in the C57B/6J mice.

The adult brain continues to learn and can recover from injury, but the elements and operation of the neural circuits responsible for this plasticity are not known. In previous work, we have shown that locomotion dramatically enhances neural activity in the visual cortex (V1) of the mouse (Niell and Stryker, 2010), identified the cortical circuit responsible for this enhancement (Fu et al., 2014), and shown that locomotion also dramatically enhances adult plasticity (Kaneko and Stryker, 2014). The circuit that is responsible for enhancing neural activity in the visual cortex contains both vasoactive intestinal peptide (VIP) and somatostatin (SST) neurons (Fu et al., 2014). Here, we ask whether this VIP-SST circuit enhances plasticity directly, independent of locomotion and aerobic activity. Optogenetic activation or genetic blockade of this circuit reveals that it is both necessary and sufficient for rapidly increasing V1 cortical responses following manipulation of visual experience in adult mice. These findings reveal a disinhibitory circuit that regulates adult cortical plasticity.

Retrograde degeneration of spiral ganglion cells in the cochlea following hair cell loss is similar to dying back in pathology. The EFR3A gene has recently been discovered to be involved in the pathogenesis of dying back. The relationship of EFR3A and spiral ganglion degeneration, however, was rarely investigated. In this study, we destroyed the hair cells of the mouse cochlea by co-administration of kanamycin and furosemide and then investigated the EFR3A expression during the induced spiral ganglion cell degeneration. Our results revealed that co-administration of kanamycin and furosemide quickly induced hair cell loss in the C57BL/6J mice and then resulted in progressive degeneration of the spiral ganglion beginning at day 5 following drug administration. The number of the spiral ganglion cells began to decrease at day 15. The expression of EFR3A increased remarkably in the spiral ganglion at day 5 and then decreased to near normal level within the next 10 days. Our study suggested that the change of EFR3A expression in the spiral ganglion was coincident with the time of the spiral ganglion degeneration, which implied that high expression of EFR3A may be important to prompt initiation of spiral ganglion degeneration following hair cell loss.

Reactive oxygen species (ROS) accumulation are involved in noise- and ototoxic drug-induced hair cell loss, which is the major cause of hearing loss. Bmi1 is a member of the Polycomb protein family and has been reported to regulate mitochondrial function and ROS level in thymocytes and neurons. In this study, we reported the expression of Bmi1 in mouse cochlea and investigated the role of Bmi1 in hair cell survival. Bmi1 expressed in hair cells and supporting cells in mouse cochlea. Bmi1 −/− mice displayed severe hearing loss and patched outer hair cell loss from postnatal day 22. Ototoxic drug-induced hair cells loss dramatically increased in Bmi1 −/− mice compared with that in wild-type controls both in vivo and in vitro , indicating Bmi1 −/− hair cells were significantly more sensitive to ototoxic drug-induced damage. Cleaved caspase-3 and TUNEL staining demonstrated that apoptosis was involved in the increased hair cell loss of Bmi1 −/− mice. Aminophenyl fluorescein and MitoSOX Red staining showed the level of free radicals and mitochondrial ROS increased in Bmi1 −/− hair cells due to the aggravated disequilibrium of antioxidant–prooxidant balance. Furthermore, the antioxidant N -acetylcysteine rescued Bmi1 −/− hair cells from neomycin injury both in vitro and in vivo , suggesting that ROS accumulation was mainly responsible for the increased aminoglycosides sensitivity in Bmi1 −/− hair cells. Our findings demonstrate that Bmi1 has an important role in hair cell survival by controlling redox balance and ROS level, thus suggesting that Bmi1 may work as a new therapeutic target for the prevention of hair cell death.