Publications using TDT

The insulin receptor substrate (IRS) proteins are key mediators of insulin and insulinlike growth factor 1 (IGF-1) signaling. Protein tyrosine phosphatase (PTP)-1B dephosphorylates and inactivates both insulin and IGF-1 receptors. IRS2-deficient mice present altered hepatic insulin signaling and β-cell failure and develop type 2-like diabetes. In addition, IRS2 deficiency leads to developmental defects in the nervous system. IGF1 gene mutations cause syndromic sensorineural hearing loss in humans and mice. However, the involvement of IRS2 and PTP1B, two IGF-1 downstream signaling mediators, in hearing onset and loss has not been studied. Our objective was to study the hearing function and cochlear morphology of Irs2-null mice and the impact of PTP1B deficiency. We have studied the auditory brainstem responses and the cochlear morphology of systemic Irs2⁻/⁻Ptpn1⁺/⁺, Irs2⁺/⁺Ptpn1⁻/⁻ and Irs2⁻/⁻Ptpn1⁻/⁻ mice at different postnatal ages. The results indicated that Irs2⁻/⁻Ptpn1⁺/⁺ mice present a profound congenital sensorineural deafness before the onset of diabetes and altered cochlear morphology with hypoinnervation of the cochlear ganglion and aberrant stria vascularis, compared with wild-type mice. Simultaneous PTP1B deficiency in Irs2⁻/⁻Ptpn1⁻/⁻ mice delays the onset of deafness. We show for the first time that IRS2 is essential for hearing and that PTP1B inhibition may be useful for treating deafness associated with hyperglycemia and type 2 diabetes.

Hypothesis: Impairments of the medial olivocochlear system (MOCS) increase the risk of environmentally induced auditory neuropathy spectrum disorder (ANSD). Background: ANSD is a problem in the neural transmission of auditory information that accounts for 10% to 15% of the cases of pediatric hearing loss. The underlying mechanisms of the disorder remain poorly understood, but noise exposure is an important risk factor. The goal of this study was to identify environmental conditions and genetic predispositions that lead to ANSD. Our approach was based on the assumption that noise induces ANSD by impeding the functional maturation of the brain's sound coding pathways. Because the MOCS adjusts the sensitivity of the inner ear to noise, impairments of this feedback are predicted to increase the disruptive effects of environmental exposures. Methods: An animal model of ANSD was created by rearing mice in noise. MOCS protection was assessed by comparing the incidence of noise-induced ANSD among knockout mice lacking feedback and wild-type (WT) controls. The mice were screened for ANSD with distortion product otoacoustic emissions, auditory brainstem responses, and behavioral measures of gap detection. Single-unit recording procedures were used to link these deficits to impaired synaptic transmission in the ventral cochlear nucleus. Results: ANSD manifested in noise-reared mice as intact distortion product otoacoustic emissions, abnormal auditory brainstem responses, and impaired gap detection. The phenotype was not observed among quiet-reared WT mice but was occasionally noted among noise-reared WT mice. The incidence of ANSD significantly increased among knockout mice, especially when they were reared in noise. Conclusion: Noise promotes ANSD by altering the functional maturation of the brain's temporal pathways. Noise-induced impairments are reduced by the sound-attenuating effects of the MOCS. Noise levels do not need to be unnaturally loud to constitute significant risk in MOCS-compromised individuals.

Previous research has shown that familiarity with a talker’s voice can improve linguistic processing (herein, “Familiar Talker Advantage”), but this benefit is constrained by the context in which the talker’s voice is familiar. The current study examined how familiarity affects intelligibility by manipulating the type of talker information available to listeners. One group of listeners learned to identify bilingual talkers’ voices from English words, where they learned language-specific talker information. A second group of listeners learned the same talkers from German words, and thus only learned language-independent talker information. After voice training, both groups of listeners completed a word recognition task with English words produced by both familiar and unfamiliar talkers. Results revealed that English-trained listeners perceived more phonemes correct for familiar than unfamiliar talkers, while German-trained listeners did not show improved intelligibility for familiar talkers. The absence of a processing advantage in speech intelligibility for the German-trained listeners demonstrates limitations on the Familiar Talker Advantage, which crucially depends on the language context in which the talkers’ voices were learned; knowledge of how a talker produces linguistically relevant contrasts in a particular language is necessary to increase speech intelligibility for words produced by familiar talkers.

Acoustically interacting males of the tropical katydid Mecopoda elongata synchronize their chirps imperfectly, so that one male calls consistently earlier in time than the other. In choice situations, females prefer the leader signal, and it has been suggested that a neuronal mechanism based on directional hearing may be responsible for the asymmetric, stronger representation of the leader signal in receivers. Here, we investigated the potential mechanism in a pair of interneurons (TN1 neuron) of the afferent auditory pathway, known for its contralateral inhibitory input in directional hearing. In this interneuron, conspecific signals are reliably encoded under natural conditions, despite high background noise levels. Unilateral presentations of a conspecific chirp elicited a TN1 response where each suprathreshold syllable in the chirp was reliably copied in a phase-locked fashion. Two identical chirps broadcast with a 180 deg spatial separation resulted in a strong suppression of the response to the follower signal, when the time delay was 20 ms or more. Muting the ear on the leader side fully restored the response to the follower signal compared with unilateral controls. Time–intensity trading experiments, in which the disadvantage of the follower signal was traded against higher sound pressure levels, demonstrated the dominating influence of signal timing on the TN1 response, and this was especially pronounced at higher sound levels of the leader. These results support the hypothesis that the female preference for leader signals in M. elongata is the outcome of a sensory mechanism that originally evolved for directional hearing.

This study investigated the benefit of a priori cues in a masked nonspeech pattern identification experiment. Targets were narrowband sequences of tone bursts forming six easily identifiable frequency patterns selected randomly on each trial. The frequency band containing the target was randomized. Maskers were also narrowband sequences of tone bursts chosen randomly on every trial. Targets and maskers were presented monaurally in mutually exclusive frequency bands, producing large amounts of informational masking. Cuing the masker produced a significant improvement in performance, while holding the target frequency band constant provided no benefit. The cue providing the greatest benefit was a copy of the masker presented ipsilaterally before the target-plus-masker. The masker cue presented contralaterally, and a notched-noise cue produced smaller benefits. One possible mechanism underlying these findings is auditory “enhancement” in which the neural response to the target is increased relative to the masker by differential prior stimulation of the target and masker frequency regions. A second possible mechanism provides a benefit to performance by comparing the spectrotemporal correspondence of the cue and target-plus-masker and is effective for either ipsilateral or contralateral cue presentation. These effects improve identification performance by emphasizing spectral contrasts in sequences or streams of sounds.

While peripheral sensory neurons respond to natural stimuli with a broad range of spatiotemporal frequencies, central neurons instead respond sparsely to specific features in general. The nonlinear transformations leading to this emergent selectivity are not well understood. Here we characterized how the neural representation of stimuli changes across successive brain areas, using the electrosensory system of weakly electric fish as a model system. We found that midbrain torus semicircularis (TS) neurons were on average more selective in their responses than hindbrain electrosensory lateral line lobe (ELL) neurons. Further analysis revealed two categories of TS neurons: dense coding TS neurons that were ELL-like and sparse coding TS neurons that displayed selective responses. These neurons in general responded to preferred stimuli with few spikes and were mostly silent for other stimuli. We further investigated whether information about stimulus attributes was contained in the activities of ELL and TS neurons. To do so, we used a spike train metric to quantify how well stimuli could be discriminated based on spiking responses. We found that sparse coding TS neurons performed poorly even when their activities were combined compared with ELL and dense coding TS neurons. In contrast, combining the activities of as few as 12 dense coding TS neurons could lead to optimal discrimination. On the other hand, sparse coding TS neurons were better detectors of whether their preferred stimulus occurred compared with either dense coding TS or ELL neurons. Our results therefore suggest that the TS implements parallel detection and estimation of sensory input.

Heterozygous mutations in the gene encoding chromodomain-DNA-binding-protein 7 (CHD7) cause CHARGE syndrome, a multiple anomaly condition which includes vestibular dysfunction and hearing loss. Mice with heterozygous Chd7 mutations exhibit semicircular canal dysgenesis and abnormal inner ear neurogenesis, and are an excellent model of CHARGE syndrome. Here we characterized Chd7 expression in mature middle and inner ears, analyzed morphological features of mutant ears and tested whether Chd7 mutant mice have altered responses to noise exposure and correlated those responses to inner and middle ear structure. We found that Chd7 is highly expressed in mature inner and outer hair cells, spiral ganglion neurons, vestibular sensory epithelia and middle ear ossicles. There were no obvious defects in individual hair cell morphology by prestin immunostaining or scanning electron microscopy, and cochlear innervation appeared normal in Chd7(Gt)(/+) mice. Hearing thresholds by auditory brainstem response (ABR) testing were elevated at 4 and 16 kHz in Chd7(Gt)(/+) mice, and there were reduced distortion product otoacoustic emissions (DPOAE). Exposure of Chd7(Gt)(/+) mice to broadband noise resulted in variable degrees of hair cell loss which inversely correlated with severity of stapedial defects. The degrees of hair cell loss and threshold shifts after noise exposure were more severe in wild type mice than in mutants. Together, these data indicate that Chd7(Gt)(/+) mice have combined conductive and sensorineural hearing loss, correlating with changes in both middle and inner ears.

Noise exposure is a major cause of hearing loss. Classical methods of studying protein involvement have provided a basis for understanding signaling pathways that mediate hearing loss and damage repair but do not lend themselves to studying large networks of proteins that are likely to increase or decrease during noise trauma. To address this issue, antibody microarrays were used to quantify the very early changes in protein expression in three distinct regions of the chinchilla cochlea 2h after exposure to a 0.5-8 kHz band of noise for 2h at 112 dB SPL. The noise exposure caused significant functional impairment 2h post-exposure which only partially recovered. Distortion product otoacoustic emissions were abolished 2h after the exposure, but at 4 weeks post-exposure, otoacoustic emissions were present, but still greatly depressed. Cochleograms obtained 4 weeks post-exposure demonstrated significant loss of outer hair cells in the basal 60% of the cochlea corresponding to frequencies in the noise spectrum. A comparative analysis of the very early (2h post-exposure) noise-induced proteomic changes indicated that the sensory epithelium, lateral wall and modiolus differ in their biological response to noise. Bioinformatic analysis of the cochlear protein profile using "The Database for Annotation, Visualization and Integrated Discovery 2008" (DAVID - http://david.abcc. ncifcrf.gov) revealed the initiation of the cell death process in sensory epithelium and modiolus. An increase in Fas and phosphorylation of FAK and p38/MAPK in the sensory epithelium suggest that noise-induced stress signals at the cell membrane are transmitted to the nucleus by Fas and focal adhesion signaling through the p38/MAPK signaling pathway. Up-regulation of downstream nuclear proteins E2F3 and WSTF in immunoblots and microarrays along with their immunolocalization in the outer hair cells supported the pivotal role of p38/MAPK signaling in the mechanism underlying noise-induced hearing loss.

Apoptosis is a significant mechanism of cochlear hair cell loss from noise. Molecules that inhibit apoptotic intracellular signaling reduce cochlear damage and hearing loss from noise. The current study is an extension of a previous study of the protective value of Src-protein tyrosine kinase inhibitors against noise (Harris et al., 2005). The current study tested three Src-inhibitors: the indole-based KX1-141, the biaryl-based KX2-329, and the ATP-competitive KX2-328. Each of the three drugs was delivered into the chinchillas' cochleae by allowing the solutions to diffuse across the round window membrane thirty minutes prior to exposure to impulse noise. Hearing thresholds were measured using auditory evoked responses from electrodes in the inferior colliculi. Ears treated with KX2-329 showed significantly lower threshold shifts and outer hair cell losses than the control group. The cochleae treated with KX1-141 and KX2-328 did not show statistically significant protection from the impulse noise. The finding of protection with KX2-329 demonstrates that a biaryl-based Src inhibitor has protective capacity against noise-induced hearing loss that is as good as that demonstrated by KX1-004, a Src inhibitor drug that has been studied extensively as an otoprotectant against noise, and suggests that KX2-329 could be useful for protection against noise.

This study examines the test-retest reliability of distortion-product otoacoustic emissions (DPOAEs) in ketamine-anesthetized common marmosets (Callithrix jacchus). DPOAE gain functions were measured at 16 f(2)-frequencies between 3 and 24 kHz. Test-retest reliability was assessed at the following time intervals: (1) Interleaved, in which two gain functions were obtained at each frequency before advancing to the next frequency, (2) Immediate, wherein one gain function was collected at all f(2)-frequencies and the retest was immediately performed without removing the probe tip, (3) Short-term, in which the retest followed a 10-min period with the probe removed, and (4) Long-term, wherein the retest was performed at least one week after the initial test. Reliability was assessed using four correlation coefficients used in the literature. Test-retest reliability was best in the interleaved interval and worst in the short-term interval. In general, reliability was best when primary-tone levels were high. Correlation coefficients decreased at frequencies above 12-kHz in the short-term and long-term intervals, but the decrease was more substantial in females than in males in the long-term interval. At frequencies below 12 kHz, same-day measurements (2, 3) were less repeatable, regardless of whether the probe was removed, which may be due to time under anesthesia. These results have implications for DPOAE studies where repeated measures are required and when treatment or group differences are small.

Past studies have explored the relative strengths of auditory features in a selective attention task by pitting features against one another and asking listeners to report the words perceived in a given sentence. While these studies show that the continuity of competing features affects streaming, they did not address whether the influence of specific features is modulated by volitionally directed attention. Here, we explored whether the continuity of a task-irrelevant feature affects the ability to selectively report one of two competing speech streams when attention is specifically directed to a different feature. Sequences of simultaneous pairs of spoken digits were presented in which exactly one digit of each pair matched a primer phrase in pitch and exactly one digit of each pair matched the primer location. Within a trial, location and pitch were randomly paired; they either were consistent with each other from digit to digit or were switched (e.g., the sequence from the primer's location changed pitch across digits). In otherwise identical blocks, listeners were instructed to report digits matching the primer either in location or in pitch. Listeners were told to ignore the irrelevant feature, if possible, in order to perform well. Listener responses depended on task instructions, proving that top-down attention alters how a subject performs the task. Performance improved when the separation of the target and masker in the task-relevant feature increased. Importantly, the values of the task-irrelevant feature also influenced performance in some cases. Specifically, when instructed to attend location, listeners performed worse as the separation between target and masker pitch increased, especially when the spatial separation between digits was small. These results indicate that task-relevant and task-irrelevant features are perceptually bound together: continuity of task-irrelevant features influences selective attention in an automatic, obligatory manner, consistent with the idea that auditory attention operates on objects.

An animal's survival may depend on detecting new events or objects in its environment, and it is likely that the brain has evolved specific mechanisms to detect such changes. In sensory systems, neurons often exhibit stimulus-specific adaptation (SSA) whereby they adapt to frequently occurring stimuli, but resume firing when “surprised” by rare or new ones. In the auditory system, SSA has been identified in the midbrain, thalamus, and auditory cortex (AC). It has been proposed that the SSA observed subcortically originates in the AC as a higher-order property that is transmitted to the subcortical nuclei via corticofugal pathways. Here we report that SSA in the auditory thalamus of the rat remains intact when the AC is deactivated by cooling, thus demonstrating that the AC is not necessary for the generation of SSA in the thalamus. The AC does, however, modulate the responses of thalamic neurons in a way that strongly indicates a gain modulation mechanism. The changes imposed by the AC in thalamic neurons depend on the level of SSA that they exhibit.

Neurotrophins prevent spiral ganglion neuron (SGN) degeneration in animal models of ototoxin-induced deafness and may be used in the future to improve the hearing of cochlear implant patients. It is increasingly common for patients with residual hearing to undergo cochlear implantation. However, the effect of neurotrophin treatment on acoustic hearing is not known. In this study, brain-derived neurotrophic factor (BDNF) was applied to the round window membrane of adult guinea pigs for 4 weeks using a cannula attached to a mini-osmotic pump. SGN survival was first assessed in ototoxically deafened guinea pigs to establish that the delivery method was effective. Increased survival of SGNs was observed in the basal and middle cochlear turns of deafened guinea pigs treated with BDNF, confirming that delivery to the cochlea was successful. The effects of BDNF treatment in animals with normal hearing were then assessed using distortion product otoacoustic emissions (DPOAEs), pure tone, and click-evoked auditory brainstem responses (ABRs). DPOAE assessment indicated a mild deficit of 5 dB SPL in treated and control groups at 1 and 4 weeks after cannula placement. In contrast, ABR evaluation showed that BDNF lowered thresholds at specific frequencies (8 and 16 kHz) after 1 and 4 weeks posttreatment when compared to the control cohort receiving Ringer's solution. Longer treatment for 4 weeks not only widened the range of frequencies ameliorated from 2 to 32 kHz but also lowered the threshold by at least 28 dB SPL at frequencies ≥16 kHz. BDNF treatment for 4 weeks also increased the amplitude of the ABR response when compared to either the control cohort or prior to treatment. We show that BDNF applied to the round window reduces auditory thresholds and could potentially be used clinically to protect residual hearing following cochlear implantation.

Aminoglycoside antibiotics rapidly enter and kill cochlear hair cells via apical mechanoelectrical transduction (MET) channels in vitro. In vivo, it remains unknown whether systemically-administered aminoglycosides cross the blood-labyrinth barrier into endolymph and enter hair cells. Here we show, for the first time, that systemic aminoglycosides are trafficked across the blood-endolymph barrier and preferentially enter hair cells across their apical membranes. This trafficking route is predominant compared to uptake via hair cell basolateral membranes during perilymph infusion.

Recent studies have shown that the phase of low-frequency local field potentials (LFPs) in sensory cortices carries a significant amount of information about complex naturalistic stimuli, yet the laminar circuit mechanisms and the aspects of stimulus dynamics responsible for generating this phase information remain essentially unknown. Here we investigated these issues by means of an information theoretic analysis of LFPs and current source densities (CSDs) recorded with laminar multi-electrode arrays in the primary auditory area of anesthetized rats during complex acoustic stimulation (music and broadband 1/ f stimuli). We found that most LFP phase information originated from discrete “CSD events” consisting of granular–superficial layer dipoles of short duration and large amplitude, which we hypothesize to be triggered by transient thalamocortical activation. These CSD events occurred at rates of 2–4 Hz during both stimulation with complex sounds and silence. During stimulation with complex sounds, these events reliably reset the LFP phases at specific times during the stimulation history. These facts suggest that the informativeness of LFP phase in rat auditory cortex is the result of transient, large-amplitude events, of the “evoked” or “driving” type, reflecting strong depolarization in thalamo-recipient layers of cortex. Finally, the CSD events were characterized by a small number of discrete types of infragranular activation. The extent to which infragranular regions were activated was stimulus dependent. These patterns of infragranular activations may reflect a categorical evaluation of stimulus episodes by the local circuit to determine whether to pass on stimulus information through the output layers.

Past studies have shown that when formants are perturbed in real time, speakers spontaneously compensate for the perturbation by changing their formant frequencies in the opposite direction to the perturbation. Further, the pattern of these results suggests that the processing of auditory feedback error operates at a purely acoustic level. This hypothesis was tested by comparing the response of three language groups to real-time formant perturbations, (1) native English speakers producing an English vowel /ε/, (2) native Japanese speakers producing a Japanese vowel (/e⊤/), and (3) native Japanese speakers learning English, producing /ε/. All three groups showed similar production patterns when F1 was decreased; however, when F1 was increased, the Japanese groups did not compensate as much as the native English speakers. Due to this asymmetry, the hypothesis that the compensatory production for formant perturbation operates at a purely acoustic level was rejected. Rather, some level of phonological processing influences the feedback processing behavior.

This study was undertaken to determine the role of adenosine signalling in the development of age-related hearing loss (ARHL). We and others have shown previously that adenosine signalling via A(1) receptors is involved in cochlear protection from noise-induced cochlear injury. Here we demonstrate that enhanced adenosine signalling in the cochlea provides partial protection from ARHL in C57BL/6J mice. We targeted adenosine kinase (ADK), the key enzyme in adenosine metabolism, using a treatment regime with the selective ADK inhibitor ABT-702 (1.5mg/kg intraperitoneally twice a week) commencing at the age of three months or six months. This treatment, intended to increase free adenosine levels in the cochlea, was maintained until the age of nine months and hearing thresholds were evaluated monthly using auditory brainstem responses (ABR). At nine months, when C57BL/6J mice normally exhibit significant ARHL, both groups treated with ABT-702 showed lower ABR threshold shifts at 10 and 16kHz compared to control animals receiving the vehicle solution. The better thresholds of the ABT-702-treated mice at these frequencies were supported by increased survival of hair cells in the apical region of the cochlea. This study provides the first evidence that ARHL can be mitigated by enhancing adenosine signalling in the cochlea.

Multiple mechanisms have been shown to shape frequency-modulated (FM) selectivity within the central nucleus of the inferior colliculus (IC) in the pallid bat. In this study we focus on the mechanisms associated with sideband inhibition. The relative arrival time of inhibition compared with excitation can be used to predict FM responses as measured with a two-tone inhibition paradigm. An early-arriving low-frequency inhibition (LFI) prevents responses to upward sweeps and thus shapes direction selectivity. A late-arriving high-frequency inhibition (HFI) suppresses slow FM sweeps and thus shapes rate selectivity for downward sweeps. Iontophoretic application of gabazine (GBZ) to block GABA A receptors or strychnine (Strych) to block glycine receptors was used to assess the effects of removal of inhibition on each form of FM selectivity. GBZ and Strych had a similar effect on FM direction selectivity, reducing selectivity in up to 86% of neurons when both drugs were coapplied. FM rate selectivity was more resistant to drug application with less than 38% of neurons affected. In addition, only Strych could eliminate FM rate selectivity, whereas GBZ alone was ineffective. The loss of FM selectivity was directly correlated to a loss of the respective inhibitory sideband that shapes that form of selectivity. The elimination of LFI correlated to a loss of FM direction selectivity, whereas elimination of HFI correlated to a loss of FM rate selectivity. Results indicate that 1) although the majority of FM direction selectivity is created within the IC, the majority of rate selectivity is inherited from lower levels of the auditory system, 2) a loss of LFI corresponds to a loss of FM direction selectivity and is created through either GABAergic or glycinergic input, and 3) a loss of HFI corresponds to a loss of FM rate selectivity and is created mainly through glycinergic input.

As opposed to visual imaging, biosonar imaging of spatial object properties represents a challenge for the auditory system because its sensory epithelium is not arranged along space axes. For echolocating bats, object width is encoded by the amplitude of its echo (echo intensity) but also by the naturally covarying spread of angles of incidence from which the echoes impinge on the bat's ears (sonar aperture). It is unclear whether bats use the echo intensity and/or the sonar aperture to estimate an object's width. We addressed this question in a combined psychophysical and electrophysiological approach. In three virtual-object playback experiments, bats of the species Phyllostomus discolor had to discriminate simple reflections of their own echolocation calls differing in echo intensity, sonar aperture, or both. Discrimination performance for objects with physically correct covariation of sonar aperture and echo intensity (“object width”) did not differ from discrimination performances when only the sonar aperture was varied. Thus, the bats were able to detect changes in object width in the absence of intensity cues. The psychophysical results are reflected in the responses of a population of units in the auditory midbrain and cortex that responded strongest to echoes from objects with a specific sonar aperture, regardless of variations in echo intensity. Neurometric functions obtained from cortical units encoding the sonar aperture are sufficient to explain the behavioral performance of the bats. These current data show that the sonar aperture is a behaviorally relevant and reliably encoded cue for object size in bat sonar.

Acoustic information is conveyed to the brain by the spike patterns in auditory-nerve fibers (ANFs). In mammals, each ANF is excited via a single ribbon synapse in a single inner hair cell (IHC), and the spike patterns therefore also provide valuable information about those intriguing synapses. Here we reexamine and model a key property of ANFs, the dependence of their spike rates on the sound pressure level of acoustic stimuli (rate–level functions). We build upon the seminal model of Sachs and Abbas (1974), which provides good fits to experimental data but has limited utility for defining physiological mechanisms. We present an improved, physiologically plausible model according to which the spike rate follows a Hill equation and spontaneous activity and its experimentally observed tight correlation with ANF sensitivity are emergent properties. We apply it to 156 cat ANF rate–level functions using frequencies where the mechanics are linear and find that a single Hill coefficient of 3 can account for the population of functions. We also demonstrate a tight correspondence between ANF rate–level functions and the Ca 2+ dependence of exocytosis from IHCs, and derive estimates of the effective intracellular Ca 2+ concentrations at the individual active zones of IHCs. We argue that the Hill coefficient might reflect the intrinsic, biochemical Ca 2+ cooperativity of the Ca 2+ sensor involved in exocytosis from the IHC. The model also links ANF properties with properties of psychophysical absolute thresholds.