Auditory Research publications

This study addresses the relationship between cochlear oxidative damage and auditory cortical injury in a rat model of repeated noise exposure. To test the effect of increased antioxidant defenses, a water-soluble coenzyme Q 10 analog (Q ter ) was used. We analyzed auditory function, cochlear oxidative stress, morphological alterations in auditory cortices and cochlear structures, and levels of coenzymes Q 9 and Q 10 (CoQ 9 and CoQ 10 , respectively) as indicators of endogenous antioxidant capability. We report three main results. First, hearing loss and damage in hair cells and spiral ganglion was determined by noise-induced oxidative stress. Second, the acoustic trauma altered dendritic morphology and decreased spine number of II–III and V–VI layer pyramidal neurons of auditory cortices. Third, the systemic administration of the water-soluble CoQ 10 analog reduced oxidative-induced cochlear damage, hearing loss, and cortical dendritic injury. Furthermore, cochlear levels of CoQ 9 and CoQ 10 content increased. These findings indicate that antioxidant treatment restores auditory cortical neuronal morphology and hearing function by reducing the noise-induced redox imbalance in the cochlea and the deafferentation effects upstream the acoustic pathway.

Individuals with terminal and interstitial deletions of chromosome 1p36 have a spectrum of defects that includes eye anomalies, postnatal growth deficiency, structural brain anomalies, seizures, cognitive impairment, delayed motor development, behavior problems, hearing loss, cardiovascular malformations, cardiomyopathy, and renal anomalies. The proximal 1p36 genes that contribute to these defects have not been clearly delineated. The arginine-glutamic acid dipeptide (RE) repeats gene (RERE) is located in this region and encodes a nuclear receptor coregulator that plays a critical role in embryonic development as a positive regulator of retinoic acid signaling. Rere-null mice die of cardiac failure between E9.5 and E11.5. This limits their usefulness in studying the role of RERE in the latter stages of development and into adulthood. To overcome this limitation, we created an allelic series of RERE-deficient mice using an Rere-null allele, om, and a novel hypomorphic Rere allele, eyes3 (c.578T>C, p.Val193Ala), which we identified in an N-ethyl-N-nitrosourea (ENU)-based screen for autosomal recessive phenotypes. Analyses of these mice revealed microphthalmia, postnatal growth deficiency, brain hypoplasia, decreased numbers of neuronal nuclear antigen (NeuN)-positive hippocampal neurons, hearing loss, cardiovascular malformations-aortic arch anomalies, double outlet right ventricle, and transposition of the great arteries, and perimembranous ventricular septal defects-spontaneous development of cardiac fibrosis and renal agenesis. These findings suggest that RERE plays a critical role in the development and function of multiple organs including the eye, brain, inner ear, heart and kidney. It follows that haploinsufficiency of RERE may contribute-alone or in conjunction with other genetic, environmental, or stochastic factors-to the development of many of the phenotypes seen in individuals with terminal and interstitial deletions that include the proximal region of chromosome 1p36.

Cisplatin (cis-diammine-dichloroplatinum; CDDP) is an anticancer drug that induces significant hearing loss and balance dysfunction as side effects. Cilostazol (CS, 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl) butoxy]-3, 4-dihydro-2-(1H)-quinolinone) has neuroprotective and antioxidant effects, whereas Ginkgo biloba extract (GbE) has preventive effects on CDDP-induced hearing loss in rats, and GbE enhances the antiatherogenic effect of CS by inhibiting the generation of reactive oxygen species (ROS). The purpose of this study was to investigate the effects of renexin (RXN), which contains GbE and CS, against CDDP-induced cochleo-vestibular dysfunction in rats and to elucidate the mechanism underlying the protective effects of RXN on auditory cells. Rats intraperitoneally injected with CDDP exhibited an increase in hearing threshold and vestibular dysfunction, which agreed with hair cell damage in the Organ of Corti and otoliths. However, these impairments were significantly prevented in a dose-dependent manner by pre- and co-treatment with RXN, and these preventive effects in RXN-treated rats were more prominent than those in GbE-treated rats. In a CDDP pharmacokinetic study, platinum concentration was very similar between CDDP-only treated and RXN+CDDP cotreated rats. RXN markedly attenuated CDDP-induced intracellular ROS and significantly reduced CDDP-activated expression of p-extracellular regulated kinase (ERK), BAX, cytochrome c, cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase, but increased BCL-XL expression. These results show that RXN may have a synergistic effect by strongly protecting hearing and vestibular dysfunction induced by CDDP by inhibiting ROS production, mitochondrial pathways and the ERK pathway, without interfering with CDDP pharmacokinetics. Therefore, RXN could potentially be used to reduce CDDP-related hearing loss and dizziness.

Natural acoustic stimuli contain slow temporal fluctuations, and the modulation of ongoing slow-wave activity by bottom-up and top-down factors plays essential roles in auditory cortical processing. However, the spatiotemporal pattern of intrinsic slow-wave activity across the auditory cortical modality is unknown. Using in vivo voltage-sensitive dye imaging in anesthetized guinea pigs, we measured spectral tuning to acoustic stimuli across several core and belt auditory cortical areas, and then recorded spontaneous activity across this defined network. We found that phase coherence in spontaneous slow-wave (delta-theta band) activity was highest between regions of core and belt areas that had similar frequency tuning, even if they were distant. Further, core and belt regions with high phase coherence were phase shifted. Interestingly, phase shifts observed during spontaneous activity paralleled latency differences for evoked activity. Our findings suggest that the circuits underlying this intrinsic source of slow-wave activity support coordinated changes in excitability between functionally matched but distributed regions of the auditory cortical network.

The Lombard effect, an involuntary rise in call amplitude in response to masking ambient noise, represents one of the most efficient mechanisms to optimize signal-to-noise ratio. The Lombard effect occurs in birds and mammals, including humans, and is often associated with several other vocal changes, such as call frequency and duration. Most studies, however, have focused on noise-dependent changes in call amplitude. It is therefore still largely unknown how the adaptive changes in call amplitude relate to associated vocal changes such as frequency shifts, how the underlying mechanisms are linked, and if auditory feedback from the changing vocal output is needed. Here, we examined the Lombard effect and the associated changes in call frequency in a highly vocal mammal, echolocating horseshoe bats. We analyzed how bandpass-filtered noise (BFN; bandwidth 20 kHz) affected their echolocation behavior when BFN was centered on different frequencies within their hearing range. Call amplitudes increased only when BFN was centered on the dominant frequency component of the bats’ calls. In contrast, call frequencies increased for all but one BFN center frequency tested. Both amplitude and frequency rises were extremely fast and occurred in the first call uttered after noise onset, suggesting that no auditory feedback was required. The different effects that varying the BFN center frequency had on amplitude and frequency rises indicate different neural circuits and/or mechanisms underlying these changes.

We previously demonstrated that a mutation in the 5' untranslated region of Diaphanous homolog 3 (DIAPH3) results in 2 to 3-fold overexpression of the gene, leading to a form of delayed onset, progressive human deafness known as AUNA1 (auditory neuropathy, nonsyndromic, autosomal dominant, 1). To investigate the mechanism of deafness, we generated two lines of transgenic mice overexpressing Diap3, the murine ortholog of DIAPH3, on an FVB/NJ background. Line 771 exhibits a relatively mild 20 dB hearing loss at 12 kHz at 4 and 8 weeks of age, progressing to 40 dB and 60 dB losses at 16 and 24 weeks, respectively, at 12 and 24 kHz. Line 924 shows no hearing loss at 4 or 8 weeks, but manifests 35 and 50 dB threshold shifts at 16 and 24 weeks, respectively, at both 12 and 24 kHz. Notably, mice from the two transgenic lines retain distortion product otoacoustic emissions, indicative of normal cochlear outer hair cell (OHC) function despite elevation of auditory thresholds. Scanning electron microscopy of the organ of Corti demonstrates striking anomalies of the inner hair cell (IHC) stereocilia, while OHCs are essentially intact. Over time, IHCs of both lines develop elongated stereocilia that appear fused with neighboring stereocilia, in parallel to the time course of hearing loss in each line. Furthermore, we observe significant reduction in the number of IHC ribbon synapses over 24 weeks in both lines, although this reduction does not correlate temporally with onset and progression of hearing loss or stereociliary anomalies. In summary, overexpression of wild-type Diap3 in two lines of transgenic mice results in hearing loss that recapitulates human AUNA1 deafness. These findings suggest an essential role of Diap3 in regulating assembly and/or maintenance of actin filaments in IHC stereocilia, as well as a potential role at the IHC ribbon synapse.

The aim of this research was to evaluate the ability to switch attention and selectively attend to relevant information in children (10-15 years) with persistent listening difficulties in noisy environments. A wide battery of clinical tests indicated that children with complaints of listening difficulties had otherwise normal hearing sensitivity and auditory processing skills. Here we show that these children are markedly slower to switch their attention compared to their age-matched peers. The results suggest poor attention switching, lack of response inhibition and/or poor listening effort consistent with a predominantly top-down (central) information processing deficit. A deficit in the ability to switch attention across talkers would provide the basis for this otherwise hidden listening disability, especially in noisy environments involving multiple talkers such as classrooms.

A subject's sensitivity to a stimulus variation can be studied by estimating the psychometric function. Generally speaking, three parameters of the psychometric function are of interest: the performance threshold, the slope of the function, and the rate at which attention lapses occur. In the present study, three psychophysical procedures were used to estimate the three-parameter psychometric function for an auditory gap detection task. These were an up-down staircase (up-down) procedure, an entropy-based Bayesian (entropy) procedure, and an updated maximum-likelihood (UML) procedure. Data collected from four young, normal-hearing listeners showed that while all three procedures provided similar estimates of the threshold parameter, the up-down procedure performed slightly better in estimating the slope and lapse rate for 200 trials of data collection. When the lapse rate was increased by mixing in random responses for the three adaptive procedures, the larger lapse rate was especially detrimental to the efficiency of the up-down procedure, and the UML procedure provided better estimates of the threshold and slope than did the other two procedures.

One in 15 school age children have dyslexia, which is characterized by phoneme-processing problems and difficulty learning to read. Dyslexia is associated with mutations in the gene KIAA0319. It is not known whether reduced expression of KIAA0319 can degrade the brain's ability to process phonemes. In the current study, we used RNA interference (RNAi) to reduce expression of Kiaa0319 (the rat homolog of the human gene KIAA0319) and evaluate the effect in a rat model of phoneme discrimination. Speech discrimination thresholds in normal rats are nearly identical to human thresholds. We recorded multiunit neural responses to isolated speech sounds in primary auditory cortex (A1) of rats that received in utero RNAi of Kiaa0319. Reduced expression of Kiaa0319 increased the trial-by-trial variability of speech responses and reduced the neural discrimination ability of speech sounds. Intracellular recordings from affected neurons revealed that reduced expression of Kiaa0319 increased neural excitability and input resistance. These results provide the first evidence that decreased expression of the dyslexia-associated gene Kiaa0319 can alter cortical responses and impair phoneme processing in auditory cortex.

In the auditory system of the big brown bat ( Eptesicus fuscus), paired conditioned tonal (CS) and unconditioned leg stimuli (US) for auditory fear conditioning elicit tone-specific plasticity represented by best-frequency (BF) shifts that are augmented by acetylcholine, whereas unpaired CS and US for pseudoconditioning elicit a small BF shift and prominent nonspecific plasticity at the same time. The latter represents the nonspecific augmentations of auditory responses accompanied by the broadening of frequency tuning and decrease in threshold. It is unknown which neuromodulators are important in evoking the nonspecific plasticity. We found that histamine (HA) and an HA3 receptor (HA3R) agonist (α-methyl-HA) decreased, but an HA3R antagonist (thioperamide) increased, cortical auditory responses; that the HA3R agonist applied to the primary auditory cortex before pseudoconditioning abolished the nonspecific augmentation in the cortex without affecting the small cortical BF shift; and that antagonists of acetylcholine, norepinephrine, dopamine, and serotonin receptors did not abolish the nonspecific augmentation elicited by pseudoconditioning. The histaminergic system plays an important role in eliciting the arousal and defensive behavior, possibly through nonspecific augmentation. Thus HA modulates the nonspecific augmentation, whereas acetylcholine amplifies the BF shifts. These two neuromodulators may mediate differential gating of cortical plasticity.

Whole-cell patch neurophysiology and pharmacological manipulations have provided unprecedented insight into the functions of central neurons, but their combined use has been largely restricted to in vitro preparations. We describe a method for performing whole-cell patch recording and focal application of pharmacological agents in vivo. A key feature of this technique involves iontophoresis of glutamate to establish proximity of drug and recording pipettes. We show data from iontophoresis of glutamate during extracellular and whole-cell recordings made in vivo from auditory neurons in the midbrain of the leopard frog, Rana pipiens, and the effects of blocking GABA(A) receptors while making a whole-cell recording. This methodology should accelerate our understanding of the roles of particular neurotransmitter systems in normal and pathological conditions, and facilitate investigation of the in vivo effects of drugs and the mechanisms underlying computations.

Two common measures of auditory temporal resolution are the temporal modulation transfer function (TMTF) and the gap detection threshold (GDT). The current study addresses the lack of efficient psychophysical procedures for collecting TMTFs and the lack of literature on the comparisons of TMTF and GDT. Two procedures for efficient measurements of the TMTF are proposed: (1) A Bayesian procedure that adaptively chooses the stimulus modulation rate and depth to maximize the information gain from each trial and (2) a procedure that reduces the data collection to two adaptive staircase tracks. Results from experiments I and II showed that, for broadband carriers, these approaches provided similar results compared to TMTFs measured using traditional methods despite taking less than 10 min for data collection. Using these efficient procedures, TMTFs were measured from a large number of naive listeners and were compared to the gap detection thresholds collected from the same ears in experiment III. Results showed that the sensitivity parameter estimated from the TMTF measurements correlated well with the GDTs, whereas the cutoff rate is either uncorrelated or positively correlated with the gap detection threshold. These results suggest caution in interpreting a lower GDT as evidence for less sluggish temporal processing.

Sound-induced motions of the surface of the tympanic membrane (TM) were measured using stroboscopic holography in cadaveric human temporal bones at frequencies between 0.2 and 18 kHz. The results are consistent with the combination of standing-wave-like modal motions and traveling-wave-like motions on the TM surface. The holographic techniques also quantified sound-induced displacements of the umbo of the malleus, as well as volume velocity of the TM. These measurements were combined with sound-pressure measurements near the TM to compute middle-ear input impedance and power reflectance at the TM. The results are generally consistent with other published data. A phenomenological model that behaved qualitatively like the data was used to quantify the relative magnitude and spatial frequencies of the modal and traveling-wave-like displacement components on the TM surface. This model suggests the modal magnitudes are generally larger than those of the putative traveling waves, and the computed wave speeds are much slower than wave speeds predicted by estimates of middle-ear delay. While the data are inconsistent with simple modal displacements of the TM, an alternate model based on the combination of modal motions in a lossy membrane can also explain these measurements without invoking traveling waves.

Photoacoustic tomography (PAT) offers three-dimensional (3D) structural and functional imaging of living biological tissue with label-free, optical absorption contrast. These attributes lend PAT imaging to a wide variety of applications in clinical medicine and preclinical research. Despite advances in live animal imaging with PAT, there is still a need for 3D imaging at centimeter depths in real-time. We report the development of four dimensional (4D) PAT, which integrates time resolutions with 3D spatial resolution, obtained using spherical arrays of ultrasonic detectors. The 4D PAT technique generates motion pictures of imaged tissue, enabling real time tracking of dynamic physiological and pathological processes at hundred micrometer-millisecond resolutions. The 4D PAT technique is used here to image needle-based drug delivery and pharmacokinetics. We also use this technique to monitor 1) fast hemodynamic changes during inter-ictal epileptic seizures and 2) temperature variations during tumor thermal therapy.

The control of vocalization is critically dependent on auditory feedback. Here, we determined the human peri-Sylvian speech network that mediates feedback control of pitch using direct cortical recordings. Subjects phonated while a real-time signal processor briefly perturbed their output pitch (speak condition). Subjects later heard the same recordings of their auditory feedback (listen condition). In posterior superior temporal gyrus, a proportion of sites had suppressed responses to normal feedback, whereas other spatially independent sites had enhanced responses to altered feedback. Behaviorally, speakers compensated for perturbations by changing their pitch. Single-trial analyses revealed that compensatory vocal changes were predicted by the magnitude of both auditory and subsequent ventral premotor responses to perturbations. Furthermore, sites whose responses to perturbation were enhanced in the speaking condition exhibited stronger correlations with behavior. This sensorimotor cortical network appears to underlie auditory feedback-based control of vocal pitch in humans.

The activity of neural populations is determined not only by sensory inputs but also by internally generated patterns. During quiet wakefulness, the brain produces spontaneous firing events that can spread over large areas of cortex and have been suggested to underlie processes such as memory recall and consolidation. Here we demonstrate a different role for spontaneous activity in sensory cortex: gating of sensory inputs. We show that population activity in rat auditory cortex is composed of transient 50–100 ms packets of spiking activity that occur irregularly during silence and sustained tone stimuli, but reliably at tone onset. Population activity within these packets had broadly consistent spatiotemporal structure, but the rate and also precise relative timing of action potentials varied between stimuli. Packet frequency varied with cortical state, with desynchronized state activity consistent with superposition of multiple overlapping packets. We suggest that such packets reflect the sporadic opening of a “gate” that allows auditory cortex to broadcast a representation of external sounds to other brain regions.

The mammalian neocortex is a six-layered structure organized into radial columns. Within sensory cortical areas, information enters in the thalamorecipient layer and is further processed in supragranular and infragranular layers. Within the neocortex, topographic maps of stimulus features are present, but whether topographic patterns of active neurons change between laminae is unknown. Here, we used in vivo two-photon Ca 2+ imaging to probe the organization of the mouse primary auditory cortex and show that the spatial organization of neural response properties (frequency tuning) within the thalamorecipient layer (L3b/4) is more homogeneous than in supragranular layers (L2/3). Moreover, stimulus-related correlations between pairs of neurons are higher in the thalamorecipient layer, whereas stimulus-independent trial-to-trial covariance is higher in supragranular neurons. These findings reveal a transformation of sensory representations that occurs between layers within the auditory cortex, which could generate sequentially more complex analysis of the acoustic scene incorporating a broad range of spectrotemporal sound features.

Background: Hearing restoration through hair cell regeneration will require revealing the dynamic interactions between proliferation and differentiation during development to avoid the limited viability of regenerated hair cells. Pax2‐Cre N‐Myc conditional knockout ( CKO ) mice highlighted the need of N‐Myc for proper neurosensory development and possible redundancy with L‐Myc . The late‐onset hair cell death in the absence of early N‐Myc expression could be due to mis‐regulation of genes necessary for neurosensory formation and maintenance, such as Neurod1, Atoh1, Pou4f3, and Barhl1 . Results: Pax2‐Cre N‐Myc L‐Myc double CKO mice show that proliferation and differentiation are linked together through Myc and in the absence of both Myc s , altered proliferation and differentiation result in morphologically abnormal ears. In particular, the organ of Corti apex is re‐patterned into a vestibular‐like organization and the base is truncated and fused with the saccule. Conclusions: These data indicate that therapeutic approaches to restore hair cells must take into account a dynamic interaction of proliferation and differentiation regulation of basic Helix‐Loop‐Helix transcription factors in attempts to stably replace lost cochlear hair cells. In addition, our data indicate that Myc is an integral component of the evolutionary transformation process that resulted in the organ of Corti development. Developmental Dynamics 242:132–147, 2013 . © 2012 Wiley Periodicals, Inc.

Many species of songbirds exhibit dramatic seasonal variation in song output. Recent evidence suggests that seasonal changes in auditory processing are coincident with seasonal variation in vocal output. Here, we show, for the first time, that frequency selectivity and temporal resolution of the songbird auditory periphery change seasonally and in a sex-specific manner. Male and female house sparrows ( Passer domesticus ) did not differ in their frequency sensitivity during the non-breeding season, nor did they differ in their temporal resolution. By contrast, female house sparrows showed enhanced frequency selectivity during the breeding season, which was matched by a concomitant reduction of temporal resolution. However, males failed to show seasonal plasticity in either of these auditory properties. We discuss potential mechanisms generating these seasonal patterns and the implications of sex-specific seasonal changes in auditory processing for vocal communication.

In this paper, we report on a cost effective and simple method for fabricating a flexible multi-electrode array for subdural neural recording. The electrode was fabricated using a PDMS-Parylene bilayer to combine the major advantages of both materials. Mechanical and electrical characterizations were performed to confirm functionality of a 16-site electrode array under various flexed/bent conditions. The electrode array was helically wound around a 3 mm diameter cylindrical tube and laid over a 2 cm diameter sphere while maintaining its recording capability. Experimental results showed impedance values between 300 kΩ and 600 kΩ at 1 kHz for 90 μm diameter gold recording sites. Acoustically evoked neural activity was successfully recorded from rat auditory cortex, confirming in vivo functionality.