Publications using TDT

In the awake big brown bat, 30 min auditory fear conditioning elicits conditioned heart rate decrease and long-term best frequency (BF) shifts of cortical auditory neurons toward the frequency of the conditioned tone; 15 min conditioning elicits subthreshold cortical BF shifts that can be augmented by acetylcholine. The fear conditioning causes stress and an increase in the cortical serotonin (5-HT) level. Serotonergic neurons in the raphe nuclei associated with stress and fear project to the cerebral cortex and cholinergic basal forebrain. Recently, it has been shown that 5-HT 2A receptors are mostly expressed on pyramidal neurons and their activation improves learning and memory. We applied 5-HT, an agonist (α-methyl-5-HT), or an antagonist (ritanserin) of 5-HT 2A receptors to the primary auditory cortex and discovered the following drug effects: (1) 5-HT had no effect on the conditioned heart rate change, although it reduced the auditory responses; (2) 4 m m 5-HT augmented the subthreshold BF shifts, whereas 20 m m 5-HT did not; (3) 20 m m 5-HT reduced the long-term BF shifts and changed them into short-term; (4) α-methyl-5-HT increased the auditory responses and augmented the subthreshold BF shifts as well as the long-term BF shifts; (5) in contrast, ritanserin reduced the auditory responses and reversed the direction of the BF shifts. Our data indicate that the BF shift can be modulated by serotonergic neurons that augment or reduce the BF shift or even reverse the direction of the BF shift. Therefore, not only the cholinergic system, but also the serotonergic system, plays an important role in cortical plasticity according to behavioral demands.

Outer hair cell (OHC) somatic motility plays a key role in mammalian cochlear frequency selectivity and hearing sensitivity, but the mechanism of cochlear amplification is not well understood and remains a matter of controversy. We have visualized and quantified the effects of electrically evoked OHC somatic motility within the gerbil organ of Corti using an excised cochlear preparation. We found that OHC motility induces oscillatory motion of the medial olivocochlear fibers where they cross the tunnel of Corti (ToC) in their course to innervate the OHCs. We show that this motion is present at physiologically relevant frequencies and remains at locations distal to the OHC excitation point. We interpret this fiber motion to be the result of oscillatory fluid flow in the ToC. We show, using a simple one-dimensional hydromechanical model of the ToC, that a fluid wave within the tunnel can travel without significant attenuation for distances larger than the wavelength of the cochlear traveling wave at its peak. This ToC fluid wave could interact with the cochlear traveling wave to amplify the motion of the basilar membrane. The ToC wave could also provide longitudinal coupling between adjacent sections of the basilar membrane, and such coupling may be critical for cochlear amplification.

The outer hair cell (OHC) of the mammalian inner ear exhibits an unusual form of somatic motility that can follow membrane-potential changes at acoustic frequencies. The cellular forces that produce this motility are believed to amplify the motion of the cochlear partition, thereby playing a key role in increasing hearing sensitivity. To better understand the role of OHC somatic motility in cochlear micromechanics, we developed an excised cochlea preparation to visualize simultaneously the electrically-evoked motion of hundreds of cells within the organ of Corti (OC). The motion was captured using stroboscopic video microscopy and quantified using cross-correlation techniques. The OC motion at approximately 2-6 octaves below the characteristic frequency of the region was complex: OHC, Deiter's cell, and Hensen's cell motion were hundreds of times larger than the tectorial membrane, reticular lamina (RL), and pillar cell motion; the inner rows of OHCs moved antiphasic to the outer row; OHCs pivoted about the RL; and Hensen's cells followed the motion of the outer row of OHCs. Our results suggest that the effective stimulus to the inner hair cell hair bundles results not from a simple OC lever action, as assumed by classical models, but by a complex internal motion coupled to the RL.

Noncoplanar polychlorinated biphenyls (PCBs) are widely dispersed in human environment and tissues. Here, an exemplar noncoplanar PCB was fed to rat dams during gestation and throughout three subsequent nursing weeks. Although the hearing sensitivity and brainstem auditory responses of pups were normal, exposure resulted in the abnormal development of the primary auditory cortex (A1). A1 was irregularly shaped and marked by internal nonresponsive zones, its topographic organization was grossly abnormal or reversed in about half of the exposed pups, the balance of neuronal inhibition to excitation for A1 neurons was disturbed, and the critical period plasticity that underlies normal postnatal auditory system development was significantly altered. These findings demonstrate that developmental exposure to this class of environmental contaminant alters cortical development. It is proposed that exposure to noncoplanar PCBs may contribute to common developmental disorders, especially in populations with heritable imbalances in neurotransmitter systems that regulate the ratio of inhibition and excitation in the brain. We conclude that the health implications associated with exposure to noncoplanar PCBs in human populations merit a more careful examination.

Performing sound recognition is a task that requires an encoding of the time-varying spectral structure of the auditory stimulus. Similarly, computation of the interaural time difference (ITD) requires knowledge of the precise timing of the stimulus. Consistent with this, low-level nuclei of birds and mammals implicated in ITD processing encode the ongoing phase of a stimulus. However, the brain areas that follow the binaural convergence for the computation of ITD show a reduced capacity for phase locking. In addition, we have shown that in the barn owl there is a pooling of ITD-responsive neurons to improve the reliability of ITD coding. Here we demonstrate that despite two stages of convergence and an effective loss of phase information, the auditory system of the anesthetized barn owl displays a graceful transition to an envelope coding that preserves the spectrotemporal information throughout the ITD pathway to the neurons of the core of the central nucleus of the inferior colliculus.

To define the role of free radical formation and potential energy depletion in noise induced hearing loss (NIHL), we measured the effectiveness of tempol (free radical scavenger) and creatine (enhances cellular energy storage) alone and in combination to attenuate NIHL. Guinea pigs were divided into four treatment groups: controls, 3% creatine diet (2 weeks prior to noise exposure), tempol (3 mM in drinking water 2 weeks prior to exposure), and creatine plus tempol and exposed to 120 dB SPL one-octave band noise centered at 4 kHz for 5 h. The noise-only control group showed frequency-dependent auditory threshold shifts (measured by auditory brainstem response, ABR) of up to 73 dB (16 kHz) on day 1, and up to 50 dB (8 kHz) on day 10. Creatine-treated subjects had significantly smaller ABR threshold shifts on day 1 and on day 10. Tempol alone significantly reduced ABR threshold shifts on day 10 but not on day 1. ABR shifts after combination treatment were similar to those in the creatine group. Hair cell loss on day 10 was equally attenuated by creatine and tempol alone or in combination. Our results indicate that the maintenance of ATP levels is important in attenuating both temporary and permanent NIHL, while the scavenging of free radicals provides protection from permanent NIHL.

Pendred syndrome, characterized by childhood deafness and postpuberty goiter, is caused by mutations of SLC26A4, which codes for the anion exchanger pendrin. The goal of the present study was to determine how loss of pendrin leads to hair cell degeneration and deafness. We evaluated pendrin function by ratiometric microfluorometry, hearing by auditory brain stem recordings, and expression of K + and Ca 2+ channels by confocal immunohistochemistry. Cochlear pH and Ca 2+ concentrations and endocochlear potential (EP) were measured with double-barreled ion-selective microelectrodes. Pendrin in the cochlea was characterized as a formate-permeable and DIDS-sensitive anion exchanger that is likely to mediate HCO 3 − secretion into endolymph. Hence endolymph in Slc26a4 +/− mice was more alkaline than perilymph, and the loss of pendrin in Slc26a4 −/− mice led to an acidification of endolymph. The stria vascularis of Slc26a4 −/− mice expressed the K + channel Kcnj10 and generated a small endocochlear potential before the normal onset of hearing at postnatal day 12. This small potential and the expression of Kcnj10 were lost during further development, and Slc26a4 −/− mice did not acquire hearing. Endolymphatic acidification may be responsible for inhibition of Ca 2+ reabsorption from endolymph via the acid-sensitive epithelial Ca 2+ channels Trpv5 and Trpv6. Hence the endolymphatic Ca 2+ concentration was found elevated in Slc26a4 −/− mice. This elevation may inhibit sensory transduction necessary for hearing and promote the degeneration of the sensory hair cells. Degeneration of the hair cells closes a window of opportunity to restore the normal development of hearing in Slc26a4 −/− mice and possibly human patients suffering from Pendred syndrome.

During development of the CNS, secreted morphogens of the fibroblast growth factor (FGF) family have multiple effects on cell division, migration, and survival depending on where, when, and how much FGF signal is received. The consequences of misregulating the FGF pathway were studied in a mouse with decreased levels of the FGF antagonist Sef . To uncover effects in the nervous system, we focused on the auditory system, which is accessible to physiological analysis. We found that the mitogen-activated protein kinase pathway is active in the rhombic lip, a germinal zone that generates diverse types of neurons, including the cochlear nucleus complex of the auditory system. Sef is expressed immediately adjacent to the rhombic lip, overlapping with FGF15 and FGFR1 , which is also present in the lip itself. This pattern suggests that Sef may normally function in non-rhombic lip cells and prevent them from responding to FGF ligand in the vicinity. Consistent with this idea, overexpression of Sef in chicks decreased the size of the auditory nuclei. Cochlear nucleus defects were also apparent in mice with reduced levels of Sef , with 13% exhibiting grossly dysmorphic cochlear nuclei and 26% showing decreased amounts of GFAP in the cochlear nucleus. Additional evidence for cochlear nucleus defects was obtained by electrophysiological analysis of Sef mutant mice, which have normal auditory thresholds but abnormal auditory brainstem responses. These results show both increases and decreases in Sef levels affect the assembly and function of the auditory brainstem.

Echolocating bats can identify three-dimensional objects exclusively through the analysis of acoustic echoes of their ultrasonic emissions. However, objects of the same structure can differ in size, and the auditory system must achieve a size-invariant, normalized object representation for reliable object recognition. This study describes both the behavioral classification and the cortical neural representation of echoes of complex virtual objects that vary in object size. In a phantom-target playback experiment, it is shown that the bat Phyllostomus discolor spontaneously classifies most scaled versions of objects according to trained standards. This psychophysical performance is reflected in the electrophysiological responses of a population of cortical units that showed an object-size invariant response (14/109 units, 13%). These units respond preferentially to echoes from objects in which echo duration (encoding object depth) and echo amplitude (encoding object surface area) co-varies in a meaningful manner. These results indicate that at the level of the bat's auditory cortex, an object-oriented rather than a stimulus-parameter-oriented representation of echoes is achieved.

Object The authors sought to examine the therapeutic efficacy of motor cortex stimulation (MCS) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–treated macaques and to characterize therapeutic differences with varying modes, frequencies, and durations of stimulation. Methods Motor cortex stimulation was delivered at currents below motor threshold and at frequencies between 5 and 150 Hz through epidural electrodes over the primary motor cortex. The animals were studied during and without MCS using video analysis, activity logging, and food retrieval tasks. Animals were examined using two different stimulation protocols. The first protocol consisted of 1 hour of MCS therapy daily. The second protocol exposed the animal to continuous MCS for more than 24 hours with at least 2 weeks between MCS treatments. Conclusions Daily MCS yielded no consistent change in symptoms, but MCS at 2-week intervals resulted in significant increases in activity. Effects of biweekly MCS disappeared, however, within 24 hours of the onset of continuous MCS. In this study, MCS only temporarily reduced the severity of MPTP-induced parkinsonism.

Previous research on foreign accent perception has largely focused on speaker-dependent factors such as age of learning and length of residence. Factors that are independent of a speaker’s language learning history have also been shown to affect perception of second language speech. The present study examined the effects of two such factors—listening context and lexical frequency—on the perception of foreign-accented speech. Listeners rated foreign accent in two listening contexts: auditory-only, where listeners only heard the target stimuli, and auditory+orthography, where listeners were presented with both an auditory signal and an orthographic display of the target word. Results revealed that higher frequency words were consistently rated as less accented than lower frequency words. The effect of the listening context emerged in two interactions: the auditory+orthography context reduced the effects of lexical frequency, but increased the perceived differences between native and non-native speakers. Acoustic measurements revealed some production differences for words of different levels of lexical frequency, though these differences could not account for all of the observed interactions from the perceptual experiment. These results suggest that factors independent of the speakers’ actual speech articulations can influence the perception of degree of foreign accent.

The cochlea is the mammalian organ of hearing. Its predominant vibratory element, the basilar membrane, is tonotopically tuned, based on the spatial variation of its mass and stiffness. The constituent collagen fibers of the basilar membrane affect its stiffness. Laser irradiation can induce collagen remodeling and deposition in various tissues. We tested whether similar effects could be induced within the basilar membrane. Trypan blue was perfused into the scala tympani of anesthetized mice to stain the basilar membrane. We then irradiated the cochleas with a 694-nm pulsed ruby laser at 15 or 180 J/cm2. The mice were sacrificed 14 to 16 days later and collagen organization was studied. Polarization microscopy revealed that laser irradiation increased the birefringence within the basilar membrane in a dose-dependent manner. Electron microscopy demonstrated an increase in the density of collagen fibers and the deposition of new fibrils between collagen fibers after laser irradiation. As an assessment of hearing, auditory brainstem response (ABR) thresholds were found to increase moderately after 15 J/cm2 and substantially after 180 J/cm2. Our results demonstrate that collagen remodeling and new collagen deposition occurs within the basilar membrane after laser irradiation in a similar fashion to that found in other tissues.

In colonial species, recognition of offspring should be under strong selection. For accurate identification to occur offspring must emit individually distinctive signals and parents must be able to discriminate between signals. Female greater spear-nosed bats (Phyllostomus hastatus) roost in stable social groups and use infant vocalizations, termed isolation calls, to locate and identify their young. In this study, we investigate both the production and perception of isolation calls in P. hastatus. First, we measured acoustic features and found that after controlling for ontogenetic effects, sufficient variation exists between pups for isolation calls to function as individual signatures. Moreover, pups from the same social group emit calls with more similar spectral and spectro-temporal features than pups from different social groups, indicating that these features are likely heritable. We used psychoacoustic experiments in the laboratory to determine if adult females could discriminate between calls from pups in the same or different social group. Females discriminated between pups when faced with a template-matching task and their performance was correlated with the salience of spectral and spectro-temporal features. We found no difference in performance when females had to discriminate between pups from the same and different social groups. These results indicate that females should be able to accurately identify their young using isolation calls.

Bone Morphogenetic Protein 4 (BMP4) is a member of the TGF-beta superfamily and is known to be important for the normal development of many tissues and organs, including the inner ear. Bmp4 homozygous null mice die as embryos, but Bmp4 heterozygous null (Bmp4(+/-)) mice are viable and some adults exhibit a circling phenotype, suggestive of an inner ear defect. To understand the role of BMP4 in inner ear development and function, we have begun to study C57BL/6 Bmp4(+/-) mice. Quantitative testing of the vestibulo-collic reflex, which helps maintain head stability, demonstrated that Bmp4(+/-) mice that exhibit circling behavior have a poor response in the yaw axis, consistent with semicircular canal dysfunction. Although the hair cells of the ampullae were grossly normal, the stereocilia were greatly reduced in number. Auditory brainstem responses showed that Bmp4(+/-) mice have elevated hearing thresholds and immunohistochemical staining demonstrated decreased numbers of neuronal processes in the organ of Corti. Thus Bmp4(+/-) mice have structural and functional deficits in the inner ear.

Developmental malformations of cortex have been shown to co-occur with language, learning, and other cognitive deficits in humans. Rodent models have repeatedly shown that animals with such developmental malformations have deficits related to auditory processing and learning. More specifically, freeze-lesion induced microgyria as well as molecular layer ectopias have been found to impair rapid auditory processing ability in rats and mice. In humans, deficits in rapid auditory processing appear to relate to later impairments of language. Recently, genetic variants of four different genes involved in early brain development have been proposed to associate with an elevated incidence of developmental dyslexia in humans. Three of these, DYX1C1, DCDC2, and KIAA0319, have been shown by in utero RNAi to play a role in neuronal migration in developing neocortex. The present study assessed the effects of in utero RNAi of Dyx1c1 on auditory processing and spatial learning in rats. Results indicate that RNAi of Dyx1c1 is associated with cortical heterotopia and is suggestive of an overall processing deficit of complex auditory stimuli in both juvenile and adult periods (p=.051, one-tail). In contrast, adult data alone reveal a significant processing impairment among RNAi treated subjects compared to shams, indicating an inability for RNAi treated subjects to improve detection of complex auditory stimuli over time (p=.022, one-tail). Further, a subset of RNAi treated rats exhibited hippocampal heterotopia centered in CA1 (in addition to cortical malformations). Malformations of hippocampus were associated with robust spatial learning impairment in this sub-group (p<.01, two-tail). In conclusion, in utero RNAi of Dyx1c1 results in heterogeneous malformations that correspond to distinct behavioral impairments in auditory processing, and spatial learning.

Deafness is the most common form of sensory impairment in the human population and is frequently caused by recessive mutations. To obtain animal models for recessive forms of deafness and to identify genes that control the development and function of the auditory sense organs, we performed a forward genetics screen in mice. We identified 13 mouse lines with defects in auditory function and six lines with auditory and vestibular defects. We mapped several of the affected genetic loci and identified point mutations in four genes. Interestingly, all identified genes are expressed in mechanosensory hair cells and required for their function. One mutation maps to the pejvakin gene, which encodes a new member of the gasdermin protein family. Previous studies have described two missense mutations in the human pejvakin gene that cause nonsyndromic recessive deafness (DFNB59) by affecting the function of auditory neurons. In contrast, the pejvakin allele described here introduces a premature stop codon, causes outer hair cell defects, and leads to progressive hearing loss. We also identified a novel allele of the human pejvakin gene in an Iranian pedigree that is afflicted with progressive hearing loss. Our findings suggest that the mechanisms of pathogenesis associated with pejvakin mutations are more diverse than previously appreciated. More generally, our findings demonstrate that recessive screens in mice are powerful tools for identifying genes that control the development and function of mechanosensory hair cells and cause deafness in humans, as well as generating animal models for disease.

Although NMDA receptors (NMDARs) are associated with synaptic plasticity, they form an essential part of responses to sensory stimuli. We compared contributions of glutamatergic NMDARs and AMPA receptors (AMPARs) to auditory responses in the inferior colliculus (IC) of awake, adult mustached bats. We examined the magnitude and temporal pattern of responses to tonal signals in single units before, during, and after local micro-iontophoretic application of selective antagonists to AMPARs [NBQX (1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide)] and NMDARs [CPP ((±)3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid)]. Combined blockade of AMPARs and NMDARs eliminated excitatory responses in nearly all neurons, whereas separate blockade of each receptor was quantitatively similar, causing substantial (>50%) spike reductions in ∼75% of units. The major result was that effects of receptor blockade were most closely related to the first-spike latency of a unit. Thus, AMPAR blockade substantially reduced spikes in all short-latency units (<12 ms) but never in long-latency units (≥12 ms). NMDAR blockade had variable effects on short-latency units but reduced spikes substantially for all long-latency units. There were no distinct contributions of AMPARs and NMDARs to early and late elements of responses. Thus, AMPAR blockade reduced early (onset) spikes somewhat more effectively than NMDAR blockade in short-latency units, but NMDAR blockade reduced onset spikes more effectively in long-latency units. AMPAR and NMDAR blockade were equally effective in reducing later elements of sustained responses in short-latency units, whereas NMDAR blockade was much more effective in long-latency units. These results indicate that NMDARs play multiple roles for signal processing in adult IC neurons.

Kv3.1b channel protein is widely distributed in the mammalian auditory brainstem, but studies have focused mainly on regions critical for temporal processing, including the medial nucleus of the trapezoid body (MNTB) and anteroventral cochlear nucleus (AVCN). Because temporal processing declines with age, this study was undertaken to determine if the expression of Kv3.1b likewise declines, and if changes are specific to these nuclei. Immunocytochemistry using an anti-Kv3.1b antibody was performed, and the relative optical density of cells and neuropil was determined from CBA/CaJ mice of four age groups. Declines in expression in AVCN, MNTB, and lateral superior olive (35, 26, and 23%) were found, but changes were limited to neuropil. Interestingly, cellular optical density declines were found in superior paraolivary nucleus, ventral nucleus of the trapezoid body, and lateral nucleus of the trapezoid body (24, 29, and 26%), which comprise the medial olivocochlear (MOC) feedback system. All declines occurred by middle age (15 months old). No age-related changes were found in the remaining regions of cochlear nucleus or in the inferior colliculus. Contralateral suppression of distortion-product otoacoustic emission amplitudes of age-matched littermates also declined by middle age, suggesting a correlation between Kv3.1 expression and MOC function. In search of more direct evidence for such a correlation, Kv3.1b knockout mice were examined. Knockouts show poor MOC function as compared to +/+ and +/- genotypes. Thus, Kv3.1b expression declines in MOC neurons by middle age, and these changes appear to correlate with functional declines in efferent activity in both middle-aged CBA mice and Kv3.1b knockout mice.

In auditory scenes containing many similar sound sources, sorting of acoustic information into streams becomes difficult, which can lead to disruptions in the identification of behaviorally relevant targets. This study investigated the benefit of providing simple visual cues for when and/or where a target would occur in a complex acoustic mixture. Importantly, the visual cues provided no information about the target content. In separate experiments, human subjects either identified learned birdsongs in the presence of a chorus of unlearned songs or recalled strings of spoken digits in the presence of speech maskers. A visual cue indicating which loudspeaker (from an array of five) would contain the target improved accuracy for both kinds of stimuli. A cue indicating which time segment (out of a possible five) would contain the target also improved accuracy, but much more for birdsong than for speech. These results suggest that in real world situations, information about where a target of interest is located can enhance its identification, while information about when to listen can also be helpful when targets are unfamiliar or extremely similar to their competitors.

The precedence effect describes the phenomenon whereby echoes are spatially fused to the location of an initial sound by selectively suppressing the directional information of lagging sounds (echo suppression). Echo suppression is a prerequisite for faithful sound localization in natural environments but can break down depending on the behavioral context. To date, the neural mechanisms that suppress echo directional information without suppressing the perception of echoes themselves are not understood. We performed in vivo recordings in Mongolian gerbils of neurons of the dorsal nucleus of the lateral lemniscus (DNLL), a GABAergic brainstem nucleus that targets the auditory midbrain, and show that these DNLL neurons exhibit inhibition that persists tens of milliseconds beyond the stimulus offset, so-called persistent inhibition (PI). Using in vitro recordings, we demonstrate that PI stems from GABAergic projections from the opposite DNLL. Furthermore, these recordings show that PI is attributable to intrinsic features of this GABAergic innervation. Implementation of these physiological findings into a neuronal model of the auditory brainstem demonstrates that, on a circuit level, PI creates an enhancement of responsiveness to lagging sounds in auditory midbrain cells. Moreover, the model revealed that such response enhancement is a sufficient cue for an ideal observer to identify echoes and to exhibit echo suppression, which agrees closely with the percepts of human subjects.