Publications using TDT

Neurons in the inferior colliculus (IC), one of the major integrative centers of the auditory system, process acoustic information converging from almost all nuclei of the auditory brain stem. During this integration, excitatory and inhibitory inputs arrive to auditory neurons at different time delays. Result of this integration determines timing of IC neuron firing. In the mammalian IC, the range of the first spike latencies is very large (5-50 ms). At present, a contribution of excitatory and inhibitory inputs in controlling neurons' firing in the IC is still under debate. In the present study we assess the role of excitation and inhibition in determining first spike response latency in the IC. Postsynaptic responses were recorded to pure tones presented at neuron's characteristic frequency or to downward frequency modulated sweeps in awake bats. There are three main results emerging from the present study: (1) the most common response pattern in the IC is hyperpolarization followed by depolarization followed by hyperpolarization, (2) latencies of depolarizing or hyperpolarizing responses to tonal stimuli are short (3-7 ms) whereas the first spike latencies may vary to a great extent (4-26 ms) from one neuron to another, and (3) high threshold hyperpolarization preceded long latency spikes in IC neurons exhibiting paradoxical latency shift. Our data also show that the onset hyperpolarizing potentials in the IC have very small jitter (<100 micros) across repeated stimulus presentations. The results of this study suggest that inhibition, arriving earlier than excitation, may play a role as a mechanism for delaying the first spike latency in IC neurons.

The interaural time difference (ITD) is the primary auditory cue used by the barn owl for localization in the horizontal direction. ITD is initially computed by circuits consisting of axonal delay lines from one of the cochlear nuclei and coincidence detector neurons in the nucleus laminaris (NL). NL projects directly to the anterior part of the dorsal lateral lemniscal nucleus (LLDa), and this area projects to the core of the central nucleus of the inferior colliculus (ICcc) in the midbrain. To show the selectivity of an NL neuron for ITD requires averaging of responses over several stimulus presentations for each ITD. In contrast, ICcc neurons detect their preferred ITD in a single burst of stimulus. We recorded extracellularly the responses of LLDa neurons to ITD in anesthetized barn owls and show that this ability is already present in LLDa, raising the possibility that ICcc inherits its noise reduction property from LLDa.

Synucleins are widely expressed synaptic proteins within the central nervous system that have been implicated in such neurodegenerative disorders as Parkinson's disease. In this study, an initial characterization of all three synucleins, alpha-, beta-, and gamma-synuclein, within the cochlea was undertaken. Reverse transcriptase-polymerase chain reaction (PCR) demonstrated all three synuclein mRNA species within microdissected cochlear tissue. Quantitative PCR suggests that beta-synuclein is the most abundantly expressed form, followed by gamma- and then alpha-synuclein. Western blot analysis similarly demonstrates all three synuclein proteins within microdissected cochlear tissue. Immunofluorescence localizes the three synucleins predominantly to the efferent neuronal system at the efferent outer hair cell synapse, with some additional localization within the efferent tunnel-crossing fibers (alpha- and gamma-synuclein), spiral ganglion (beta-synuclein), inner spiral bundle (gamma-synuclein), and stria vascularis (alpha- > beta-synuclein). Developmentally, gamma-synuclein can be seen in the region of the outer hair cells by E19, while alpha- and beta-synuclein do not clearly appear there until approximately P10. Additional studies in a null-mutant gamma-synuclein mouse show no histological changes in the organ of Corti with normal hair cell and spiral ganglion cell counts, and normal ABR and DPOAE thresholds in wild-type vs mutant littermates. Together, these results localize synucleins to the efferent cholinergic neuronal auditory system, pointing to a role in normal auditory function, and raising the potential implications for their role in auditory neurodegenerative disorders. However, gamma-synuclein alone is not required for the development and maintenance of normal hearing through P21. Whether overlapping roles of the other synucleins help compensate for the loss of gamma-synuclein remains to be determined.

Genetic methods available in mice are likely to be powerful tools in dissecting cortical circuits. However, the visual cortex, in which sensory coding has been most thoroughly studied in other species, has essentially been neglected in mice perhaps because of their poor spatial acuity and the lack of columnar organization such as orientation maps. We have now applied quantitative methods to characterize visual receptive fields in mouse primary visual cortex V1 by making extracellular recordings with silicon electrode arrays in anesthetized mice. We used current source density analysis to determine laminar location and spike waveforms to discriminate putative excitatory and inhibitory units. We find that, although the spatial scale of mouse receptive fields is up to one or two orders of magnitude larger, neurons show selectivity for stimulus parameters such as orientation and spatial frequency that is near to that found in other species. Furthermore, typical response properties such as linear versus nonlinear spatial summation (i.e., simple and complex cells) and contrast-invariant tuning are also present in mouse V1 and correlate with laminar position and cell type. Interestingly, we find that putative inhibitory neurons generally have less selective, and nonlinear, responses. This quantitative description of receptive field properties should facilitate the use of mouse visual cortex as a system to address longstanding questions of visual neuroscience and cortical processing.

Voluntary orienting of visual spatial attention has been shown to be associated with activation in a distributed network of frontal and parietal brain areas. Neuropsychological data suggest that at least some of these areas should be sensitive to the direction in which attention is shifted. The aim of this study was to use rapid event‐related functional magnetic resonance imaging to investigate whether spatial attention in the auditory modality is subserved by the same or different brain areas as in the visual modality, and whether the auditory and visual attention networks show any degree of hemispheric lateralisation or sensitivity to the direction of attention shifts. The results suggest that auditory and visual spatial attention shifts are controlled by a supramodal network of frontal, parietal and temporal areas. Areas activated included the precuneus and superior parietal cortex, the inferior parietal cortex and temporo‐parietal junction, as well as the premotor and supplementary motor areas and dorsolateral prefrontal cortex (DLPFC). In the auditory task, some of these areas, in particular the precuneus as well as the inferior parietal cortex and temporo‐parietal junction, showed ‘relative’ asymmetry, in that they responded more strongly to attention shifts towards the contralateral than the ipsilateral hemispace. Some areas, such as the right superior parietal cortex and left DLPFC, showed ‘absolute’ asymmetry, in that they responded more strongly in one than in the other hemisphere. Human Brain Mapp 2009. © 2008 Wiley‐Liss, Inc.

Background: The mammalian auditory cortex can be subdivided into various fields characterized by neurophysiological and neuroarchitectural properties and by connections with different nuclei of the thalamus. Besides the primary auditory cortex, echolocating bats have cortical fields for the processing of temporal and spectral features of the echolocation pulses. This paper reports on location, neuroarchitecture and basic functional organization of the auditory cortex of the microchiropteran bat Phyllostomus discolor (family: Phyllostomidae). Results: The auditory cortical area of P. discolor is located at parieto-temporal portions of the neocortex. It covers a rostro-caudal range of about 4800 mum and a medio-lateral distance of about 7000 mum on the flattened cortical surface. The auditory cortices of ten adult P. discolor were electrophysiologically mapped in detail. Responses of 849 units (single neurons and neuronal clusters up to three neurons) to pure tone stimulation were recorded extracellularly. Cortical units were characterized and classified depending on their response properties such as best frequency, auditory threshold, first spike latency, response duration, width and shape of the frequency response area and binaural interactions. Based on neurophysiological and neuroanatomical criteria, the auditory cortex of P. discolor could be subdivided into anterior and posterior ventral fields and anterior and posterior dorsal fields. The representation of response properties within the different auditory cortical fields was analyzed in detail. The two ventral fields were distinguished by their tonotopic organization with opposing frequency gradients. The dorsal cortical fields were not tonotopically organized but contained neurons that were responsive to high frequencies only. Conclusion: The auditory cortex of P. discolor resembles the auditory cortex of other phyllostomid bats in size and basic functional organization. The tonotopically organized posterior ventral field might represent the primary auditory cortex and the tonotopically organized anterior ventral field seems to be similar to the anterior auditory field of other mammals. As most energy of the echolocation pulse of P. discolor is contained in the high-frequency range, the non-tonotopically organized high-frequency dorsal region seems to be particularly important for echolocation.

Background: The Fischer 344/NHsd rat undergoes age-related, progressive, high-frequency hearing loss beginning at age 12 months. The loss has been linked to defects/death in the outer hair cells related to oxidative stress originating in the mitochondria. Acetyl L-carnitine (ALCAR) is known to enhance mitochondrial bioenergetics and membrane efficiency. Therefore, ALCAR was targeted as a possible pharmacologic intervention to prevent, or even restore, hearing loss from aging. Methods: Three different paradigms were used to deliver ALCAR to aging Fischer 344/NHsd rats. Rats in each condition had their hearing evaluated by auditory brainstem responses before, during, and after treatment. First, 24-month-old rats were given ALCAR (100 mg/kg dissolved 25 mg/ml in saline) by IP injection daily for one month. Second, 18-month-old rats were given ALCAR (100 mg/kg) by oral gavage for 90 days. Third, 15-month-old rats were given ALCAR (100 mg/kg) by oral gavage for 90 days. Control rats in each condition received saline by i.p. injection or gavage. Results: Hearing thresholds of the three sets of ALCAR-treated animals were never significantly different from their matched controls before, during, or after the treatments at any of the five test stimuli (5, 10, 20, and 40 kHz tone bursts and a click). Conclusion: The current study does not provide evidence that age-related hearing loss in the Fischer 344/NHsd rat can be altered with systemic administration of ALCAR.

The dominant cue for localization of low-frequency sounds are microsecond differences in the time-of-arrival of sounds at the two ears [interaural time difference (ITD)]. In mammals, ITD sensitivity is established in the medial superior olive (MSO) by coincidence detection of excitatory inputs from both ears. Hence the relative delay of the binaural inputs is crucial for adjusting ITD sensitivity in MSO cells. How these delays are constructed is, however, still unknown. Specifically, the question of whether inhibitory inputs are involved in timing the net excitation in MSO cells, and if so how, is controversial. These inhibitory inputs derive from the nuclei of the trapezoid body, which have physiological and structural specializations for high-fidelity temporal transmission, raising the possibility that well timed inhibition is involved in tuning ITD sensitivity. Here, we present physiological and pharmacological data from in vivo extracellular MSO recordings in anesthetized gerbils. Reversible blockade of synaptic inhibition by iontophoretic application of the glycine antagonist strychnine increased firing rates and significantly shifted ITD sensitivity of MSO neurons. This indicates that glycinergic inhibition plays a major role in tuning the delays of binaural excitation. We also tonically applied glycine, which lowered firing rates but also shifted ITD sensitivity in a way analogous to strychnine. Hence tonic glycine application experimentally decoupled the effect of inhibition from the timing of its inputs. We conclude that, for proper ITD processing, not only is inhibition necessary, but it must also be precisely timed.

Rodent ultrasonic vocalizations (USVs) are ethologically critical social signals. Rats emit 22kHz USVs and 50kHz USVs, respectively, in conjunction with negative and positive affective states. Little is known about what controls emotional reactivity to these social signals. Using male Sprague-Dawley rats, we examined unconditional and conditional freezing behavior in response to the following auditory stimuli: three 22kHz USVs, a discontinuous tone whose frequency and on-off pattern matched one of the USVs, a continuous tone with the same or lower frequencies, a 4kHz discontinuous tone with an on-off pattern matched to one of the USVs, and a 50kHz USV. There were no differences among these stimuli in terms of the unconditional elicitation of freezing behavior. Thus, the stimuli were equally neutral before conditioning. During differential fear conditioning, one of these stimuli (the CS(+)) always co-terminated with a footshock unconditional stimulus (US) and another stimulus (the CS(-)) was explicitly unpaired with the US. There were no significant differences among these cues in CS(+)-elicited freezing behavior. Thus, the stimuli were equally salient or effective as cues in supporting fear conditioning. When the CS(+) was a 22kHz USV or a similar stimulus, rats discriminated based on the principal frequency and/or the temporal pattern of the stimulus. However, when these same stimuli served as the CS(-), discrimination failed due to generalization from the CS(+). Thus, the stimuli differed markedly in the specificity of conditioning. This strikingly asymmetrical stimulus generalization is a novel bias in discrimination.

Nicotinic acetylcholine receptors (nAChRs) contribute to sensory-cognitive function, as demonstrated by evidence that nAChR activation enhances, and nAChR blockade impairs, neural processing of sensory stimuli and sensory-cognitive behavior. To better understand the relationship between nAChR function and behavior, here we compare the strength of nAChR-mediated physiology in individual animals to their prior auditory behavioral performance. Adult rats were trained on an auditory-cued, active avoidance task over 4 days and classified as "good," "intermediate" or "poor" performers based on their initial rate of learning and eventual level of performance. Animals were then anesthetized, and tone-evoked local field potentials (LFPs) recorded in layer 4 of auditory cortex (ACx) before and after a test dose of nicotine (0.7mg/kg, s.c.) or saline. In "good" performers, nicotine enhanced LFP amplitude and decreased response threshold to characteristic frequency (CF) stimuli, yet had opposite effects (decreased amplitude, increased threshold) on responses to spectrally distant stimuli; i.e., cortical receptive fields became more selective for CF stimuli. In contrast, nicotine had little effect on LFP amplitude in "intermediate" or "poor" performing animals. Nicotine did, however, reduce LFP onset latency in all three groups, indicating that all received an effective dose of the drug. Our findings suggest that nicotinic regulation of cortical receptive fields may be a distinguishing feature of the best-performing animals, and may facilitate sensory-related learning by enhancing receptive field selectivity.

Cochlear implant speech processors transmit temporal features of sound as amplitude modulation of constant-rate electrical pulse trains. This study evaluated the central representation of amplitude modulation in the form of phase-locked firing of neurons in the auditory cortex. Anesthetized pigmented guinea pigs were implanted with cochlear electrode arrays. Stimuli were 254 pulse/s (pps) trains of biphasic electrical pulses, sinusoidally modulated with frequencies of 10–64 Hz and modulation depths of −40 to −5 dB re 100% (i.e., 1–56.2% modulation). Single- and multiunit activity was recorded from multi-site silicon-substrate probes. The maximum frequency for significant phase locking (limiting modulation frequency) was ≥60 Hz for 42% of recording sites, whereas phase locking to pulses of unmodulated pulse trains rarely exceeded 30 pps. The strength of phase locking to frequencies ≥40 Hz often varied nonmonotonically with modulation depth, commonly peaking at modulation depths around −15 to −10 dB. Cortical phase locking coded modulation frequency reliably, whereas a putative rate code for frequency was confounded by rate changes with modulation depth. Group delay computed from the slope of mean phase versus modulation frequency tended to increase with decreasing limiting modulation frequency. Neurons in cortical extragranular layers had lower limiting modulation frequencies than did neurons in thalamic afferent layers. Those observations suggest that the low-pass characteristic of cortical phase locking results from intracortical filtering mechanisms. The results show that cortical neurons can phase lock to modulated electrical pulse trains across the range of modulation frequencies and depths presented by cochlear implant speech processors.

Little is known about the basic processes underlying the behavior of singing. This experiment was designed to examine differences in the representation of the mapping between fundamental frequency (F0) feedback and the vocal production system in singers and nonsingers. Auditory feedback regarding F0 was shifted down in frequency while participants sang the consonant-vowel /ta/. During the initial frequency-altered trials, singers compensated to a lesser degree than nonsingers, but this difference was reduced with continued exposure to frequency-altered feedback. After brief exposure to frequency altered auditory feedback, both singers and nonsingers suddenly heard their F0 unaltered. When participants received this unaltered feedback, only singers' F0 values were found to be significantly higher than their F0 values produced during baseline and control trials. These aftereffects in singers were replicated when participants sang a different note than the note they produced while hearing altered feedback. Together, these results suggest that singers rely more on internal models than nonsingers to regulate vocal productions rather than real time auditory feedback.

Middle-ear sound transmission was evaluated as the middle-ear transfer admittance HMY (the ratio of stapes velocity to ear-canal sound pressure near the umbo) in gerbils during closed-field sound stimulation at frequencies from 0.1to60kHz, a range that spans the gerbil’s audiometric range. Similar measurements were performed in two laboratories. The HMY magnitude (a) increased with frequency below 1kHz, (b) remained approximately constant with frequency from 5to35kHz, and (c) decreased substantially from 35to50kHz. The HMY phase increased linearly with frequency from 5to35kHz, consistent with a 20–29μs delay, and flattened at higher frequencies. Measurements from different directions showed that stapes motion is predominantly pistonlike except in a narrow frequency band around 10kHz. Cochlear input impedance was estimated from HMY and previously-measured cochlear sound pressure. Results do not support the idea that the middle ear is a lossless matched transmission line. Results support the ideas that (1) middle-ear transmission is consistent with a mechanical transmission line or multiresonant network between 5 and 35kHz and decreases at higher frequencies, (2) stapes motion is pistonlike over most of the gerbil auditory range, and (3) middle-ear transmission properties are a determinant of the audiogram.

Previous studies have shown large decreases in cochlear implant psychophysical detection thresholds during the weeks following the onset of electrical testing. The current study sought to determine the variables underlying these threshold decreases by examining the effects of four deafening and implantation procedures on detection thresholds and implant impedances. Thirty-two guinea pigs were divided into four matched groups. Group I was deafened and implanted Day 0 and began electrical testing Day 1. Group II was deafened and implanted Day 0 and began electrical testing Day 45. Group III was deafened Day 0, implanted Day 45 and began electrical testing Day 46. Group IV was not predeafened but was implanted Day 0 and began electrical testing Day 1. All groups showed threshold decreases over time but the magnitude of change, time course and final stable threshold levels depended on the type and time course of treatment. Impedances increased over the first two weeks following the onset of electrical testing except in Group II. Results suggest that multiple mechanisms underlie the observed threshold shifts including (1) recovery of the cochlea from a temporary pathology caused by the deafening and/or implantation procedures, (2) effects of electrical stimulation on the auditory pathway, and (3) tissue growth in the implanted cochlea. They also suggest that surviving hair cells influence electrical threshold levels.

Studies of the F344 rat have shown a variety of age-related auditory anatomy and physiology changes. The current study was undertaken to clarify the ARHL in the F344 rat, by examining the auditory pathway of the F344/NHsd substrain that is distributed by Harlan Laboratories for research in the United States. The F344/NHsd rat begins to lose its hearing at about 12 months, and by 24 months, there are 50-60 dB auditory brainstem response threshold shifts at 20 and 40 kHz and 20 dB losses at 5-10 kHz. Distortion product otoacoustic emissions (DPOAE) amplitudes at 1.8-12 kHz stimuli were depressed in the older (18-24 months) rats. Amplitude input-output functions of the compound action potential (CAP) were also depressed across frequency. The endocochlear potential (EP) was 90-100 mV in the 3 month old rats. All but one of the 24 month old rats' EPs were in the +75-85 mV range. Tympanometry revealed no differences in middle ear function between the young and older rats. Collectively, these findings suggest damage to the outer hair cells, but anatomical examination of the outer hair cells revealed a relative lack of cell loss compared to the magnitude of the hearing and DPOAE loss.

Cisplatin, a widely used anticancer drug, preferentially damages outer hair cells (OHCs) of the inner ear. In this study, an antibody microarray was used to identify early changes in protein expression in the rat cochlea induced by cisplatin. Only small changes in hearing thresholds (4-34 dB elevation) were detected two days after cisplatin treatment (12 mg/kg). OHC function, measured by otoacoustic emissions, was slightly depressed (10 dB), and little or no receptor cell loss was observed. However, cisplatin induced large changes in the expression of 19 proteins involved in apoptosis, cell survival, or progression through the cell cycle. Fifteen of the proteins are novel to the study of the inner ear. Immunoblotting confirmed increases in the levels of the pro-survival activating transcription factor 2 (ATF2), of pro-apoptotic serine-threonine protein kinase, receptor interacting protein, and a 70/75 kDa nitrotyrosine bearing doublet of unknown function. Anti-nitrotyrosine antibodies localized these oxidatively damaged proteins to the stereocilia of OHCs, the Golgi-centrosome region of Hensen's cells, nuclei of outer pillar cells, and tunnel crossing fibers innervating OHCs. The results of this proteomic analysis reflect the commencement of ototoxic and cell survival responses before the observation of a significant functional or anatomical loss.

Studies of sound localization in humans have used various behavioral measures to quantify the observers' perceptions; a non-comprehensive list includes verbal reports, head pointing, gun pointing, stylus pointing, and laser aiming. Comparison of localization performance reveals that in humans, just as in animals, different results are obtained with different experimental tasks. Accordingly, to circumvent problems associated with task selection and training, this study used gaze, an ethologically valid behavior for spatial pointing in species with a specialized area of the fovea, to measure sound localization perception of human subjects. Orienting using gaze as a pointer does not require training, preserves the natural link between perception and action, and allows for direct behavioral comparisons across species. The results revealed, unexpectedly, a large degree of variability across subjects in both accuracy and precision. The magnitude of the average angular localization errors for the most eccentric horizontal targets, however, were very similar to those documented in studies that used head pointing, whereas the magnitude of the localization errors for the frontal targets were considerably larger. In addition, an overall improvement in sound localization in the context of the memory-saccade task, as well as a lack of effect of initial eye and head position on perceived sound location were documented.

Auditory neurons must represent accurately a wide range of sound levels using firing rates that vary over a far narrower range of levels. Recently, we demonstrated that this "dynamic range problem" is lessened by neural adaptation, whereby neurons adjust their input-output functions for sound level according to the prevailing distribution of levels. These adjustments in input-output functions increase the accuracy with which levels around those occurring most commonly are coded by the neural population. Here, we examine how quickly this adaptation occurs. We recorded from single neurons in the auditory midbrain during a stimulus that switched repeatedly between two distributions of sound levels differing in mean level. The high-resolution analysis afforded by this stimulus showed that a prominent component of the adaptation occurs rapidly, with an average time constant across neurons of 160 ms after an increase in mean level, much faster than our previous experiments were able to assess. This time course appears to be independent of both the timescale over which sound levels varied and that over which sound level distributions varied, but is related to neural characteristic frequency. We find that adaptation to an increase in mean level occurs more rapidly than to a decrease. Finally, we observe an additional, slow adaptation in some neurons, which occurs over a timescale of tens of seconds. Our findings provide constraints in the search for mechanisms underlying adaptation to sound level. They also have functional implications for the role of adaptation in the representation of natural sounds.

The acoustical cues for sound location are generated by spatial- and frequency-dependent filtering of propagating sound waves by the head and external ears. Although rats have been a common model system for anatomy, physiology, and psychophysics of localization, there have been few studies of the acoustical cues available to rats. Here, directional transfer functions (DTFs), the directional components of the head-related transfer functions, were measured in six adult rats. The cues to location were computed from the DTFs. In the frontal hemisphere, spectral notches were present for frequencies from ∼16to30kHz; in general, the frequency corresponding to the notch increased with increases in source elevation and in azimuth toward the ipsilateral ear. The maximum high-frequency envelope-based interaural time differences (ITDs) were 130μs, whereas low-frequency (<3.5kHz) fine-structure ITDs were 160μs; both types of ITDs were larger than predicted from spherical head models. Interaural level differences (ILDs) strongly depended on location and frequency. Maximum ILDs were <10dB for frequencies <8kHz and were as large as 20–40dB for frequencies >20kHz. Removal of the pinna eliminated the spectral notches, reduced the acoustic gain and ILDs, altered the acoustical axis, and reduced the ITDs.

Purpose This study examined how repeated presentations of words in noise affected understanding of both trained and untrained words in noise (in isolation and in sentences). Method Eight older listeners with hearing impairment completed a word-based auditory training protocol lasting approximately 12 weeks. Training materials were presented in a closed-set condition with both orthographic and auditory feedback on a trial-to-trial basis. Performance on both trained and untrained lexically easy and hard words, as well as generalization to sentences, was measured. Listeners then returned for an additional 14 weeks to monitor retention of the trained materials. Results Training listeners on 1 set of words improved both their open- and closed-set recognition of the trained materials but did not improve performance on another set of untrained words. When training switched to the other set, performance for the new set of words improved significantly, whereas significant improvements on the previously trained words were maintained. Training generalized to unfamiliar talkers but did not generalize to untrained words or untrained keywords within running speech. Listeners were able to maintain improved performance over an extended period. Conclusion Older listeners were able to improve their word-recognition performance in noise on a set of 150 words with training.