Publications using TDT

Focal electric stimulation of the auditory cortex is well suited for exploration of the function of the corticofugal (descending) system and the neural mechanism of plasticity in the central auditory system, because it evokes changes in frequency-tuning, called best frequency (BF) shifts, as does auditory fear conditioning. The Doppler-shifted constant frequency (DSCF) area of the primary auditory cortex of the mustached bat is highly specialized for fine frequency analysis. Focal electric stimulation of the DSCF area evokes the BF shifts of ipsilateral cortical and collicular neurons away from the BF of stimulated neurons, whereas the stimulation evokes the BF shifts of contralateral cortical and collicular neurons either toward or away from the stimulated BF. The direction of contralateral BF shifts shows a flip-flop, depending on the spatial relationship between the stimulated and recorded neurons. This asymmetry in corticofugal modulation is mostly, if not totally, created by two subdivisions of the stimulated DSCF area that transmit signals to the contralateral DSCF area, presumably through the corpus callosum. This intriguing asymmetry in corticofugal modulation presumably functions for equalization of the reorganization of the frequency maps of the DSCF areas and subcortical auditory nuclei on both sides.

We examined whether the detection of audio–visual temporal synchrony is determined by a pre-attentive parallel process, or by an attentive serial process using a visual search paradigm. We found that detection of a visual target that changed in synchrony with an auditory stimulus was gradually impaired as the number of unsynchronized visual distractors increased (experiment 1), whereas synchrony discrimination of an attended target in a pre-cued location was unaffected by the presence of distractors (experiment 2). The effect of distractors cannot be ascribed to reduced target visibility nor can the increase in false alarm rates be predicted by a noisy parallel processing model. Reaction times for target detection increased linearly with number of distractors, with the slope being about twice as steep for target-absent trials as for target-present trials (experiment 3). Similar results were obtained regardless of whether the audio–visual stimulus consisted of visual flashes synchronized with amplitude-modulated pips, or of visual rotations synchronized with frequency-modulated up–down sweeps. All of the results indicate that audio–visual perceptual synchrony is judged by a serial process and are consistent with the suggestion that audio–visual temporal synchrony is detected by a ‘mid-level’ feature matching process.

Little is known about the neural bases of the reduced auditory and cortical processing speeds that have been recorded in language-impaired, autistic, schizophrenic, and other disabled human populations. Although there is strong evidence for genetic contributions to etiologies, epigenetic factors such as perinatal anoxia (PA) have been argued to be contributors, or causal, in a significant proportion of cases. In this article, we explored the consequences of PA on this elementary aspect of auditory behavior and on auditory system function in rats that were briefly perinatally anoxic. PA rats had increased acoustic thresholds and reduced processing efficiencies recorded in an auditory behavioral task. These rats had modestly increased interpeak intervals in their auditory brainstem responses, and substantially longer latencies in poststimulus time histogram responses recorded in the primary auditory cortex. The latter were associated with degraded primary auditory cortex receptive fields and a disrupted tonotopy. These processing deficits are consistent with the parallel behavioral and physiological deficits recorded in children and adults with a history of language-learning impairment and autism.

To perform the jamming avoidance response (JAR), the weakly electric fish Gymnarchus detects time disparities on the order of microseconds between electrosensory signals received by electroreceptors in different parts of the body surface. This paper describes time-disparity thresholds of output neurons of the electrosensory lateral line lobe (ELL), where the representation of timing information is converted from a time code to a firing-rate code. We recorded extracellular single-unit responses from pyramidal cells in the ELL to sinusoidally modulated time disparity with various depths (0-200 μs). Threshold sensitivity to time disparities measured in 123 units ranged from 0.5 to 100 μs and was ≤5 μs in 60% of the units. The units from pyramidal cells in the inner and outer cell layers of the ELL responded equally well to small time disparities. The neuronal thresholds to time disparities found in the ELL are comparable with those demonstrated in behavioral performance of the JAR. The sensitivity of ELL units to small time disparities was unaffected when the center of the cyclic time-disparity modulation was shifted over a wide range (up to 250 μs), indicating an adaptation mechanism for steady-state time disparities that preserves the sensitivity to small dynamic changes in time disparities. Phase-locked input neurons, which provide time information to the ELL by phase-locked firing of action potentials, did not adapt to steady-state time shifts of sensory signals. This suggests that the adaptation emerges within the ELL.

Two-tone stimuli have traditionally been used to reveal regions of inhibition in auditory spectral receptive fields, particularly for neurons with low spontaneous rates. These techniques reveal how different frequencies excite or suppress the response to an excitatory frequency of a cell, but have often been assessed at a fixed masker-probe time interval. We used a variation of this methodology to determine whether two-tone spectrotemporal interactions can account for rate-dependent directional selectivity for frequency modulations (FM) in the mustached bat inferior colliculus (IC). First, we quantified the response to upward and downward sweeping, linear, fixed-bandwidth FM tones centered at a unit's characteristic frequency (CF) at 6 sweep durations ranging from 2 to 64 ms. Then, to examine how responses to instantaneous frequencies contained within the sweeps might interact in time, we varied the frequency and relative onset of a brief (4 ms) "conditioner" tone paired with a fixed 4-ms CF probe tone. We constructed "conditioned response areas" (CRA) depicting regions of suppression and facilitation of the probe tone caused by the conditioning tone. We classified the CRAs as predominantly excitatory (40.9%), inhibitory (22.7%), or mixed (36.4%). To generate FM response predictions, the CRAs were multiplied with spectrograms of the same sweeps used to assess response to FM. The predictions of FM rate and directionality were accurate by our criteria in approximately 20% of units. Conversely, the CRAs from the remaining units failed to predict FM responses as accurately, suggesting that most IC units respond differently to FM sweeps than they do to tone-pairs matched to the instantaneous frequencies contained in those sweeps. The implications of these results for models of FM directionality are discussed.

A superior semicircular canal dehiscence (SCD) is a break or hole in the bony wall of the superior semicircular canal. Patients with SCD syndrome present with a variety of symptoms: some with vestibular symptoms, others with auditory symptoms (including low-frequency conductive hearing loss) and yet others with both. We are interested in whether or not mechanically altering the superior canal by introducing a dehiscence is sufficient to cause the low-frequency conductive hearing loss associated with SCD syndrome. We evaluated the effect of a surgically introduced dehiscence on auditory responses to air-conducted (AC) stimuli in 11 chinchilla ears. Cochlear potential (CP) was recorded at the round-window before and after a dehiscence was introduced. In each ear, a decrease in CP in response to low frequency (<2 kHz) sound stimuli was observed after the introduction of the dehiscence. The dehiscence was then patched with cyanoacrylate glue leading to a reversal of the dehiscence-induced changes in CP. The reversible decrease in auditory sensitivity observed in chinchilla is consistent with the elevated AC thresholds observed in patients with SCD. According to the 'third-window' hypothesis the SCD shunts sound-induced stapes velocity away from the cochlea, resulting in decreased auditory sensitivity to AC sounds. The data collected in this study are consistent with predictions of this hypothesis.

The visual cortex is organized into retinotopic maps that preserve an orderly representation of the visual world, achieved by topographically precise inputs from the lateral geniculate nucleus. We show here that geniculocortical mapping is imprecise when the waves of spontaneous activity in the retina during the first postnatal week are disrupted genetically. This anatomical mapping defect is present by postnatal day 8 and has functional consequences, as revealed by optical imaging and microelectrode recording in adults. Pharmacological disruption of these retinal waves during the first week phenocopies the mapping defect, confirming both the site and the timing of the disruption in neural activity responsible for the defect. Analysis shows that the geniculocortical miswiring is not a trivial or necessary consequence of the retinogeniculate defect. Our findings demonstrate that disrupting early spontaneous activity in the eye alters thalamic connections to the cortex.

Age-related hearing loss frequently results in a loss in the ability to discriminate speech signals, especially in noise. This is attributable, in part, to a loss in temporal resolving power and ability to adjust dynamic range. Circuits in the adult dorsal cochlear nucleus (DCN) have been shown to preserve signal in background noise. Fusiform cells, major DCN output neurons, receive focused glycinergic inputs from tonotopically aligned vertical cells that also project to the ventral cochlear nucleus. Glycine-mediated inhibition onto fusiform cells results in decreased tone-evoked activity as intensity is increased at frequencies adjacent to characteristic frequency (CF). DCN output is thus shaped by glycinergic inhibition, which can be readily assessed in recordings from fusiform cells. Previous DCN studies suggest an age-related loss of markers for glycinergic neurotransmission. The present study postulated that response properties of aged fusiform cells would show a loss of inhibition, resembling conditions observed with glycine receptor blockade. The functional impact of aging was examined by comparing response properties from units meeting fusiform-cell criteria in young and aged rats. Fusiform cells in aged animals displayed significantly higher maximum discharge rates to CF tones than those recorded from young-adult animals. Fusiform cells of aged rats displayed significantly fewer nonmonotonic CF rate-level functions and an age-related change in temporal response properties. These findings are consistent with an age-related loss of glycinergic input, likely from vertical cells, and with findings from other sensory aging studies suggesting a selective age-related decrement in inhibitory amino acid neurotransmitter function.

In nature, sounds from multiple sources sum at the eardrums, generating complex cues for sound localization and identification. In this clutter, the auditory system must determine “what is where.” We examined this process in the auditory space map of the barn owl's ( Tyto alba ) inferior colliculus using two spatially separated sources simultaneously emitting uncorrelated noise bursts, which were uniquely identified by different frequencies of sinusoidal amplitude modulation. Spatial response profiles of isolated neurons were constructed by testing the source-pair centered at various locations in virtual auditory space. The neurons responded whenever a source was placed within the receptive field, generating two clearly segregated foci of activity at appropriate loci. The spike trains were locked strongly to the amplitude modulation of the source within the receptive field, whereas the other source had minimal influence. Two sources amplitude modulated at the same rate were resolved successfully, suggesting that source separation is based on differences of fine structure. The spike rate and synchrony were stronger for whichever source had the stronger average binaural level. A computational model showed that neuronal activity was primarily proportional to the degree of matching between the momentary binaural cues and the preferred values of the neuron. The model showed that individual neurons respond to and synchronize with sources in their receptive field if there are frequencies having an average binaural-level advantage over a second source. Frequencies with interaural phase differences that are shared by both sources may also evoke activity, which may be synchronized with the amplitude modulations from either source.

Using a closed-set speech recognition paradigm thought to be heavily influenced by informational masking, auditory selective attention was measured in 38 children (ages 4–16years) and 8 adults (ages 20–30years). The task required attention to a monaural target speech message that was presented with a time-synchronized distracter message in the same ear. In some conditions a second distracter message or a speech-shaped noise was presented to the other ear. Compared to adults, children required higher target∕distracter ratios to reach comparable performance levels, reflecting more informational masking in these listeners. Informational masking in most conditions was confirmed by the fact that a large proportion of the errors made by the listeners were contained in the distracter message(s). There was a monotonic age effect, such that even the children in the oldest age group (13.6–16years) demonstrated poorer performance than adults. For both children and adults, presentation of an additional distracter in the contralateral ear significantly reduced performance, even when the distracter messages were produced by a talker of different sex than the target talker. The results are consistent with earlier reports from pure-tone masking studies that informational masking effects are much larger in children than in adults.

Ephrin-As and their receptors, EphAs, are expressed in the developing cortex where they may act to organize thalamic inputs. Here, we map the visual cortex (V1) in mice deficient for ephrin-A2, -A3, and -A5 functionally, using intrinsic signal optical imaging and microelectrode recording, and structurally, by anatomical tracing of thalamocortical projections. V1 is shifted medially, rotated, and compressed and its internal organization is degraded. Expressing ephrin-A5 ectopically by in utero electroporation in the lateral cortex shifts the map of V1 medially, and expression within V1 disrupts its internal organization. These findings indicate that interactions between gradients of EphA/ephrin-A in the cortex guide map formation, but that factors other than redundant ephrin-As are responsible for the remnant map. Together with earlier work on the retinogeniculate map, the current findings show that the same molecular interactions may operate at successive stages of the visual pathway to organize maps.

Gentamicin is a widely used ototoxic agent. In this study, we shed light on the mechanisms underlying gentamicin-induced hearing loss. More importantly, we demonstrate in vivo and in vitro the effectiveness of a strategy for preventing drug-induced hearing loss using l -carnitine (LCAR), a safe micronutrient that plays a key role in energy metabolism and detoxification [Rebouche, C. J. & Seim, H. (1998) Annu. Rev. Nutr. 18, 39-61]. We show that LCAR prevents changes in hearing threshold and cochlear damage in newborn guinea pigs exposed to gentamicin in utero . Mechanistically, gentamicin-induced apoptosis of auditory cells is mediated by the extracellular signal-regulated kinase (ERK) 1/2 mitogen-activated protein kinase (MAPK) pathway through up-regulation of the proapoptotic factor Harakiri ( Hrk ). Most important, small interfering RNA (siRNA) experiments demonstrate that Hrk up-regulation is crucial for gentamicin-induced apoptosis. LCAR, in contrast, prevents both gentamicin-induced Hrk up-regulation and apoptosis acting by means of c-Jun N-terminal kinase (JNK). Together, these results outline pathways for gentamicin-induced hearing loss and its prevention and assign a key role to Hrk in these processes. Thus, our data offer a conceptual framework for designing clinical trials using a safe micronutrient, LCAR, as a simple preventive strategy for iatrogenically induced ototoxicity.

We hypothesized that learning-induced representational expansion in the primary auditory cortex (AI) directly encodes the degree of behavioral importance of a sound. Rats trained on an operant auditory conditioning task were variably motivated to the conditioned stimulus (CS) through different levels of water deprivation. Mean performance values correlated with deprivation level, validating them as a measure of the overall control and, therefore, behavioral importance of the CS. Electrophysiological mapping revealed expanded representations of the CS, compared with other frequencies in experimental subjects, but not in naive or visually trained controls that received noncontingent CS tones. Importantly, representational area showed a significant positive correlation with mean performance levels for only the CS band, with significant effects for relative area in contrast to only modest changes in absolute area. CS representational expansion was asymmetric into high-frequency zones, thus performance level also was significantly correlated with the relative anterior-posterior location of the enlarged representation. An increased representation of low frequencies, related to the acoustic spectrum of the reward delivery equipment, also was discovered in both experimental and control trained subjects, supporting the conclusion that behaviorally important sounds gain representational area. Furthermore, there was a surprising reduction in total AI area for the experimental and control groups, compared with untrained naive subjects, indicating that the functional dimensions of AI are not fixed. Overall, the findings support the encoding of acquired stimulus importance based on representational size in AI.

Superoxide has been implicated as a contributing factor to cochlear pathology from a number of sources, including noise and ototoxic drugs. The effects of NADPH oxidase-dependent superoxide on the cochlea were investigated in the current study using paraquat (PQ). PQ is a toxic herbicide that causes tissue damage by generating superoxide through reduction of molecular oxygen in a reaction catalyzed by NADPH oxidase. The current study examined the effects of round window PQ administration on inferior colliculus (IC) evoked potential thresholds (EVP) and hair cell damage. Using implanted IC electrodes, chinchillas were tested for IC EVP thresholds before and after PQ exposure. Ears were exposed to PQ at one of four concentrations: 10, 5, 3 mM, and vehicle control. Thresholds were increased in a dose-dependent manner, and peaked between one and seven days post-exposure. Thresholds then showed a small amount of recovery before reaching PTS by Day 22. Outer and inner hair cell losses were consistent with PTS. The similarities between PQ ototoxicity and noise-induced hearing loss suggest the possibility of similar biochemical pathways involving superoxide.

A central tenet in brain research is that early sensory cortex is modality specific, and, only in exceptional cases, such as deaf and blind subjects or professional musicians, is influenced by other modalities. Here we describe extensive cross-modal activation in the auditory cortex of two monkeys while they performed a demanding auditory categorization task: after a cue light was turned on, monkeys could initiate a tone sequence by touching a bar and then earn a reward by releasing the bar on occurrence of a falling frequency contour in the sequence. In their primary auditory cortex and posterior belt areas, we found many acoustically responsive neurons whose firing was synchronized to the cue light or to the touch or release of the bar. Of 315 multiunits, 45 exhibited cue light-related firing, 194 exhibited firing that was related to bar touch, and 268 exhibited firing that was related to bar release. Among 60 single units, we found one neuron with cue light-related firing, 21 with bar touch-related firing, and 36 with release-related firing. This firing disappeared at individual sites when the monkeys performed a visual detection task. Our findings corroborate and extend recent findings on cross-modal activation in the auditory cortex and suggests that the auditory cortex can be activated by visual and somatosensory stimulation and by movements. We speculate that the multimodal corepresentation in the auditory cortex has arisen from the intensive practice of the subjects with the behavioral procedure and that it facilitates the performance of audiomotor tasks in proficient subjects.

Cochlear and vestibular sensory cells undergo apoptosis when exposed to aminoglycoside antibiotics in organ culture, but mechanisms of chronic drug-induced hair cell loss in vivo are unclear. We investigated cell death pathways in a mouse model of progressive kanamycin-induced hair cell loss. Hair cell nuclei showed both apoptotic- and necrotic-like appearances but markers for classic apoptotic pathways (cytochrome c, caspase-9, caspase-3, JNK, TUNEL) were absent. In contrast, drug treatment caused EndoG translocation, activation of mu-calpain, and both the synthesis and activation of cathepsin D. Poly (ADP-ribose) polymerase 1 (PARP1) was decreased, but a caspase-derived 89 kDa PARP1 fragment was not present. The mRNA level of PARP1 remained unchanged. Thus, chronic administration of aminoglycosides causes multiple forms of cell death, without a major contribution by classic apoptosis. These results provide a better understanding of the toxic effects of aminoglycosides and are relevant to design protection from aminoglycoside-induced hearing loss.

The response of neurons in the primary visual cortex to an optimally oriented grating is usually suppressed quite dramatically when a second grating of, for example, orthogonal orientation is superimposed. Such “cross-orientation suppression” has been implicated in the generation of cortical orientation selectivity and local response normalization. Until recently, little experimental evidence was available concerning the neurophysiological substrate of this phenomenon, although an involvement of intracortical inhibition was commonly assumed. However, Freeman et al. (2002) proposed that cortical cross-orientation suppression is caused by suppression in the thalamus and depression at geniculocortical synapses. Here, we examine a dichoptic form of cross-orientation suppression, termed interocular suppression and thought to be involved in binocular rivalry (Sengpiel et al., 1995a). We show that its dependency on the drift rate of the suppressing stimulus is consistent with a cortical origin; unlike monocular cross-orientation suppression, it cannot be evoked by very fast-moving stimuli. Moreover, we find that previous adaptation to the orthogonal stimulus essentially eliminates interocular suppression. Because adaptation is a cortical phenomenon, this result also argues in favor of a cortical locus of suppression, again unlike monocular cross-orientation suppression, which is not affected by adaptation to the suppressor (Freeman et al., 2002). Finally, interocular suppression is greatly reduced in the presence of the GABA antagonist bicuculline. Together, our study demonstrates that interocular suppression is substantially different from monocular cross-orientation suppression and is mediated by inhibitory circuitry within the visual cortex.

We investigated the role of GABAergic inhibition on the responses of inferior colliculus (IC) neurons sensitive to interaural time differences (ITDs) in anesthetized guinea pigs. Responses to static and dynamic ITDs were obtained before, during, and after recovery from ionotophoretic application of GABA, or antagonists to the GABA A receptor gabazine and bicuculline. For most neurons, a linear relationship was observed between discharge rates evoked by a particular ITD during drug application and control discharge rates. Blocking GABAergic inhibition, or adding exogenous GABA, scaled IC discharge rates in a multiplicative (divisive) and/or additive (subtractive) manner. When the influence of iontophoresed GABA antagonists or exogenous GABA on discharge rates was accounted for, GABAergic inhibition was found to have no effect on the ITD tuning properties of IC neurons. The tuning sharpness of ITD functions, the ITD that evoked 50% response magnitude, and the relative symmetry of ITD functions around their peak response were unaffected by blockade of inhibition or addition of tonic inhibition. However, the ability of neurons to discriminate between ITDs by virtue of differences in their discharge rate was altered by blocking or adding GABA. We propose that inhibition in the IC is involved in the control of the neural gain of the output of IC neurons rather than the regulation of ITD tuning. This gain control appears to arise from a combination of additive and multiplicative processes, and may involve mechanisms such as shunting inhibition or changes in the efficacy of inhibitory and excitatory inputs.

The superior colliculus (SC) is a midbrain structure that plays a central role in the integration of information from different sensory modalities and the generation of orienting responses. Its normal function is thought to be governed by a strictly held balance between excitation and inhibition. This hypothesis was tested by recording from the same single units in the SC of cats before the injection of anesthetics, while anesthetics took effect, and after the injections during recovery. Sodium pentobarbital and ketamine, two agents commonly used in sensory physiology, were used. The results show a plethora of dose-dependent and nonlinear effects: the magnitude of evoked responses, receptive field properties, first spike latency, and bimodal integration were affected by both anesthetics in all units tested. Notably, prominent facilitation was observed at low levels of anesthesia, and inhibitory responses were changed into excitatory. Overall, the results challenge a fundamental tenet of sensory physiology: anesthesia, while decreasing single-unit responsiveness, leaves unaltered basic physiological properties.

All sonic vertebrates face the problem of sound production interfering with their ability to detect and process external acoustic signals, including conspecific vocalizations. Direct efferent inputs to the inner ear of all vertebrates, and the lateral line system of some aquatic vertebrates, represent a potential mechanism to adjust peripheral sensitivity during sound production. We recorded from single efferent neurons that innervate the inner ear and lateral line in a sound-producing teleost fish while evoking fictive vocalizations predictive of the temporal features of natural vocalizations. The majority of efferent neurons showed an increase in activity that occurred in-phase with modulations in the fine temporal structure of the fictive vocalizations. Many of these neurons also showed a decrease in activity at fictive vocal offset. Efferents to the sacculus, the main auditory end organ, showed features especially well adapted for maintaining sensitivity to external acoustic signals during sound production. These included robust phase locking of efferent activity to each cycle of a fictive vocalization and a long-duration rebound suppression after each fictive vocalization that could provide a rapid, long-lasting period of sensitization to external acoustic stimuli such as the call of a conspecific. These results suggest that efferent activation by the vocal motor system can directly modulate auditory sensitivity to self-generated sounds and maintain sensitivity to ongoing external sounds. Given the conserved organization of the auditory efferent system across vertebrates, such mechanisms may be operative among all sonic vertebrates.