Publications using TDT

Categorization is an important cognitive process. However, the correct categorization of a stimulus is often challenging because categories can have overlapping boundaries. Whereas perceptual categorization has been extensively studied in vision, the analogous phenomenon in audition has yet to be systematically explored. Here, we test whether and how human subjects learn to use category distributions and prior probabilities, as well as whether subjects employ an optimal decision strategy when making auditory-category decisions. We asked subjects to classify the frequency of a tone burst into one of two overlapping, uniform categories according to the perceived tone frequency. We systematically varied the prior probability of presenting a tone burst with a frequency originating from one versus the other category. Most subjects learned these changes in prior probabilities early in testing and used this information to influence categorization. We also measured each subject's frequency-discrimination thresholds (i.e., their sensory uncertainty levels). We tested each subject's average behavior against variations of a Bayesian model that either led to optimal or sub-optimal decision behavior (i.e. probability matching). In both predicting and fitting each subject's average behavior, we found that probability matching provided a better account of human decision behavior. The model fits confirmed that subjects were able to learn category prior probabilities and approximate forms of the category distributions. Finally, we systematically explored the potential ways that additional noise sources could influence categorization behavior. We found that an optimal decision strategy can produce probability-matching behavior if it utilized non-stationary category distributions and prior probabilities formed over a short stimulus history. Our work extends previous findings into the auditory domain and reformulates the issue of categorization in a manner that can help to interpret the results of previous research within a generative framework.

In the visual, auditory, and electrosensory modalities, stimuli are defined by first- and second-order attributes. The fast time-pressure signal of a sound, a first-order attribute, is important, for instance, in sound localization and pitch perception, while its slow amplitude-modulated envelope, a second-order attribute, can be used for sound recognition. Ascending the auditory pathway from ear to midbrain, neurons increasingly show a preference for the envelope and are most sensitive to particular envelope modulation frequencies, a tuning considered important for encoding sound identity. The level at which this tuning property emerges along the pathway varies across species, and the mechanism of how this occurs is a matter of debate. In this paper, we target the transition between auditory nerve fibers and the cochlear nucleus angularis (NA). While the owl's auditory nerve fibers simultaneously encode the fast and slow attributes of a sound, one synapse further, NA neurons encode the envelope more efficiently than the auditory nerve. Using in vivo and in vitro electrophysiology and computational analysis, we show that a single-cell mechanism inducing spike threshold adaptation can explain the difference in neural filtering between the two areas. We show that spike threshold adaptation can explain the increased selectivity to modulation frequency, as input level increases in NA. These results demonstrate that a spike generation nonlinearity can modulate the tuning to second-order stimulus features, without invoking network or synaptic mechanisms.

Noise-induced hearing loss is at least in part due to disruption of endocochlear potential, which is maintained by various K(+) transport apparatuses including Na(+), K(+)-ATPase and gap junction-mediated intercellular communication in the lateral wall structures. In this study, we examined the changes in the ion-trafficking-related proteins in the spiral ligament fibrocytes (SLFs) following in vivo acoustic overstimulation or in vitro exposure of cultured SLFs to 4-hydroxy-2-nonenal, which is a mediator of oxidative stress. Connexin (Cx)26 and Cx30 were ubiquitously expressed throughout the spiral ligament, whereas Na(+), K(+)-ATPase α1 was predominantly detected in the stria vascularis and spiral prominence (type 2 SLFs). One-hour exposure of mice to 8 kHz octave band noise at a 110 dB sound pressure level produced an immediate and prolonged decrease in the Cx26 expression level and in Na+, K(+)-ATPase activity, as well as a delayed decrease in Cx30 expression in the SLFs. The noise-induced hearing loss and decrease in the Cx26 protein level and Na(+), K(+)-ATPase activity were abolished by a systemic treatment with a free radical-scavenging agent, 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl, or with a nitric oxide synthase inhibitor, N(ω)-nitro-L-arginine methyl ester hydrochloride. In vitro exposure of SLFs in primary culture to 4-hydroxy-2-nonenal produced a decrease in the protein levels of Cx26 and Na(+), K(+)-ATPase α1, as well as Na(+), K(+)-ATPase activity, and also resulted in dysfunction of the intercellular communication between the SLFs. Taken together, our data suggest that disruption of the ion-trafficking system in the cochlear SLFs is caused by the decrease in Cxs level and Na(+), K(+)-ATPase activity, and at least in part involved in permanent hearing loss induced by intense noise. Oxidative stress-mediated products might contribute to the decrease in Cxs content and Na(+), K(+)-ATPase activity in the cochlear lateral wall structures.

The firing rates of neurons in primary visual cortex (V1) are suppressed by large stimuli, an effect known as surround suppression. In cats and monkeys, the strength of suppression is sensitive to orientation; responses to regions containing uniform orientations are more suppressed than those containing orientation contrast. This effect is thought to be important for scene segmentation, but the underlying neural mechanisms are poorly understood. We asked whether it is possible to study these mechanisms in the visual cortex of mice, because of recent advances in technology for studying the cortical circuitry in mice. It is unknown whether neurons in mouse V1 are sensitive to orientation contrast. We measured the orientation selectivity of surround suppression in the different layers of mouse V1. We found strong surround suppression in layer 4 and the superficial layers, part of which was orientation tuned: iso-oriented surrounds caused more suppression than cross-oriented surrounds. Surround suppression was delayed relative to the visual response and orientation-tuned suppression was delayed further, suggesting two separate suppressive mechanisms. Previous studies proposed that surround suppression depends on the activity of inhibitory somatostatin-positive interneurons in the superficial layers. To test the involvement of the superficial layers we topically applied lidocaine. Silencing of the superficial layers did not prevent orientation-tuned suppression in layer 4. These results show that neurons in mouse V1, which lacks orientation columns, show orientation-dependent surround suppression in layer 4 and the superficial layers and that surround suppression in layer 4 does not require contributions from neurons in the superficial layers.

Brain-machine interfaces can allow neural control over assistive devices. They also provide an important platform for studying neural plasticity. Recent studies have suggested that optimal engagement of learning is essential for robust neuroprosthetic control. However, little is known about the neural processes that may consolidate a neuroprosthetic skill. On the basis of the growing body of evidence linking slow-wave activity (SWA) during sleep to consolidation, we examined whether there is 'offline' processing after neuroprosthetic learning. Using a rodent model, we found that, after successful learning, task-related units specifically experienced increased locking and coherency to SWA during sleep. Moreover, spike-spike coherence among these units was substantially enhanced. These changes were not present with poor skill acquisition or after control awake periods, demonstrating the specificity of our observations to learning. Notably, the time spent in SWA predicted the performance gains. Thus, SWA appears to be involved in offline processing after neuroprosthetic learning.

Subcortical auditory nuclei were traditionally viewed as non-plastic in adulthood so that acoustic information could be stably conveyed to higher auditory areas. Studies in a variety of species, including humans, now suggest that prolonged acoustic training can drive long-lasting brainstem plasticity. The neurobiological mechanisms for such changes are not well understood in natural behavioral contexts due to a relative dearth of in vivo animal models in which to study this. Here, we demonstrate in a mouse model that a natural life experience with increased demands on the auditory system - motherhood - is associated with improved temporal processing in the subcortical auditory pathway. We measured the auditory brainstem response to test whether mothers and pup-naïve virgin mice differed in temporal responses to both broadband and tone stimuli, including ultrasonic frequencies found in mouse pup vocalizations. Mothers had shorter latencies for early ABR peaks, indicating plasticity in the auditory nerve and the cochlear nucleus. Shorter interpeak latency between waves IV and V also suggest plasticity in the inferior colliculus. Hormone manipulations revealed that these cannot be explained solely by estrogen levels experienced during pregnancy and parturition in mothers. In contrast, we found that pup-care experience, independent of pregnancy and parturition, contributes to shortening auditory brainstem response latencies. These results suggest that acoustic experience in the maternal context imparts plasticity on early auditory processing that lasts beyond pup weaning. In addition to establishing an animal model for exploring adult auditory brainstem plasticity in a neuroethological context, our results have broader implications for models of perceptual, behavioral and neural changes that arise during maternity, where subcortical sensorineural plasticity has not previously been considered.

Neurons in sensory brain regions shape our perception of the surrounding environment through two parallel operations: decomposition and integration. For example, auditory neurons decompose sounds by separately encoding their frequency, temporal modulation, intensity, and spatial location. Neurons also integrate across these various features to support a unified perceptual gestalt of an auditory object. At higher levels of a sensory pathway, neurons may select for a restricted region of feature space defined by the intersection of multiple, independent stimulus dimensions. To further characterize how auditory cortical neurons decompose and integrate multiple facets of an isolated sound, we developed an automated procedure that manipulated five fundamental acoustic properties in real time based on single-unit feedback in awake mice. Within several minutes, the online approach converged on regions of the multidimensional stimulus manifold that reliably drove neurons at significantly higher rates than predefined stimuli. Optimized stimuli were cross-validated against pure tone receptive fields and spectrotemporal receptive field estimates in the inferior colliculus and primary auditory cortex. We observed, from midbrain to cortex, increases in both level invariance and frequency selectivity, which may underlie equivalent sparseness of responses in the two areas. We found that onset and steady-state spike rates increased proportionately as the stimulus was tailored to the multidimensional receptive field. By separately evaluating the amount of leverage each sound feature exerted on the overall firing rate, these findings reveal interdependencies between stimulus features as well as hierarchical shifts in selectivity and invariance that may go unnoticed with traditional approaches.

The primary auditory cortex (AI) modulates the sound information processing in the lemniscal subcortical nuclei, including the anteroventral cochlear nucleus (AVCN), in a frequency-specific manner. The dorsal cochlear nucleus (DCN) is a non-lemniscal subcortical nucleus but it is tonotopically organized like the AVCN. However, it remains unclear how the AI modulates the sound information processing in the DCN. This study examined the impact of focal electrical stimulation of AI on the auditory responses of the DCN neurons in mice. We found that the electrical stimulation induced significant changes in the best frequency (BF) of DCN neurons. The changes in the BFs were highly specific to the BF differences between the stimulated AI neurons and the recorded DCN neurons. The DCN BFs shifted higher when the AI BFs were higher than the DCN BFs and the DCN BFs shifted lower when the AI BFs were lower than the DCN BFs. The DCN BFs showed no change when the AI and DCN BFs were similar. Moreover, the BF shifts were linearly correlated to the BF differences. Thus, our data suggest that corticofugal modulation of the DCN is also highly specific to frequency information, similar to the corticofugal modulation of the AVCN. The frequency-specificity of corticofugal modulation does not appear limited to the lemniscal ascending pathway.

The serine hydrolase α/β-hydrolase domain 6 (ABHD6) hydrolyzes the most abundant endocannabinoid (eCB) in the brain, 2-arachidonoylglycerol (2-AG), and controls its availability at cannabinoid receptors. We show that ABHD6 inhibition decreases pentylenetetrazole (PTZ)-induced generalized tonic-clonic and myoclonic seizure incidence and severity. This effect is retained in Cnr1(-/-) or Cnr2(-/-) mice, but blocked by addition of a subconvulsive dose of picrotoxin, suggesting the involvement of GABAA receptors. ABHD6 inhibition also blocked spontaneous seizures in R6/2 mice, a genetic model of juvenile Huntington's disease known to exhibit dysregulated eCB signaling. ABHD6 blockade retained its antiepileptic activity over chronic dosing and was not associated with psychomotor or cognitive effects. While the etiology of seizures in R6/2 mice remains unsolved, involvement of the hippocampus is suggested by interictal epileptic discharges, increased expression of vGLUT1 but not vGAT, and reduced Neuropeptide Y (NPY) expression. We conclude that ABHD6 inhibition may represent a novel antiepileptic strategy.

High-frequency ripple oscillations, observed most prominently in the hippocampal CA1 pyramidal layer, are associated with memory consolidation. The cellular and network mechanisms underlying the generation, frequency control, and spatial coherence of the rhythm are poorly understood. Using multisite optogenetic manipulations in freely behaving rodents, we found that depolarization of a small group of nearby pyramidal cells was sufficient to induce high-frequency oscillations, whereas closed-loop silencing of pyramidal cells or activation of parvalbumin- (PV) or somatostatin-immunoreactive interneurons aborted spontaneously occurring ripples. Focal pharmacological blockade of GABAA receptors abolished ripples. Localized PV interneuron activation paced ensemble spiking, and simultaneous induction of high-frequency oscillations at multiple locations resulted in a temporally coherent pattern mediated by phase-locked interneuron spiking. These results constrain competing models of ripple generation and indicate that temporally precise local interactions between excitatory and inhibitory neurons support ripple generation in the intact hippocampus.

The mammalian superior paraolivary nucleus (SPON) is a major source of GABAergic inhibition to neurons in the inferior colliculus (IC), a well-studied midbrain nucleus that is the site of convergence and integration for the majority ascending auditory pathways en route to the cortex. Neurons in the SPON and IC exhibit highly precise responses to temporal sound features, which are important perceptual cues for naturally occurring sounds. To determine how inhibitory input from the SPON contributes to the encoding of temporal information in the IC, a reversible inactivation procedure was conducted to silence SPON neurons, while recording responses to amplitude-modulated tones and silent gaps between tones in the IC. The results show that SPON-derived inhibition shapes responses of onset and sustained units in the IC via different mechanisms. Onset neurons appear to be driven primarily by excitatory inputs and their responses are shaped indirectly by SPON-derived inhibition, whereas sustained neurons are heavily influenced directly by transient offset inhibition from the SPON. The findings also demonstrate that a more complete dissection of temporal processing pathways is critical for understanding how biologically important sounds are encoded by the brain.

Recovery from sensory deprivation is slow and incomplete in adult visual cortex. In this study, we show that visual stimulation during locomotion, which increases the gain of visual responses in primary visual cortex, dramatically enhances recovery in the mouse. Excitatory neurons regained normal levels of response, while narrow-spiking (inhibitory) neurons remained less active. Visual stimulation or locomotion alone did not enhance recovery. Responses to the particular visual stimuli viewed by the animal during locomotion recovered, while those to another normally effective stimulus did not, suggesting that locomotion promotes the recovery only of the neural circuits that are activated concurrent with the locomotion. These findings may provide an avenue for improving recovery from amblyopia in humans.

The sound-induced flash illusion (SIFI) is a multisensory perceptual phenomenon in which the number of brief visual stimuli perceived by an observer is influenced by the number of concurrently presented sounds. While the strength of this illusion has been shown to be modulated by the temporal congruence of the stimuli from each modality, there is conflicting evidence regarding its dependence upon their spatial congruence. We addressed this question by examining SIFIs under conditions in which the spatial reliability of the visual stimuli was degraded and different sound localization cues were presented using either free-field or closed-field stimulation. The likelihood of reporting a SIFI varied with the spatial cue composition of the auditory stimulus and was highest when binaural cues were presented over headphones. SIFIs were more common for small flashes than for large flashes, and for small flashes at peripheral locations, subjects experienced a greater number of illusory fusion events than fission events. However, the SIFI was not dependent on the spatial proximity of the audiovisual stimuli, but was instead determined primarily by differences in subjects' underlying sensitivity across the visual field to the number of flashes presented. Our findings indicate that the influence of auditory stimulation on visual numerosity judgments can occur independently of the spatial relationship between the stimuli.

Restoring perfusion to the penumbra during the hyperacute phase of ischemic stroke is a key goal of neuroprotection. Thrombolysis is currently the only approved treatment for ischemic stroke. However, its use is limited by the narrow therapeutic window and side effect of bleeding. Therefore, other interventions are desired that could potentially increase the perfusion of the penumbra. Here, we hypothesized that bilateral peripheral electrical stimulation will improve cerebral perfusion and restore cortical neurovascular response. We assess the outcomes of bilateral forepaw electrical stimulation at intensities of 2 and 4 mA, administered either unilaterally or bilaterally. We developed a combined electrocorticogram (ECoG)-functional photoacoustic microscopy (fPAM) system to evaluate the relative changes in cerebral hemodynamic function and electrophysiologic response to acute, focal stroke. The fPAM system is used for cerebral blood volume (CBV) and hemoglobin oxygen saturation (SO2) and the ECoG for neural activity, namely somatosensory-evoked potential (SSEP), interhemispheric coherence, and alpha-delta ratio (ADR) in response to forepaw stimulation. Our results confirmed the neuroprotective effect of bilateral forepaw stimulation at 2 mA as indicated by the 82% recovery of ADR and 95% improvement in perfusion into the region of penumbra. This experimental model can be used to study other potential interventions such as therapeutic hypertension and hypercarbia.

Cholinergic inputs to the auditory cortex can modulate sensory processing and regulate stimulus‐specific plasticity according to the behavioural state of the subject. In order to understand how acetylcholine achieves this, it is essential to elucidate the circuitry by which cholinergic inputs influence the cortex. In this study, we described the distribution of cholinergic neurons in the basal forebrain and their inputs to the auditory cortex of the ferret, a species used increasingly in studies of auditory learning and plasticity. Cholinergic neurons in the basal forebrain, visualized by choline acetyltransferase and p75 neurotrophin receptor immunocytochemistry, were distributed through the medial septum, diagonal band of Broca, and nucleus basalis magnocellularis. Epipial tracer deposits and injections of the immunotoxin ME 20.4‐ SAP (monoclonal antibody specific for the p75 neurotrophin receptor conjugated to saporin) in the auditory cortex showed that cholinergic inputs originate almost exclusively in the ipsilateral nucleus basalis. Moreover, tracer injections in the nucleus basalis revealed a pattern of labelled fibres and terminal fields that resembled acetylcholinesterase fibre staining in the auditory cortex, with the heaviest labelling in layers II / III and in the infragranular layers. Labelled fibres with small en‐passant varicosities and simple terminal swellings were observed throughout all auditory cortical regions. The widespread distribution of cholinergic inputs from the nucleus basalis to both primary and higher level areas of the auditory cortex suggests that acetylcholine is likely to be involved in modulating many aspects of auditory processing.

The purpose of the current study was to evaluate hydrogen-saturated saline protecting intensive narrow band noise-induced hearing loss. Guinea pigs were divided into three groups: hydrogen-saturated saline; normal saline; and control. For saline administration, the guinea pigs were given daily abdominal injections (1 ml/100 g) 3 days before and 1 h before narrow band noise exposure (2.5-3.5 kHz 130 dB SPL, 1 h). The guinea pigs in the control group received no treatment. The hearing function was assessed by the auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) recording. The changes of free radicals in the cochlea before noise exposure, and immediately and 7 days after noise exposure were also examined. By Scanning electron microscopy and succinate dehydrogenase staining, we found that pre-treatment with hydrogen-saturated saline significantly reduced noise-induced hair cell damage and hearing loss. We also found that the malondialdehyde, lipid peroxidation, and hydroxyl levels were significantly lower in the hydrogen-saturated saline group after noise trauma, indicating that hydrogen-saturated saline can decrease the amount of harmful free radicals caused by noise trauma. Our findings suggest that hydrogen-saturated saline is effective in preventing intensive narrow band noise-induced hearing loss through the antioxidant effect.

Although localization of sound in elevation is believed to depend on spectral cues, it has been shown with human listeners that the temporal features of sound can also greatly affect localization performance. Of particular interest is a phenomenon known as the negative level effect, which describes the deterioration of localization ability in elevation with increasing sound level and is observed only with impulsive or short-duration sound. The present study uses the gaze positions of domestic cats as measures of perceived locations of sound targets varying in azimuth and elevation. The effects of sound level on localization in terms of accuracy, precision, and response latency were tested for sound with different temporal features, such as a click train, a single click, a continuous sound that had the same frequency spectrum of the click train, and speech segments. In agreement with previous human studies, negative level effects were only observed with click-like stimuli and only in elevation. In fact, localization of speech sounds in elevation benefited significantly when the sound level increased. Our findings indicate that the temporal continuity of a sound can affect the frequency analysis performed by the auditory system, and the variation in the frequency spectrum contained in speech sound does not interfere much with the spectral coding for its location in elevation.

From behavioral studies it is known that auditory spatial resolution of azimuthal space declines over age. To date, it is not clear how age affects the respective sensory auditory processing at the pre-attentive level. Here we tested the hypothesis that pre-attentive processing of behaviorally perceptible spatial changes is preserved in older adults. An EEG-study was performed in older adults (65-82 years of age) and a mismatch negativity (MMN) paradigm employed. Sequences of frequent standard stimuli of defined azimuthal positions were presented together with rarely occurring deviants shifted by 10° or 20° to the left or to the right of the standard. Standard positions were at +5° (central condition) from the midsagittal plane and at 65° in both lateral hemifields (±65°; lateral condition). The results suggest an effect of laterality on the pre-attentive change processing of spatial deviations in older adults: While for the central conditions deviants close to MAA threshold (i.e., 10°) yielded discernable MMNs, for lateral positions the respective MMN responses were only elicited by spatial deviations of 20° toward the midline (i.e., ±45°). Furthermore, MMN amplitudes were found to be insensitive to the magnitude of deviation (10°, 20°), which is contrary to recent studies with young adults (Bennemann et al., 2013) and hints to a deteriorated pre-attentive encoding of sound sources in older adults. The discrepancy between behavioral MAA data and present results are discussed with respect to the possibility that under the condition of active stimulus processing older adults might benefit from recruiting additional attentional top-down processes to detect small magnitudes of spatial deviations even within the lateral acoustic field.

Cisplatin (cis-diaminedichloroplatinum-II) is an extensively used chemotherapeutic agent, and one of its most adverse effects is ototoxicity. A number of studies have demonstrated that these effects are related to oxidative stress and DNA damage. However, the precise mechanism underlying cisplatin-associated ototoxicity is still unclear. The cofactor nicotinamide adenine dinucleotide (NAD(+)) has emerged as a key regulator of cellular energy metabolism and homeostasis. Here, we demonstrate for the first time that, in cisplatin-mediated ototoxicity, the levels and activities of SIRT1 are suppressed by the reduction of intracellular NAD(+) levels. We provide evidence that the decrease in SIRT1 activity and expression facilitated by increasing poly(ADP-ribose) transferase (PARP)-1 activation and microRNA-34a through p53 activation aggravates cisplatin-mediated ototoxicity. Moreover, we show that the induction of cellular NAD(+) levels using β-lapachone (β-Lap), whose intracellular target is NQO1, prevents the toxic effects of cisplatin through the regulation of PARP-1 and SIRT1 activity. These results suggest that direct modulation of cellular NAD(+) levels by pharmacological agents could be a promising therapeutic approach for protection from cisplatin-induced ototoxicity.

Microelectrode arrays (wire diameter <50 μm) were compared to traditional macroelectrodes for deep brain stimulation (DBS). Understanding the neuronal activation volume may help solve some of the mysteries associated with DBS, e.g., its mechanisms of action. We used c-fos immunohistochemistry to investigate neuronal activation in the rat hippocampus caused by multi-micro- and macroelectrode stimulation. At ± 1V stimulation at 25 Hz, microelectrodes (33 μm diameter) had a radius of activation of 100 μm, which is 50% of that seen with 150 μm diameter macroelectrode stimulation. Macroelectrodes activated about 5.8 times more neurons than a single microelectrode, but displaced ~20 times more neural tissue. The sphere of influence of stimulating electrodes can be significantly increased by reducing their impedance. By ultrasonic electroplating (sonicoplating) the microelectrodes with platinum to increase their surface area and reduce their impedance by an order of magnitude, the radius of activation increased by 50 μm and more than twice the number of neurons were activated within this increased radius compared to unplated microelectrodes. We suggest that a new approach to DBS, one that uses multiple high-surface area microelectrodes, may be more therapeutically effective due to increased neuronal activation.