Publications using TDT

The inferior colliculus (IC) has traditionally been regarded as an important relay in the auditory pathway, primarily involved in relaying auditory information from the brainstem to the thalamus. However, this study uncovers the multifaceted role of the IC in bridging auditory processing, sensory prediction, and reward prediction. Through extracellular recordings in monkeys engaged in a sound duration-based deviation detection task, we observed a 'climbing effect' in neuronal firing rates, indicative of an enhanced response over sound sequences linked to sensory prediction rather than reward anticipation. Moreover, our findings demonstrate reward prediction errors within the IC, highlighting its complex integration in auditory and reward processing. Further analysis revealed a direct correlation between IC neuronal activity and behavioral choices, suggesting its involvement in decision-making processes. This research highlights a more complex role for the IC than traditionally understood, showcasing its integral role in cognitive and sensory processing and emphasizing its importance in integrated brain functions.

Introduction Perceived loudness is challenging to study in non-human animals. However, reaction time to an acoustic stimulus is a useful behavioral proxy for the assessment of perceived loudness. Understanding the effect of sound frequency and level on perceived loudness would improve prediction and modeling of anthropogenic noise impacts on marine mammals. Methods In this study, behavioral hearing tests conducted with two killer whales were analyzed to capture conditioned vocal response latency, which is the time between the onset of the acoustic signal and the onset of the response (i.e., reaction time). Results The results showed that vocal reaction times decreased with increasing sensation level (i.e., sound pressure level above the baseline hearing threshold), while the effect of frequency on reaction time varied between the subjects. Reaction time as a function of sound duration is described, and equal-latency contours are presented. Discussion The data suggest that vocal reaction time decreases with increasing sensation level, therefore supporting the use of reaction time as a proxy for loudness perception in killer whales.

In the mammalian cochlea, the transduction from vibrations to inner hair cell receptor currents is preceded by a stage of mechanical pre-processing that involves a rapid, strongly nonlinear compression. The mechanisms by which the cochlea realizes this dynamic compression are still poorly understood. Previous work by our group suggested that compression does not occur locally, but is realized by a cascade of weakly nonlinear elements along the cochlear partition. The resulting progressive accumulation of nonlinearity was termed the spatial buildup of compression. Here we studied mechanical compression in the basal turn of the sensitive gerbil cochlea using optical coherence tomography. We recorded vibrations at multiple positions along the length of the cochlear partition. Such longitudinal studies were virtually impossible with previous techniques. Using a tailored two-tone stimulus we quantified the spatial profile of compression. We found that the amount of compression grew gradually in an intensity-dependent fashion along our measurement stretch, as we moved apically toward the place of maximum vibration. This gradual buildup of compression was not mirrored by a gradual reduction beyond the peak. In fact the amount of compression accumulated even beyond the peak. This asymmetric pattern supports the view that mechanical compression is realized in a cascaded, distributed fashion which hinges on the traveling wave nature of cochlear vibrations.

Neurons in the cerebral cortex and hippocampus discharge synchronously in a brain state-dependent manner to transfer information. Published studies have highlighted the temporal coordination of neuronal activities between the hippocampus and a neocortical area; however, how the spatial extent of neocortical activity relates to hippocampal activity remains partially unknown. We imaged mesoscopic neocortical activity while recording hippocampal local field potentials in anesthetized and unanesthetized GCaMP-expressing transgenic mice. We found that neocortical activity elevates around hippocampal sharp wave ripples (SWRs). SWR-associated neocortical activities occurred predominantly in vision-related regions including the visual, retrosplenial, and frontal cortex. While pre-SWR neocortical activities were frequently observed in awake and natural sleeping states, post-SWR neocortical activity decreased significantly in the latter. Urethane-anesthetized mice also exhibited SWR-correlated calcium elevation, but in longer timescale than observed in natural sleeping mice. During hippocampal theta oscillation states, phase-locked oscillations of calcium activity were observed throughout the entire neocortical areas. In addition, possible environmental effects on neocortico-hippocampal dynamics were assessed in this study by comparing mice reared in ISO (isolated condition) and ENR (enriched environment). In both SWR and theta oscillations, mice reared in ISO exhibited clearer brain state-dependent dynamics than those reared in ENR. Our data demonstrate that the neocortex and hippocampus exhibit heterogeneous activity patterns that characterize brain states, and postnatal experience plays a significant role in modulating these patterns.

The cerebellum is critical for coordinating movements related to eating, drinking and swallowing, all of which require proper control of the tongue. Cerebellar Purkinje cells can encode tongue movements, but it is unclear how their simple spikes and complex spikes induce changes in the shape of the tongue that contribute to goal‐directed movements. To study these relations, we recorded and stimulated Purkinje cells in the vermis and hemispheres of mice during spontaneous licking from a stationary or moving water spout. We found that Purkinje cells can encode rhythmic licking with both their simple spikes and complex spikes. Increased simple spike firing during tongue protrusion induces ipsiversive bending of the tongue. Unexpected changes in the target location trigger complex spikes that alter simple spike firing during subsequent licks, adjusting the tongue trajectory. Furthermore, we observed increased complex spike firing during behavioural state changes at both the start and the end of licking bouts. Using machine learning, we confirmed that alterations in Purkinje cell activity accompany licking, with different Purkinje cells often exerting heterogeneous encoding schemes. Our data highlight that directional movement control is paramount in cerebellar function and that modulation of the complex spikes and that of the simple spikes are complementary during acquisition and execution of sensorimotor coordination. These results bring us closer to understanding the clinical implications of cerebellar disorders during eating, drinking and swallowing. image Key points When drinking, mice make rhythmic tongue movements directed towards the water source. Cerebellar Purkinje cells can fire rhythmically in tune with the tongue movements. Purkinje cells encode changes in the position of the water source with complex spikes. Purkinje cell simple spike firing affects the direction of tongue movements. Purkinje cells that report changes in the position of the target can also adjust movements in the right direction.

Implantable neural electrode arrays can be inserted in the brain to provide single‐cell electrophysiology recording for neuroscience research and brain–machine interface applications. However, maintaining signal quality over time is complicated by inflammatory tissue responses and degradation of electrode materials. Organic electrode coatings offer a solution by enhancing recording and stimulation capabilities, including reduced impedance, increased charge injection capacity, and the ability to incorporate and release anti‐inflammatory drugs. Herein, acid‐functionalized multiwalled carbon nanotubes (CNTs) loaded with dexamethasone (Dex) are incorporated into poly(3,4‐ethylendioxythiophene) (PEDOT) as electrode coatings. The electrochemical stability and recording performance of the PEDOT/CNT/Dex coating over an extended period of ≈18 months are investigated. Cyclic voltammetry (CV) stimulation is used to release Dex in half of the recording sites during the first 11 days of implantation to reduce the acute inflammation. The PEDOT/CNT/Dex‐coated floating microelectrode arrays demonstrate stable in vivo electrode impedance and successful detection of visually evoked neural activity from the rat visual cortex even at chronic time points. Additionally, the CV‐stimulated sites exhibit higher single‐unit (SU) recording yield, amplitudes, and signal‐to‐noise ratio compared to unstimulated sites. These results highlight the potential of anti‐inflammatory treatments to improve the quality and longevity of chronic neural recordings.

Assembly of actin-based stereocilia is critical for cochlear hair cells to detect sound. To tune their mechanosensivity, stereocilia form bundles composed of graded rows of ascending height, necessitating the precise control of actin polymerization. Myosin 15 (MYO15A) drives hair bundle development by delivering critical proteins to growing stereocilia that regulate actin polymerization via an unknown mechanism. Here, we show that MYO15A is itself an actin nucleation-promoting factor. Moreover, a deafness-causing mutation in the MYO15A actin-binding interface inhibits nucleation activity but still preserves some movement on filaments in vitro and partial trafficking on stereocilia in vivo. Stereocilia fail to elongate correctly in this mutant mouse, providing evidence that MYO15A-driven actin nucleation contributes to hair bundle biogenesis. Our work shows that in addition to generating force and motility, the ATPase domain of MYO15A can directly regulate actin polymerization and that disrupting this activity can promote cytoskeletal disease, such as hearing loss.

Cochlear implants are well established devices for treating severe hearing loss. However, due to the trauma caused by the insertion of the electrode and the subsequent formation of connective tissue, their clinical effectiveness varies. The aim of the current study was to achieve a long-term reduction in connective tissue growth and impedance by combining surface patterns on the electrode array with a poly-L-lactide coating containing 20% diclofenac. Three groups of six guinea pigs each (control, structure, structure with diclofenac in the coating) were implanted for four weeks. The hearing thresholds were measured before implantation and after 28 days, and impedances were monitored over time. After histological preparation, connective tissue growth and spiral ganglion neuron (SGN) survival were quantified. The hearing thresholds and impedances increased over time in all groups, showing no significant differences. The treatment groups showed increased damage in the cochlea, which appeared to be caused by the elevated parts of the microstructures. This seems to be amplified by the trauma model used in the current study. The impedances correlated with connective tissue growth near the electrode contacts. In addition, SGN survival was negatively correlated with the presence of connective tissue, both of which highlight the importance of successfully reducing connective tissue formation after cochlear implantation.

Homeostatic sleep regulation is essential for optimizing the amount and timing of sleep for its revitalizing function, but the mechanism underlying sleep homeostasis remains poorly understood. Here, we show that optogenetic activation of locus coeruleus (LC) noradrenergic neurons immediately increased sleep propensity following a transient wakefulness, contrasting with many other arousal-promoting neurons whose activation induces sustained wakefulness. Fiber photometry showed that repeated optogenetic or sensory stimulation caused a rapid reduction of calcium activity in LC neurons and steep declines in noradrenaline/norepinephrine (NE) release in both the LC and medial prefrontal cortex (mPFC). Knockdown of α 2 A adrenergic receptors in LC neurons mitigated the decline of NE release induced by repetitive stimulation and extended wakefulness, demonstrating an important role of α 2 A receptor–mediated auto-suppression of NE release. Together, these results suggest that functional fatigue of LC noradrenergic neurons, which reduces their wake-promoting capacity, contributes to sleep pressure.

Gravitational changes have been shown to cause significant abnormalities in various body systems, including the cardiovascular, immune, vestibular, and musculoskeletal systems. While numerous studies have examined the response of the vestibular system to gravitational stimulation, research on functional changes in the peripheral inner ear remains limited. The inner ear comprises two closely related structures: the vestibule and cochlea. These components share similar structures and neural functions, highlighting the importance of investigating changes in auditory nerve cells in response to gravitational alterations. To address this gap, we studied the functional and structural changes in the inner ear following exposure to hypergravity stimuli. Our findings demonstrate changes in auditory brainstem responses (ABRs) in the cochlea. ABR recordings were used to analyze click thresholds, as well as the amplitude and latency of tone bursts. The click thresholds at all frequencies increased in the group exposed to hypergravity in the long term. Additionally, tone burst results revealed significantly reduced amplitudes at high frequencies and delayed latencies in the hypergravity models. Notably, greater hair cell loss was observed in the middle and basal turns of the cochlea, indicating that mid and high-frequency regions are more vulnerable to hypergravity stimulation. Furthermore, nerve damage on the cochlear surface was evident in subjects exposed to 4G stimulation for 4 weeks. These findings suggest that the inner ear and its neural activity can be functionally and structurally affected by prolonged exposure to hypergravity.

Background Parkinson’s disease (PD) is often characterized by altered rates and patterns of neuronal activity in the sensorimotor regions of the basal ganglia thalamocortical network. Little is known, however, regarding how neuronal activity in the executive control network of the brain changes in the parkinsonian condition. Objective Investigate the impact of parkinsonism on neuronal activity in the dorsolateral prefrontal cortex (DLPFC), a key region in executive control, during a go/nogo reaching task. Methods Using a within-subject design, single and multi-unit neuronal activity was recorded in the DLPFC of a nonhuman primate ( n = 1) before and after the induction of mild parkinsonism using the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Results Coincident with development of mild parkinsonian motor signs, there was a marked reduction in the percentage of DLPFC cells with significant task-related firing rate modulation during go and nogo conditions. Conclusion These results suggest that DLPFC dysfunction may occur early in parkinsonism and contribute to cognitive impairments and disrupted executive function often observed in PD patients.

Utilizing single-cell transcriptome sequencing (scRNA-seq) technology, this study explores the viability of employing mesenchymal stem cells (MSCs) as a therapeutic approach for age-related hearing loss (ARHL). The research demonstrates MSCs' ability to differentiate into inner ear cell subpopulations, particularly hair cells, delivering Apelin via extracellular vesicles (EVs) to promote M2 macrophage polarization. In vitro experiments show reduced inflammation and preservation of hair cell health. In elderly mice, MSCs transplantation leads to hair cell regeneration, restoring auditory function. These findings highlight the regenerative capabilities of MSCs and EV-mediated therapeutic approaches for ARHL.

The manner in which neural activity unfolds over time is thought to be central to sensory, motor and cognitive functions in the brain. Network models have long posited that the brain's computations involve time courses of activity that are shaped by the underlying network. A prediction from this view is that the activity time courses should be difficult to violate. We leveraged a brain-computer interface to challenge monkeys to violate the naturally occurring time courses of neural population activity that we observed in the motor cortex. This included challenging animals to traverse the natural time course of neural activity in a time-reversed manner. Animals were unable to violate the natural time courses of neural activity when directly challenged to do so. These results provide empirical support for the view that activity time courses observed in the brain indeed reflect the underlying network-level computational mechanisms that they are believed to implement.

We hypothesized that active outer hair cells drive cochlear fluid circulation. The hypothesis was tested by delivering the neurotoxin, kainic acid, to the intact round window of young gerbil cochleae while monitoring auditory responses in the cochlear nucleus. Sounds presented at a modest level significantly expedited kainic acid delivery. When outer-hair-cell motility was suppressed by salicylate, the facilitation effect was compromised. A low-frequency tone was more effective than broadband noise, especially for drug delivery to apical locations. Computational model simulations provided the physical basis for our observation, which incorporated solute diffusion, fluid advection, fluid–structure interaction, and outer-hair-cell motility. Active outer hair cells deformed the organ of Corti like a peristaltic tube to generate apically streaming flows along the tunnel of Corti and basally streaming flows along the scala tympani. Our measurements and simulations coherently suggest that active outer hair cells in the tail region of cochlear traveling waves drive cochlear fluid circulation.

Loud noise exposure is one of the leading causes of permanent hearing loss. Individuals with noise-induced hearing loss (NIHL) suffer from speech comprehension deficits and experience impairments to cognitive functions such as attention and decision-making. Here, we investigate the specific underlying cognitive processes during auditory perceptual decision-making that are impacted by NIHL. Gerbils were trained to perform an auditory decision-making task that involves discriminating between slow and fast presentation rates of amplitude-modulated (AM) noise. Decision-making task performance was assessed across pre- versus post-NIHL sessions within the same gerbils. A single exposure session (2 h) to loud broadband noise (120 dB SPL) produced permanent NIHL with elevated threshold shifts in auditory brainstem responses (ABRs). Following NIHL, decision-making task performance was tested at sensation levels comparable to those prior to noise exposure in all animals. Our findings demonstrate NIHL diminished perceptual acuity, reduced attentional focus, altered choice bias, and slowed down evidence accumulation speed. Finally, video-tracking analysis of motor behavior during task performance demonstrates that NIHL can impact sensory-guided decision-based motor execution. Together, these results suggest that NIHL impairs the sensory, cognitive, and motor factors that support auditory decision-making.

Binaural speech intelligibility in rooms is a complex process that is affected by many factors including room acoustics, hearing loss, and hearing aid (HA) signal processing. Intelligibility is evaluated in this paper for a simulated room combined with a simulated hearing aid. The test conditions comprise three spatial configurations of the speech and noise sources, simulated anechoic and concert hall acoustics, three amounts of multitalker babble interference, the hearing status of the listeners, and three degrees of simulated HA processing provided to compensate for the noise and/or hearing loss. The impact of these factors and their interactions is considered for normal-hearing (NH) and hearing-impaired (HI) listeners for sentence stimuli. Both listener groups showed a significant reduction in intelligibility as the signal-to-noise ratio (SNR) decreased, and showed a reduction in intelligibility in reverberation when compared to anechoic listening. There was no significant improvement in intelligibility for the NH group for the noise suppression algorithm used here, and no significant improvement in intelligibility for the HI group for more advanced HA processing algorithms as opposed to linear amplification in either of the two acoustic spaces or at any of the three SNRs.

Introduction Cisplatin is extensively employed in the treatment of multiple solid malignant tumors. Nevertheless, side effects such as cisplatin-induced ototoxicity (CIO) pose obstacles to tumor therapy.The important natural product chiisanoside from Acanthopanax sessiliflorus has abundant activity against CIO. Methods In this study, 26 chiisanoside derivatives were screened, and compound 19 demonstrated significant protective activity against CIO damage. A cisplatin—induced HEI—OC1 cell injury model and a mouse ototoxicity model were established. The regulatory effects were revealed through transcriptome sequencing, and the protein expression levels were analyzed by molecular docking, ELISA, Western blotting, and immunofluorescence. Results It was found that compound 19 inhibited cell apoptosis, alleviated abnormal hearing and spiral ganglion damage. Transcriptome sequencing revealed its regulatory effects. Compound 19 treatment increased autophagy levels, thereby alleviating mitochondrial dysfunction and reducing the accumulation of reactive oxygen species (ROS).In-depth studies have found that the autophagy inhibitor 3-methyladenine (3-MA) weakens the regulatory effect of compound 19 on autophagy and inhibits the clearance of damaged cells, resulting in oxidative stress damage, apoptosis and necrosis. By knocking down LRP6, it was found that the protective effect of compound 19 was eliminated, the autophagy level was significantly reduced, oxidative stress and ROS production were induced, and apoptosis after cisplatin exposure was promoted. Finally, the inhibitor LiCl was used to suppress the expression of GSK3β. It was found that inhibiting GSK3β could protect cells from cisplatin-induced damage by activating autophagy. Discussion These findings suggest that compound 19 is capable of preventing ototoxicity by activating autophagy via the LRP6/GSK3β axis and consequently inhibiting oxidative stress, offering a new approach for treating CIO and sensorineural hearing loss.

High-frequency stimulation (HFS)-induced long–term potentiation (LTP) is generally regarded as a homosynaptic Hebbian-type LTP, where synaptic changes are thought to occur at the synapses that project from the stimulation site and terminate onto the neurons at the recording site. In this study, we first investigated HFS-induced LTP on urethane-anesthetized rats and found that cortical HFS enhances neural responses at the recording site through the strengthening of local connectivity with nearby neurons at the stimulation site rather than through synaptic strengthening at the recording site. This enhanced local connectivity at the stimulation site leads to increased output propagation, resulting in signal potentiation at the recording site. Additionally, we discovered that HFS can also nonspecifically strengthen distant afferent synapses at the HFS site, thereby expanding its impact beyond local neural connections. This form of plasticity exhibits a neo-Hebbian characteristic as it exclusively manifests in the presence of cholecystokinin release, induced by HFS. The cortical HFS-induced local LTP was further supported by a behavioral task, providing additional evidence. Our results unveil a previously overlooked mechanism underlying cortical plasticity: synaptic plasticity is more likely to occur around the soma site of strongly activated cortical neurons rather than solely at their projection terminals.

Tinnitus, a widespread condition affecting numerous individuals worldwide, remains a significant challenge due to limited effective therapeutic interventions. Intriguingly, patients using cochlear implants (CIs) have reported significant relief from tinnitus symptoms, although the underlying mechanisms remain unclear and intracochlear implantation risks cochlear damage and hearing loss. This study demonstrates that targeted intracochlear electrical stimulation (ES) in guinea pigs with noise‐induced hearing loss reversed tinnitus‐related maladaptive plasticity in the cochlear nucleus (CN), characterized by reduced auditory innervation, increased somatosensory innervation, and diminished inhibitory neural networks. Additionally, a customized extracochlear ES delivered by a newly designed extracochlear electrode array to guinea pigs with salicylate‐induced tinnitus also reversed the aforementioned maladaptive plasticity and alleviated tinnitus without causing additional cochlear damage or hearing loss. These findings suggest that CI‐delivered ES may alleviate tinnitus by reversing maladaptive CN plasticity. Additionally, the extracochlear ES strategy offers a promising tinnitus treatment with minimal risk to hearing.

While soundscapes shape the structure and function of auditory systems over evolutionary timescales, there is limited information regarding the adaptation of wild fish populations to their natural acoustic environments. This is particularly relevant for freshwater ecosystems, which are extremely diverse and face escalating pressures from human activities and associated noise pollution. The Siamese fighting fish Betta splendens is one of the most important cultured species in the global ornamental fish market and is increasingly recognized as a model organism for genetics and behavioural studies. This air-breathing species (Anabantoidei), characterized by the presence of a suprabranchial labyrinth organ that enhances auditory sensitivity, is native to Southeast Asia and inhabits low flow freshwater ecosystems that are increasingly threatened due to habitat destruction and pollution. We characterized the underwater soundscape, along with various ecological parameters, across five marshland habitats of B. splendens , from lentic waterbodies to small canals near a lake in Chiang Rai province (Thailand). All habitats exhibited common traits of low dissolved oxygen and dense herbaceous vegetation. Soundscapes were relatively quiet with Sound Pressure Level (SPL) around 102–105 dB re 1 µPa and most spectral energy below 1,000 Hz. Sound recordings captured diverse biological sounds, including potential fish vocalizations, but primarily insect sounds. Hearing thresholds were determined using auditory evoked potential (AEP) recordings, revealing best hearing range within 100–400 Hz. Males exhibited lower hearing thresholds than females at 400 and 600 Hz. This low-frequency tuning highlights the potential susceptibility of B. splendens to anthropogenic noise activities. This study provides first characterization of the auditory sensitivity and natural soundscape of B. splendens, establishing an important ground for future hearing research in this species. The information provided on the auditory sensory adaptation of B. splendens emphasizes the importance of preserving quiet soundscapes from lentic freshwater ecosystems.