Publications using TDT

Social relationships, including dominance status, are powerful regulators of mental health, and social experiences impact the continued expression of these behaviors. However, very little is known about the neuronal mechanisms that regulate the positive reinforcing effects of aggression that underlie social dominance, including potential sex differences. To address this gap, we used viral-mediated gene expression in Syrian hamsters to investigate how nucleus accumbens neurons regulate behavioral adaptations caused by aggression and other social interactions in both males and females. We found that females, but not males, display an increase in the efficiency to establish aggression with repeated experience. Females also displayed a more rapid potentiation of calcium signals from nucleus accumbens neurons over repeated social interactions. Chemogenetic inhibition of nucleus accumbens neurons specifically decreased aggression in females. Optogenetic stimulation of excitatory synaptic input from the prefrontal cortex to the nucleus accumbens decreased social investigation in females but increased social investigation and reduced aggression in males. Collectively, these studies suggest that the activity of nucleus accumbens neurons drives behavioral adaptations related to social interactions in general, and aggressive experience in particular, in opposite directions in females and males. This mechanism may contribute to the enhanced reward for social interactions in females compared with males and help explain the sex differences in the susceptibility to disorders associated with deficits in social behavior.

How neuronal firing within a circuit encodes behavioural intensity, like running speed, is largely unknown. Projections from temporal association cortex (TeA) and superior colliculus (SC) to dorsal periaqueductal grey (dPAG) circuit can both trigger running behaviour. Using in vivo loose-patch recordings with circuit manipulations in mice, we quantified a firing - speed relationship and established its encoding model. Here, we report two behavioural patterns induced by circuit activation: backing away and rebound running. Mechanistically, dPAG CaMKIIα neurons receiving inputs from either TeA or SC, function as distinct “behavioural units”, controlling two “unit behaviours” of running and backing away, respectively. The unidirectional inhibition from the backing away unit to the running unit is mediated by somatostatin (SOM) neurons in dPAG, enabling transitions among four behavioural states: running, backing away, stopping, and rebound running. Both running and backing away behaviours follow a unified motor encoding model, quantified by a single-phase association equation.

A central goal in neuroscience is to clarify how neural circuits translate sensory input into adaptive behaviours. Although unisensory evoked escape circuits in mice are well defined, it remains unclear whether a single nucleus contains specialized sensory, sensory‒motor decision, and motor command neurons for escapes driven by distinct sensory cues, and how these neurons form functional microcircuits. Using multiple sensory stimuli in mice, we identified the temporal association cortex (TeA) as a critical escape hub. Combining in vivo electrophysiology, optogenetics and chemogenetics, we characterized three distinct neuron subtypes within TeA layer 5 (L5) CaMKII neurons that correspond to these three functional classes. Intratelencephalic (IT) neurons serve as sensory‒motor decision neurons, while layer matched pyramidal tract (PT) neurons projecting to the dorsal periaqueductal grey (dPAG) act as motor command neurons. We reveal a laminar IT–PT microcircuit that converts sensory input into sensory-motor decisions and commands for escape locomotion.

Noise-induced hearing loss (NIHL) remains highly prevalent in occupational settings, and no pharmacological agent or combination thereof has demonstrated a protective or restorative impact against noise-induced damage in clinic till now. Biomass-derived carbon dots (CDs) are known for their unique biological activities and excellent safety. Marine organisms account for 78% of the planet’s biomass. In this vast and diversified habitat, marine animals make and gather significant amounts of compounds with distinct structural and physiological properties. Here, using eight different marine fauna and flora as carbon sources, safe and green CDs were synthesized through one-pot hydrothermal method. All eight CDs displayed good stability and radical quenching abilities. In ABR testing, the Undaria pinnatifida Suringar-derived CDs (USCDs) exerted the strongest hearing protection abilities under noise exposure in vivo among the eight samples. The structure–activity relationships of marine-derived CDs suggested that improved content of heteroatom or reductive function groups was essential for their radical scavenging and in vivo anti-NIHL activities. The cytoprotective activity for auditory nerve and hair cells in vivo were confirmed by confocal microscopy. Notably, in vitro cell tests demonstrated that USCDs could prevent apoptosis and ferroptosis through ROS scavenging and Fe 2+ -chelating, respectively. Moreover, both in vivo and in vitro experiments demonstrated that USCDs possessed excellent biosafety and blood–labyrinth barrier (BLB) permeability, supporting their potential for systemic administration. These findings broaden the potential applications of CDs in the treatment of inner ear diseases, and provided some insights into the development marine drugs. Graphical Abstract

Classic theories propose opponent functions for striatal dopamine (DA) and serotonin (5-hydroxytryptamine; 5HT), with DA promoting approach and 5HT promoting patience or avoidance. How these neuromodulators regulate downstream circuits to achieve such antagonistic effects remains mysterious. Here, we mapped striatal 5HT receptor expression in mice to reveal preferential enrichment of putatively excitatory, Gq-coupled 5HT receptors on medium spiny neurons expressing inhibitory D2 DA receptors (D2-MSNs). Acute slice recordings from genetically identified striatal neurons showed that DA and 5HT inversely regulate D2-MSN firing and confirmed that 5HT's excitatory effect on these cells is blocked by 5HT2a and 5HT2c receptor antagonists. Pharmacologically upregulating striatal 5HT release preferentially induced cfos expression in D2-MSNs, validating that 5HT's excitatory effect on these cells also occurs in vivo. Finally, 5HT2c receptor loss-of-function in D2-MSNs, but not D1-MSNs, enhanced animals' sensitivity to the behavioral effects of cocaine - a potent releaser of DA and 5HT - showing that 5HTergic excitation of D2-MSNs counteracts the reinforcing effects of striatal DA release. Altogether these results demonstrate that DA and 5HT inversely modulate D2-MSN activity to regulate cocaine reward, identifying a key circuit mechanism underlying the opponent behavioral effects of these important neuromodulators.

The unique gyral patterns of the human brain demand patient‐specific neural interfaces to achieve precise neuromodulation, mitigate adverse tissue responses, and optimize therapeutic efficacy and safety. One‐size‐fits‐all, conventional rigid electrocorticography (ECoG) electrodes, standardized for mass production through lithographic techniques, exhibit limited conformability to the brain's heterogeneous cortical topography. This mechanical mismatch results in poor electrode‐tissue contact, signal loss, and foreign body responses. To address these limitations, we present an integrated novel platform, synergizing MRI‐based anatomical mapping, finite element analysis (FEA)—optimized mechanical design, and direct ink writing (DIW) 3D printing to fabricate electrodes customized to individual gyral patterns. The resulting honeycomb‐inspired printable gel electrode (HiPGE) employs a bioinspired honeycomb architecture with ultra‐soft hydrogels, engineered to match the bending stiffness of brain tissue (0.1–10 kPa) while maintaining cost‐efficiency and long‐term durability. This mechanical congruence ensures exceptional cortical conformability and adaptive interfacing, circumventing the geometric and material limitations of traditional rigid electrodes. By combining patient‐specific design with scalable fabrication, our platform establishes a transformative framework for neural interface engineering, enhancing precision, biocompatibility, and functional performance in neuromodulation therapies and neuroprosthetic applications.

In the auditory cortex, neural responses to stimuli inside receptive fields (RFs) can be further facilitated by behavioral demands, such as attending to a spatial location. It is less clear how off-RF stimuli modulate neural responses and contribute to behavioral tasks. Our recent study revealed a particular form of location-specific facilitation evoked by repeated stimulation from an off-RF location, suggesting behavioral modulation of spatial RFs. To further explore this question, we trained marmosets to attend to sound locations that were either inside or outside the RFs of auditory cortical neurons. The majority of neurons showed increased firing rates at target locations inside their RFs. Interestingly, this increase also occurred outside the RFs, sometimes exceeding the responses at the RF center during passive listening. This task-related off-RF facilitation was much more common in the caudal area than in the rostral area and the primary auditory cortex. A normalization model reproduced the off-RF facilitation using widespread suppression. The model’s prediction was confirmed by experimental observations of widespread reductions in firing rate and hyperpolarized membrane potentials for off-RF stimuli. These results suggest that behavioral task demands recruit a broader range of neurons than those that are responsive to a target sound in the passive state.

Our brains constantly filter incoming sounds to understand our environment. While extensively studied in adults, how this ability develops across childhood remains unclear. We recorded intracranial brain activity from 54 participants aged 4-21 while they watched movie clips containing simultaneous speech and music. We used deep neural networks to separate the mixed audio into isolated speech and music streams, then built encoding models to determine which stream best predicted neural responses in the auditory cortex. Although participants heard only the original mixture with no instruction to attend to either stream, higher-order auditory regions including the superior temporal gyrus (STG), superior temporal sulcus (STS) and middle temporal gyrus (MTG), responded preferentially to speech. This speech-bias strengthened with age in STG, suggesting that this region progressively sharpens its representation of socially relevant sound across development. These findings indicate that speech prioritization in the developing brain emerges automatically, without directed attention.

A major threat to the declining European hedgehog (Erinaceus europaeus) is road traffic. Devising methods to reduce the number of collisions would increase hedgehog welfare in an urbanized world and serve to protect this flagship species, and this goal might be advanced by an understanding of their hearing. This study investigates the auditory capabilities and anatomy of the ear of the European hedgehog. Using auditory brainstem response testing on 20 live hedgehogs from Danish wildlife rescue centres, we measured hearing thresholds across 4–85 kHz and found a peak sensitivity around 40 kHz, revealing that European hedgehogs can hear sound frequencies of at least 4–85 kHz. Complementary postmortem micro-CT scans enabled a detailed three-dimensional reconstruction of the inner ear, revealing small middle ear bones with a cochlear spiral of approximately 1.7 turns. Results show that hedgehogs can perceive a broad ultrasonic range, which provides important cues for directional hearing and may additionally function in prey detection and communication. These findings provide critical insights into hedgehog sensory biology and inform the potential development of ultrasonic repellents to mitigate traffic collisions and habitat disturbances, contributing to conservation strategies for this declining species.

The acoustic flutter is processed through complementary monotonic rate coding and cannot be modulated by other acoustic parameters in the auditory cortex (AC). However, it remains unclear how the inferior colliculus (IC) encodes acoustic flutter, especially when changing other acoustic parameters. Here, we recorded IC neural activity in response to acoustic flutter and determined the existence of conjunctive processing between repetition rate and other acoustic parameters. We found that most IC neurons also encode the repetition rate at the flutter range through complementary monotonic rate coding. In addition, although the acoustic parameters did not change their monotonicity, most IC neurons encode both repetition rate and other acoustic parameters, different from the flutter processing in AC. Thus, complementary monotonic rate coding for acoustic flutter was widespread in the auditory system; however, coding specificity for repetition rate increased from IC to AC, and the capacity for conjunctive coding with other acoustic parameters decreased.

Age-related hearing loss is a global public health issue that impacts the quality of life in the elderly population. Macrophages are the main immune cell population in the cochlea, yet the role in the development and progression of age-related hearing loss is still unclear. This study analyzed single-cell sequencing data from cochlear tissues of C57BL/6J mice across different ages and identified notable increase in CD74 expression in macrophages with aging. Validation revealed that CD74 levels were elevated in the aged cochlea, while macrophage migration inhibitory factor (MIF) levels decreased. MIF was significantly reduced in both senescent HEI-OC1 cells and supernatant. Notably, the senescent HEI-OC1 supernatant stimulated BV2 cells CD74 expression increased. rCD74 significantly upregulated apoptosis-related genes expression levels in HEI-OC1 cells, while decreasing MIF levels. In the co-culture system of scrambled/CD74 - BV2 cells and HEI-OC1 cells, CD74 - BV2 cells markedly reduced the apoptosis-related genes expression in senescent HEI-OC1 cells. MIF could improve the mitochondrial membrane potential of both groups of HEI-OC1 cells, and decreased the TUNEL positive cells significantly. Our findings using the HEI-OC1 cell model reveal that macrophages secrete CD74 into the microenvironment, where it interacts with MIF, reducing local MIF levels. This interaction weakens MIF’s protective effect on senescent HEI-OC1 cells, promoting apoptosis in these auditory cells. This suggests a potential mechanism whereby elevated CD74 in the aging cochlear microenvironment may contribute to the loss of hair cells in vivo . Targeting macrophage CD74 may offer therapeutic potential for preventing and treating age-related hearing loss.

The transition of bioelectronic medicine to clinical use is currently limited by a lack of non-invasive sensors capable of measuring autonomic tone during active neuromodulation. Conventional monitoring modalities, such as mean arterial pressure (MAP) and Ag/AgCl chest electrodes, are often invasive, cumbersome, or susceptible to motion artifacts. Here, we present a novel framework employing an in-ear sensor (AURIS) to continuously monitor heart rate variability (HRV) during therapeutic neuromodulation. These sensors utilize a polydimethylsiloxane (PDMS) substrate to ensure biocompatibility and superior conformability. Experiments in a rodent model ( n = 3 ) demonstrate that the AURIS platform achieves gold-standard fidelity, with mean heart rate differences of 6.03 BPM and mean RR interval deltas of 3.18 ms compared to chest electrodes. Sensor agreement was statistically validated using independent t-tests, showing no significant difference between modalities (all p > 0.46 ). While time-domain shifts trended toward significance, complexity metrics showed robust sequential responses with large effect sizes, including the SD1/SD2 ratio ( d = 1.474 ) and the DFA α ratio ( d = 1.091 ). These findings validate a sensor architecture that is durable, accessible, and provides the necessary technical foundation for closed-loop feedback and non-invasive clinical trials.

Humans localise sounds in the horizontal plane by processing level and timing differences between the ears. This neurocomputational process is continuously and adaptively calibrated using visual input, as seen in the ventriloquism aftereffect: a shift in sound perception toward a previously seen light. It is unknown from where in the brain this aftereffect originates; adaptation could occur at an early level in the auditory system where neurons are narrowly tuned to frequency, at a later level in the auditory system where localisation cues are extracted, or outside the auditory system at a higher-level spatial map. To investigate this, we examined how the ventriloquism aftereffect generalises across sound frequencies. Participants localised seven narrowband sounds (0.5–8 kHz), targeting different localisation cues. We found that sound localisation accuracy in darkness varied slightly with frequency. When sounds were paired with a visual stimulus that was offset by 10 deg, participants exhibited a pronounced bias toward the light of about ~ 63%, corresponding to the well-known ventriloquism effect. The bias was stronger for narrowband compared to broadband sounds. After exposure to a block of these audiovisual stimuli, a ventriloquism aftereffect in the form of a spatial bias of ~ 12% was observed across all tested frequencies, largely independent of the frequency of the exposure sound. Together with earlier reports of both frequency-specific and frequency-general recalibration, our results indicate that under conditions of a fixed and consistent audiovisual spatial offset, the ventriloquism aftereffect generalises across sound frequencies, consistent with adaptation at a frequency-independent multisensory spatial stage.

Background: Age-related hearing loss (ARHL), also known as presbycusis, is a prevalent condition among older adults and affects a substantial proportion of the global aging population. The underlying mechanisms of ARHL remain unclear, and this study aimed to explore the role of superenhancers (SEs) and the transcription factor Sp1 in regulating hair cell (HC) aging and ferroptosis, a form of regulated cell death associated with iron metabolism. Methods: We utilized a combination of bioinformatics analysis, including transcriptional regulatory element enrichment analysis (TREA) and SE prediction, with SEdb 2.0 to identify key transcriptional regulators and their target genes. Experimental validation was performed using auditory brainstem response (ABR) measurements, immunofluorescence staining, Western blot analysis and quantitative real-time PCR (RT‒qPCR) in mouse and cell models. Additionally, we employed CUT&Tag assays to map Sp1 binding sites and performed statistical analyses using SPSS Statistics 25 and GraphPad Prism. Results: Our study revealed that reduced binding of Sp1 to the Fth1 superenhancer triggered HC ferroptosis and the progression of ARHL. We identified Sp1 as a key upstream transcriptional regulator whose binding to the Fth1 SE decreased with aging, leading to reduced Fth1 gene transcription and increased intracellular iron levels. This phenomenon resulted in cellular iron overload, subsequent ferroptosis, and increased reactive oxygen species (ROS) levels, ultimately promoting HC and cochlear aging. In vivo studies with the SE inhibitor JQ-1 confirmed the importance of SE activity in maintaining auditory function. Conclusions: This study provides evidence for the role of Sp1 and Fth1 in the regulation of HC aging and ARHL. These findings suggest that manipulating SE sites and inhibiting ferroptosis may offer novel therapeutic strategies for treating ARHL. Understanding the interplay between SEs, Sp1, Fth1 and ferroptosis reveals novel targets for AAV gene therapy to preserve hearing in aging populations by modulating iron homeostasis during sensory cell senescence.

BACKGROUND: Chronic hearing impairment represents a major global health burden, profoundly diminishing quality of life due to its association with depression and cognitive decline. Recent studies have identified metabolic-dysfunction-associated steatohepatitis (MASH) as an independent systemic risk factor for accelerated hearing loss, implicating a functional liver–inner ear axis. However, the molecular and vascular mechanisms through which MASH-induced systemic inflammation compromises cochlear integrity remain uncertain. METHODS: We investigated the impact of MASH on cochlear pathology and auditory function. MASH was induced in 8-week-old male BALB/c mice by feeding a methionine–choline-deficient (MCD) diet for 4 weeks. After this induction period, the mice were exposed to acoustic trauma and maintained on the same diet for an additional 2 weeks. Systemic and cochlear evaluations were performed to assess the impact of MASH on auditory function and related physiological alterations. RESULTS: The MCD diet induced severe hepatic steatosis and lobular inflammation, accompanied by cochlear stria vascularis (SV) hyperpermeability and inflammation characterized by elevated interleukin (IL)-1β and lipocalin-2 (LCN2), without overt hearing loss or hair cell damage. Following noise exposure, MCD-fed mice demonstrated significantly delayed auditory recovery compared to chow-fed controls. This delay was associated with cochlear synaptopathy (CtBP2 degeneration), exacerbated BLB dysfunction, and ultrastructural alterations in endothelial cells, pericytes, and perivascular macrophages within the stria vascularis. PDGFRβ expression was significantly reduced, while proinflammatory mediators (IL-6, IL-1β, and LCN2) were upregulated, suggesting concurrent vascular injury and inflammatory activation. CONCLUSION: These findings demonstrate that MASH sensitizes the cochlea to noise-induced injury through disruption of the BLB and sustained inflammation, providing a preclinical model and mechanistic insight into the link between MASH and hearing loss.

Evolutionary shifts in diel activity patterns shape sensory remodeling across mammals, yet the genetic basis remains poorly understood. Tapirs represent a unique natural experiment, having reverted from a cathemeral ancestor to a nocturnal niche characterized by reduced vision but enhanced hearing and olfaction. Here, we investigate the genetic basis of this phenomenon by generating high-quality chromosome-level genomes for Tapirus terrestris and Tapirus indicus . Comparative analyses revealed extensive lineage-specific remodeling of genes and cis-regulatory elements linked to sensory pathways. Notably, functional validation via CRISPR-Cas9 editing of a tapir-specific conserved noncoding element (CNE74) upstream of the FLT1 gene in mice revealed coordinated sensory effects, including retinal degeneration and reduced visual acuity, yet enhanced auditory sensitivity. These findings suggest that regulatory element evolution may induce pleiotropic effects on competing sensory modalities, offering genetic insights into sensory evolution during temporal niche adaptation and potential relevance to human retinal vascular diseases.

Age-related hearing loss (ARHL) is a prevalent neurodegenerative condition characterized by the progressive loss of spiral ganglion neurons (SGNs). Although oxidative stress is recognized as a central pathogenic driver of ARHL, the precise molecular triggers that initiate and amplify SGN damage remain elusive. Here, we investigated the role of the Transient Receptor Potential Vanilloid 2 (TRPV2) channel in ARHL. We found that TRPV2 expression was significantly upregulated in the SGNs of aged mice, which was associated with elevated oxidative stress. Pharmacological activation of TRPV2 in 6-month-old mice (a pre-senescent stage with preserved baseline hearing) accelerated the onset of high-frequency hearing damage, as evidenced by auditory brainstem response (ABR) measurements. Consistently, TRPV2 activation exacerbated oxidative damage (assessed by 4-HNE staining) and increased apoptotic cell death (detected via TUNEL) in the SGN population. In primary SGN cultures, TRPV2 overexpression aggravated oxidative stress, whereas TRPV2 knockdown in SH-SY5Y cells (a human neuroblastoma cell line) markedly mitigated the oxidative injury as reflected by reduced 4-HNE. Our findings establish that the age-related upregulation of TRPV2 sensitizes SGNs to oxidative stress, thereby promoting neuronal damage and exacerbating ARHL. This work highlights TRPV2 as a promising therapeutic target for intervening in the progression of ARHL.

Reconstructing speech from neural recordings is crucial for understanding human speech coding and developing brain-computer interfaces (BCIs). However, existing methods trade off acoustic richness (pitch, prosody) for linguistic intelligibility (words, phonemes). To overcome this limitation, we propose a dual-path framework to concurrently decode acoustic and linguistic representations. The acoustic pathway uses a long-short term memory (LSTM) decoder and a high-fidelity generative adversarial network (HiFi-GAN) to reconstruct spectrotemporal features. The linguistic pathway employs a transformer adaptor and text-to-speech (TTS) generator for word tokens. These two pathways merge via voice cloning to combine both acoustic and linguistic validity. Using only 20 min of electrocorticography (ECoG) data per human subject, our approach achieves highly intelligible synthesized speech (mean opinion score = 4.0/5.0, word error rate = 18.9%). Our dual-path framework reconstructs natural and intelligible speech from ECoG, resolving the acoustic-linguistic trade-off.

BACKGROUND: Noise-induced hearing loss (NIHL) has been traditionally attributed to outer hair cell (OHC) damage, but synaptic injury at inner hair cell (IHC)–spiral ganglion neuron (SGN) junctions may better explain persistent functional deficits. OBJECTIVE: To test whether IHC ribbon loss and functional synapse loss scale with pathological noise intensity and to define their longitudinal relationship to hearing function. METHODS: A rodent NIHL model was exposed to 100 dB SPL for 2 h or 110 dB SPL for 4 h. Cochleae were immunolabeled for CtBP2 (presynaptic ribbons) and GluA2 (postsynaptic AMPA receptor puncta). Putative functional synapses were quantified as closely apposed CtBP2/GluA2 pairs. Hearing function was assessed longitudinally and correlated with synaptic measures. RESULTS: Both exposure conditions produced graded reductions in IHC ribbon counts and CtBP2/GluA2 pairs, with greater losses after 110 dB/4 h. The number of CtBP2/GluA2 apposed pairs closely tracked preserved hearing function, providing a stronger association with functional outcome than ribbon counts alone. Ribbon loss remained largely stable across post-exposure intervals, whereas functional synapse loss was disproportionately larger at early time points, consistent with transient pre–post misalignment. Over time, CtBP2/GluA2 pairing partially recovered toward levels predicted by surviving ribbons, suggesting re-alignment or reconnection of a subset of remaining synaptic elements. CONCLUSION: Pathological noise intensity drives exposure-dependent IHC synaptopathy in addition to OHC injury. Functional synapse counts (CtBP2/GluA2 pairs) sensitively reflect stored hearing function and indicate a potential post-exposure window for synaptic re-establishment.

Neural interfaces for monitoring and modulating spinal nerve activity are increasingly being designed to be flexible and stretchable to enhance their biomechanical compatibility and integration. However, excessive flexibility introduces practical limitations such as difficulty in insertion into narrow spinal spaces and long-term electrical instability, hindering real-world applications. In this study, we developed a spinal nerve interface by incorporating a liquid-metal conductor and dynamic stiffness-based variable-compliance structure, which can address the challenges of current flexible neural interface technologies. During insertion, the dynamic stiffness enhancer minimizes unintended buckling and ensures minimally invasive implantation into the intended target. The proximity of the proposed device to the spinal cord increases as it flexes automatically and rapidly in a humid environment. The liquid-metal conductor maintained stable electrical properties in freely moving rats, ensuring reliable and sustained functionality. This study lays the foundation for practical, fully implantable spinal bioelectronics designed with a focus on ease of implantation and long-term functionality.