Publications using TDT

Recent work shows that the brain’s arousal system remains active during sleep, with rhythmic locus coeruleus (LC) activity shaping sleep architecture and supporting memory consolidation. The LC releases norepinephrine (NE) in infraslow (~0.02 Hz) bouts that gate NREM sleep spindles. Here, we demonstrate that heart rate (HR) fluctuations during NREM are tightly phase-locked to these NE rhythms, identifying the LC as a key driver of very-low-frequency HR variability (VLF-HRV), an understudied autonomic signal. Using optogenetics, transient LC inhibition blunts HR slowing, whereas LC activation produces rapid HR acceleration, demonstrating a direct LC-HR relationship during sleep that is maintained across a defined range of LC activity levels but breaks down when LC activity becomes excessive. We further show that infraslow HR variability is a cross-species marker of spindle-dependent memory processing. In mice, the amplitude of HR decelerations during NREM correlates with spindle activity and subsequent memory performance. Remarkably, human sleepers show the same pattern: stronger VLF-HR fluctuations during NREM correspond to increased spindle expression and better overnight memory retention. These findings reveal a mechanistic pathway through which graded changes in LC activity, up to a critical level, modulates autonomic physiology during sleep and identify infraslow HR variability as a non-invasive marker of brainstem function and memory-promoting sleep. Because LC degeneration occurs early in neurodegenerative disease, sleep-derived HR metrics may provide a scalable indicator of emerging neuromodulatory dysfunction.

Background Approximately one in three adults aged 65–74 years reports hearing difficulty, including age-related hearing loss (AHL, presbycusis). The C57BL/6 mouse is widely used in preclinical AHL research because it develops AHL relatively early. Calorie restriction (CR) attenuates AHL and improves healthspan and longevity in this strain. A recently developed transgenic C57BL/6 mouse expressing naked mole-rat hyaluronan synthase 2 ( nmrHas2 ), which produces very high molecular mass hyaluronan (vHMM-HA), also exhibits improved healthspan, reduced inflammaging, and increased longevity. Therefore, we evaluated nmrHas2 mice for evidence of alleviated AHL. Objective To determine whether AHL is attenuated in nmrHas2 mice . Methods This study supplemented a larger investigation of nmrHas2 and female reproductive aging. Tamoxifen administered at 1 month induced ubiquitous nmrHas2 expression in nmrHas2+ females; nmrHas2− controls received tamoxifen or vehicle. Auditory brainstem response (ABR) testing was performed approximately 2 weeks before mice reached 3 or 12 months of age. Cochleae and reproductive tissues were collected following euthanasia approximately 2 weeks later. Results ABR thresholds to clicks and six tones (4–32 kHz) showed marked hearing loss from 3 to 12 months of age in both nmrHas2+ mice and controls, with no evidence that nmrHas2 attenuated AHL. Cochlear nmrHas2 expression in nmrHas2+ mice was confirmed by quantitative RT-PCR. Conclusion Ubiquitous nmrHas2 expression did not attenuate AHL in C57BL/6 mice despite previously reported benefits for other aging phenotypes. These findings contrast with CR, suggesting that vHMM-HA and CR influence aging through distinct mechanisms.

The ability to detect deviations from expected sensory input is fundamental for adaptive behavior. We recorded electrocorticographic activity from the auditory (AC) and prefrontal (PFC) cortices of behaving macaques during an auditory oddball task to probe the cortical dynamics of predictive processing. Repetition of standard stimuli evoked suppression and facilitation in AC and strong low-frequency (2 Hz) enhancement in PFC, accompanied by bidirectional delta-band GC-defined interactions indicative of a shared predictive state. Deviant stimuli triggered earlier AC responses followed by PFC activation and increased GC-defined directed interactions across theta, alpha, and conventional gamma bands. Behavioral engagement amplified both repetition-related and deviance-related ECoG responses, strengthening cortical network coordination. Together, these findings reveal behaviorally gated auditory–prefrontal dynamics that are consistent with hierarchical predictive-processing accounts, while also allowing for contributions from repetition-, novelty-, and salience-related mechanisms.

Noise-induced hearing loss (NIHL) is a major public health problem caused by damage to cochlear hair cells, synapses, and spiral ganglion neurons (SGNs). Since effective treatments are lacking, we investigated cellular stress responses induced by moderate and loud noise in a mouse model of cochlear synaptopathy. RNA sequencing and spatial transcriptomics revealed that noise exposure elicited a robust but transient upregulation of endoplasmic reticulum chaperones and proteasome subunits in SGNs and their supporting cells. To target this response, we administered TRC051384, a small-molecule activator of the heat shock transcription factor Hsf1, prior to noise exposure. TRC051384 crossed the blood–labyrinth barrier and reached the cochlea, induced heat shock protein gene expression, and restored ubiquitin–proteasome function in SGNs. Notably, TRC051384 treatment enhanced auditory brainstem response threshold recovery, preserved Wave I amplitudes, and maintained ribbon synapse density. Together with the existing literature, these findings identify proteotoxic stress in spiral ganglion neurons as a contributor to noise-induced hearing loss and support pharmacological activation of HSF1 as a promising therapeutic strategy.

Difficulties understanding speech in noise remain a common complaint even among listeners with normal hearing sensitivity, highlighting the need for objective, more effective measures of real-world listening. The goal of this study was to validate the use of a novel, chirped-speech (Cheech) stimulus—continuous, naturally-spoken speech fused with chirps designed to elicit robust auditory evoked potentials—to characterize relationships between speech recognition, listening effort, and auditory neural encoding. Twenty-five normal-hearing adults completed a sentence-recognition task using both original (unmodified) and Cheech-modified AzBio sentence lists in quiet, +3 dB, and −3 dB signal-to-noise ratio (SNR) conditions while neural responses from the brainstem through cortex were recorded simultaneously. Speech recognition remained near ceiling in quiet but declined with decreasing SNR for both original and Cheech stimuli. Compared with clean speech, Cheech-modified speech showed slightly poorer recognition performance as SNR decreased and somewhat higher perceived effort overall. Yet, Cheech was highly effective at evoking auditory responses from the brainstem (auditory brainstem response, ABR) through the cortex (including middle- and late-latency responses, MLR and LLR) even with <5 minutes listening time per condition. Neural responses showed reduced amplitudes and prolonged latencies as SNR decreased. In general, ABR latencies and wave I amplitudes were associated with speech-in-noise recognition performance, whereas cortical responses (MLR Na, Nb, and LLR P1) were associated with subjective workload. These findings show that Cheech-modified speech preserves intelligibility while yielding robust, multilevel neural recordings during sentence perception, offering a promising approach to examine hierarchical auditory processing under ecologically relevant speech-in-noise conditions.

Cisplatin is a potent, broad-spectrum chemotherapeutic agent widely used against multiple malignancies, yet its clinical utility is substantially restricted by dose-limiting adverse effects dominated by nephrotoxicity and ototoxicity. Although cisplatin-induced ototoxicity has been recognized for decades, the precise molecular cascades triggering cisplatin-evoked permanent hearing impairment remain incompletely defined. Therefore, in-depth investigation into the molecular mechanisms of cisplatin-induced ototoxicity and the development of effective prevention strategies represent key scientific issues. Herein, we constructed a chronic cisplatin-exposed animal model and verified prominent pathological features encompassing excessive DNA damage and mitochondrial dysfunction, paralleled by marked downregulation of the DNA repair enzyme MUTYH. Follow-up in vitro assays validated that overexpression of MUTYH significantly alleviated cisplatin-induced ROS accumulation, cell apoptosis, and DNA damage, suggesting that downregulation of MUTYH may be a key molecular event in cisplatin-induced ototoxicity. Notably, exogenous short-chain fatty acid supplementation robustly rescued cisplatin-induced sensory cell loss and hearing loss, concurrent with restored MUTYH abundance. Collectively, our findings reveal that short-chain fatty acids protect cochlear sensory cells from cisplatin-initiated DNA damage via sustaining MUTYH expression, thereby preserving auditory function. As indispensable gut microbial metabolites in humans, short-chain fatty acids supplementation holds promising translational potential as a clinically viable regimen to counteract cisplatin-associated ototoxicity.

Mammalian cochlear hair cells convert acoustic stimuli into electrical signals, which are relayed to the central auditory pathway via auditory neurons. Progressive loss of hair cells and their synapses is a characteristic of age‐related hearing loss (ARHL), but the underlying mechanisms remain poorly understood. In this study, we tested the hypothesis that hair cell physiological properties change with age in CBA/CaJ mice, a strain known for its slow ARHL progression. We found that hair cell size began to decrease from 10 months of age, well before detectable increase in hearing thresholds from auditory brainstem responses. This structural change was associated with a significant decrease in the size of the basolateral membrane current, in particular that carried by the large conductance calcium‐activated potassium (BK) channel currents ( I K,f ) in the apical inner hair cells (IHCs). However, the size of the mechanoelectrical transducer (MET) current measured in the IHCs remained unaffected at least up to 22 months of age. Our results provide clear evidence of an early change in the physiological properties of apical IHCs with age, which precedes measurable hearing loss, suggesting that these cellular deficits might define a distinct pathological route in the CBA/CaJ mice.

Introduction The mitochondrial calcium uniporter (MCU) mediates mitochondrial Ca 2⁺ uptake, but its involvement in cisplatin-induced ototoxicity remains poorly understood. We investigated MCU expression and its association with cisplatin-induced injury in mouse cochlear basilar membranes and HEI-OC1 cells. Methods MCU protein abundance and localization were assessed by Western blotting and immunofluorescence. MCU expression was genetically reduced by lentiviral knockdown, and Ru360 was used as a pharmacological intervention. Apoptosis-related proteins and transcriptomic changes were evaluated. An acute cisplatin-induced ototoxicity model was established in C57BL/6 mice and assessed using auditory brainstem response (ABR) measurements and outer hair cell counts. Results Cisplatin increased MCU expression and reduced SERCA2 expression; the cisplatin-induced increase in MCU was partially reversed by BAPTA-AM and the endoplasmic reticulum stress inhibitor 4-PBA. MCU knockdown did not affect basal cell viability but attenuated cisplatin-induced reductions in viability, TUNEL positivity, and cleaved caspase-3. It was also associated with increased SERCA2 and decreased IP3R, GRP75, and VDAC1 expression. RNA sequencing identified differentially expressed genes enriched in autophagy-related processes and mTOR signaling. MCU knockdown was associated with increased PI3K/AKT/mTOR signaling and changes in Beclin1, LC3B-II, and p62. Ru360 cotreatment partially reproduced the protective phenotype in vitro and was associated with attenuated ABR threshold elevation at selected frequencies and reduced outer hair cell loss in vivo . Discussion These findings support an association between MCU-related signaling, PI3K/AKT/mTOR pathway activation, altered autophagy-related markers, and reduced cisplatin-induced cochlear injury.

Understanding the molecular basis of hair cell function is essential for elucidating inner ear physiology and developing therapies for auditory–vestibular disorders. Here, we identify acyl-CoA binding domain-containing 7 ( Acbd7 ) as a hair cell-specific gene critical for sensory maintenance. Single-cell transcriptomics of mouse cochlear organoids revealed Acbd7 as a top hair cell-enriched transcript, with its spatiotemporal expression confirmed from embryonic development through adulthood in both auditory and vestibular hair cells. Acbd7 ‑deficient mice exhibited pronounced hair cell degeneration, characterized by synaptic defects and diminished calcium currents in inner hair cells and loss of outer hair cells. Transcriptomic and proteomic analyses linked Acbd7 to the regulation of Ca 2+ signaling and fatty acid metabolism pathways. Our findings establish Acbd7 as a critical regulator of Ca 2+ homeostasis and functional integrity in hair cells, thereby elucidating a key mechanism by which a fatty acid metabolism factor sustains hair cell function and providing potential therapeutic targets for inner ear disorders.

The detection of unexpected sounds, or auditory deviance detection, is thought to be achieved by comparing prediction signals and sensory inputs in the auditory cortex. This process is markedly impaired in patients with schizophrenia. However, the local circuit properties underlying deviance detection, together with their dysfunction in schizophrenia-related conditions, remain poorly understood. We used two-photon calcium imaging to monitor the population activity of cortical neurons during auditory deviance detection. The deviance-detecting component was predominant in layer 2/3 neurons of the higher-order auditory cortex. The deviance-detecting cells were spatially clustered, exhibited robust synchronization, and constitutively expressed immediate-early genes. In the Del(1.5 megabase)/+ mouse model of 22q11.2 deletion syndrome, a model of schizophrenia, deviance-detecting activity in the upper-layer network was disrupted, accompanied by dysregulated gene expression and selective loss of dendritic spines in immediate-early gene–positive neurons. Our findings support the hypothesis that ensemble activation of this neuronal subpopulation amplifies unexpected inputs, driving error signals that propagate to higher-order cortical areas.

Cochlear damage triggers compensatory primary auditory cortex (A1) plasticity that amplifies responses to residual sensory inputs, thereby contributing to the restoration of both cortical responsiveness to sound and perceptual sound detection threshold. However, this adaptation can become maladaptive, producing neuronal hyperactivity that contributes to tinnitus and hyperacusis. The neuromodulatory mechanisms governing these adaptive and maladaptive changes remain unknown. Here, we demonstrate that noise-induced cochlear injury triggers bidirectional synaptic zinc signaling plasticity that potentiates activity in excitatory principal neurons and parvalbumin-expressing interneurons, while suppressing activity in somatostatin-expressing interneurons. These cell-type-specific effects of synaptic zinc plasticity contribute to restoring A1 responsiveness to sound and perceptual detection thresholds, while being necessary for neural hyperactivity. Together, our findings establish synaptic zinc as a pivotal neuromodulator that shapes both adaptive and maladaptive cortical plasticity and identify a promising therapeutic target for improving perceptual recovery after cochlear damage and mitigating tinnitus and hyperacusis.

High-intensity noise exposure induces cochlear injury through mechanical trauma, disruption of ionic homeostasis, and secondary oxidative stress, ultimately leading to noise-induced hearing loss (NIHL). Increasing evidence suggests that oxidative stress not only causes direct cellular damage but also drives pathological remodeling of the cochlear microenvironment by triggering persistent inflammatory activation and impairing endogenous nitric oxide (NO) biocatalysis. However, current therapeutic strategies based solely on antioxidants or anti-inflammatory agents are insufficient to simultaneously restore inflammatory homeostasis and endogenous catalytic regulation within the injured cochlea. Here, we developed a carrier-free arginine–dexamethasone nanoplatform (AD NPs) through a one-step ultrasound-assisted self-assembly strategy to achieve biocatalytic remodeling of the pathological cochlear microenvironment. By integrating the anti-inflammatory activity of dexamethasone with the physiological substrate function of L-arginine for endothelial nitric oxide synthase (eNOS), AD was designed to coordinately suppress inflammatory signaling while restoring endogenous NO biocatalysis. The resulting nanoparticles exhibited an average diameter of approximately 169.9 nm, a positive surface charge (+ 17.18 mV), sustained ROS-responsive drug release, excellent biocompatibility, and prolonged cochlear retention following tympanic bulla administration. In H₂O₂-induced cellular models, AD markedly reduced intracellular reactive oxygen species (ROS) accumulation, inhibited NF-κB signaling activation, promoted macrophage polarization toward a pro-repair phenotype, restored eNOS/iNOS-associated NO biocatalytic homeostasis, improved endothelial functional phenotypes, and protected HEI-OC1 cells against oxidative injury. In a C57BL/6 mouse model of NIHL, AD significantly preserved high-frequency hearing, reduced cochlear hair cell loss, maintained ribbon synapse integrity, and corrected the pathological imbalance between eNOS and iNOS within the stria vascularis. Mechanistically, AD remodeled the pathological cochlear microenvironment through coordinated suppression of ROS/NF-κB-mediated inflammatory activation and restoration of endogenous NO biocatalysis, thereby interrupting the reciprocal amplification between inflammatory dysregulation and vascular dysfunction following acoustic injury. Collectively, this work establishes a carrier-free biocatalytic nanoplatform that harnesses endogenous enzymatic regulation to remodel the pathological cochlear microenvironment. This strategy provides a mechanistic framework for microenvironment-oriented biocatalytic nanomedicine and offers a promising therapeutic approach for the treatment of noise-induced hearing loss.

Background: Noise-induced hearing loss (NIHL) is a pervasive occupational health challenge, yet the individual susceptibility mechanisms remain unclear. Ferroptosis, an iron-dependent form of programmed cell death, has been implicated in cochlear hair cell damage. This study aims to elucidate the regulatory role of the transcription factor FOXA2 and the deacetylase SIRT1 in ferroptosis and to investigate the association between SIRT1 genetic polymorphisms and NIHL susceptibility in occupational populations. Methods: We employed a multi-level study design combining epidemiological investigation, animal models, and cellular experiments. First, a case–control study was conducted involving 1314 noise-exposed workers (639 cases vs. 675 controls) from a chemical fiber enterprise in Jiangsu Province to analyze the association between SIRT1 single nucleotide polymorphisms (SNPs) and NIHL risk. Second, a C57BL/6J mouse model exposed to 120 dB white noise was established to assess cochlear morphology and protein expression. Third, in HEI-OC1 cochlear hair cells, we performed siRNA-mediated knockdown of Foxa2 and dual-luciferase reporter assays to verify the transcriptional regulation of SIRT1 and its downstream effects on the ferroptosis pathway. Results: Population analysis revealed that the SIRT1 rs12778366 C allele was significantly associated with increased NIHL risk (OR = 1.386, 95% CI: 1.084–1.772, p = 0.009), and this association remained significant after adjustment (p = 0.041). Stratified analysis further revealed a significant gene–environment interaction in workers with >15 years of noise exposure (OR = 2.126, 95% CI: 1.401–3.226, p < 0.001). In vivo, noise exposure led to significant downregulation of Sirt1 and Foxa2 in cochlear tissues, accompanied by elevated ferroptosis markers (Fe2+, MDA) and depleted antioxidant defenses (GSH, xCT, and GPX4). Mechanistically, we demonstrate that FOXA2 transcriptionally activates SIRT1 by binding to its promoter. Knockdown of FOXA2 in vitro suppressed SIRT1 expression, suppressed xCT, a key component of the System Xc−/GPX4 antioxidant axis, and promoted ferroptosis-related cellular changes. Conclusions: This study identifies a novel protective axis where FOXA2 prevents noise-induced ferroptosis in cochlear hair cells by transcriptionally upregulating SIRT1 and maintaining xCT-mediated antioxidant defense. Furthermore, the SIRT1 rs12778366 polymorphism is identified as a candidate variant warranting further investigation in independent cohorts before clinical translation.

Introduction Sensory processing depends on interactions between neural circuits that convey and regulate information across cortical and subcortical networks. Classical frameworks distinguish driving inputs, which transmit sensory content via suprathreshold activation, from modulatory inputs, which alter neuronal excitability without directly eliciting spiking. However, physiological signatures of these circuit types that generalize widely across distributed brain regions remain unclear. Methods We functionally differentiated driving and modulatory circuits in the awake macaque brain by jointly quantifying suprathreshold multiunit activity (MUA) and oscillatory phase coherence (inter-trial coherence, ITC) across eight cortical and thalamic structures during auditory, visual, and eye-movement conditions. Results Preferred sensory stimuli elicited broadband ITC increases accompanied by robust MUA, yielding relatively uniform spectral distributions across adjacent frequency bands, consistent with driving inputs. In contrast, non-preferred sensory and eye-movement related events produced narrowband, frequency-specific ITC modulation without concurrent firing, characterized by dominant peaks at stimulation or event rates, consistent with modulatory inputs. These two response types were observed within individual regions, revealing two separable modes of neural activity. Discussion This narrowband ITC modulation is indicative of coordinated phase alignment, capable of dynamically regulating information transfer mediated by driving inputs across thalamocortical circuits. These findings identify distinct spectrotemporal signatures of driving and modulatory circuit properties across cortical and thalamic levels and demonstrate that subthreshold oscillatory modulation is a widespread phenomenon reflecting cross-modal and saccadic-related influences on neural excitability.

In nature, animals learn to replace predisposed behaviors with new strategies, yet the neural constraints on these transitions are unclear. Using an ethological search task in mice, we reveal medial prefrontal cortical (mPFC) neural correlates of a predisposed win-stay strategy that decays as animals learn to follow a more reliable auditory cue. Auditory cortex (ACx) activity predicts correct trial-by-trial sound-guided search, even on day one of training. This prognostic coding strengthens with learning and emerges from suppressed spiking, most pronounced in neurons tuned laterally to the cue’s spectrum. Chemogenetic disruption reveals ACx contributions to improving performance. Unexpectedly, the global silencing of mPFC accelerates successful usage of sound-tracking, contrary to its canonical role in flexible or stimulus-dependent behavior. Instead, a decentralized multiexpert competition model best predicts behavior and causal perturbations. These findings suggest that mPFC implements a default strategy based on prior knowledge, which actively hinders the expression of more efficient strategies.

The auditory nerve (AN) glial transition zone (GTZ), where myelination shifts from Schwann cells in the peripheral AN to oligodendrocytes in the central AN, is a unique biological niche housed within the cochlear modiolus. Although age-related hearing loss (ARHL) is associated with AN degeneration, the neuroimmune mechanisms contributing to age-related myelin pathology and altered immune cell function remain poorly defined. We hypothesized that the AN GTZ is especially vulnerable to age-related immune activity which may contribute to AN degeneration and myelin pathology. Using an ARHL mouse model, we combined large-field light sheet microscopy of tissue-cleared mouse temporal bones, three-dimensional high-resolution imaging, and quantitative immunohistochemistry to evaluate the AN GTZ. RNA-sequencing was used to evaluate age-related changes in gene expression of the whole AN. Human temporal bones were also examined to evaluate the AN and its macrophages/microglia. RNA-sequencing revealed age-associated enrichment of neuroinflammation and myelin degeneration-related pathways. Aging was associated with an increase in Iba1 + macrophages/microglia throughout the AN, with prominent accumulation at the AN GTZ. The aged AN GTZ contained Iba1 + subpopulations expressing CD206, Gal3, CD163, and Lamp1, suggesting enhanced phagocytic activity and altered activation state at the AN GTZ. CD68 + cells were also increased at the AN GTZ, as well as the central AN, with aging. Macrophages/microglia contained significantly more internalized myelin debris across all regions of the AN with aging, including myelin localized within Lamp1 + lysosomes of Iba1 + cells. More importantly, normal-appearing myelin was frequently observed within macrophages/microglia at the AN GTZ, but not in the peripheral or central regions of the AN. Myelin debris within Iba1 + cells was also found in the human AN, consistent with our findings in mouse. Together, these findings identify the AN GTZ as a unique microenvironment with age-related alterations in phagocytic activity and immune activation. The immune cell heterogeneity and enhanced myelin phagocytosis observed in the aging AN emphasize the importance of defining how distinct macrophage/microglia populations contribute to AN degeneration and ARHL.

Animals defend protein intake strongly, yet how protein status shapes moment-to-moment reward signalling in mesolimbic circuits remains unclear. Here, we examined how dietary protein restriction shapes nucleus accumbens (NAc) core dopamine signalling during operant feeding in the home-cage. C57BL/6 mice expressing the GRAB DA sensor in NAc core performed 1 h fixed-ratio 1 (FR1) and progressive ratio (ProgRatio) sessions to earn grain or sucrose pellets across three dietary phases; an initial non-restricted phase (NR1), a protein-restricted phase (PR), and a return to the non-restricted diet (NR2). Home-cage food intake remained stable across phases, whereas bodyweight gain was markedly reduced during PR and partially recovered in NR2. Behaviourally, operant responding increased during PR under both FR1 and ProgRatio schedules, with the most robust enhancement observed for grain pellets. Fibre photometry revealed a more selective neural effect. During FR1, pellet delivery evoked a larger NAc dopamine response for grain than for sucrose specifically during PR, whereas no pellet-type difference was detected during NR1 or NR2. By contrast, under progressive ratio, dopamine responses at pellet delivery and pellet retrieval did not differ between pellet types in any dietary phase. Together, these findings show that protein restriction does not globally amplify reward-related behaviour or dopamine signalling, but instead selectively biases NAc dopamine encoding in a manner that depends on nutritional status of the animal, nutrient context, and task demands.

Brain activity consists of neural signals dynamically coordinated across spatial and temporal scales. To sample distributed brain-wide activity, we combine chronically implanted ultra-flexible electrodes for subcortical recordings with simultaneous two-photon calcium imaging in mouse neocortex. Flexible electrodes preserve optical access even at steep insertion angles and enable weeks-long single-neuron tracking. With these combined recordings, we demonstrate how subcortical-cortical coupling is modulated across slow brain states and around fast ripple events.