Publications using TDT

Oxidative stress and inflammation are interconnected drivers of cellular damage in pathologies ranging from neurodegenerative disorders to sensorineural hearing loss. We aimed to develop a chitosan-Prussian blue nanozyme (CS-PB) to target these processes in sensorineural hearing loss. CS-PB (35 μg/mL) pretreatment of H 2 O 2 -injured HEI-OC1 cochlear cells for 4 h markedly decreased the levels of reactive oxygen species (ROS) inside cells (from 3.8 to 2.4 relative fluorescence intensity) by approximately 37% ( P < 0.001)-and concomitantly significantly decreased expression of the oxidative damage markers 4-HNE and 3-NT (both P < 0.001). The rate of apoptosis decreased from 27.5% in the H 2 O 2 -treated group to 14.1% following CS-PB treatment (P < 0.01). This reduction was accompanied by a significant downregulation of the pro-apoptotic proteins Bax (P < 0.05) and Cleaved-caspase-3 (P < 0.001), as well as an upregulation of the anti-apoptotic protein Bcl-XL (P < 0.01).Western blot analysis confirmed that CS–PB significantly downregulated TLR4 expression and inhibited downstream phosphorylation of p-P65/P65, while upregulating p-IκBα/IκBα protein (all P < 0.01) associated with reduction in the production of inflammatory cytokines like TNF-α, IL-1β, and IL-6. Treatment with the specific TLR4 antagonist TAK-242 (2 μM) mimicked the effect of CS-PB, with coadministration showing no additional ant-inflammatory effect (although HEI-OC1 viability was additionally increased), indicating that the anti-inflammatory properties of CS-PB were facilitated via the TLR4/NF-κB signaling pathway. In vivo , CS-PB pretreatment (2 mg/mL, 2 μL) was administered by carefully applying the solution to the round window membrane (RWM) using a microsyringe in a noise-induced hearing loss rat model, which significantly curtailed the noise-induced activation of the TLR4/NF-κB pathway in the cochlea. After 24 hours, the levels of p-P65/P65 and TLR4 decreased by 54% and 50%, respectively. ( P < 0.001), and levels of the inflammatory cytokines IL-6, TNF-α and IL-1β were decreased by 53%, 48%, and 51% ( P < 0.001). Furthermore, the degree of pathway inhibition showed a strong correlation with cytokine reduction (r = 0.87–0.89, all P < 0.001). CS-PB showed no significant cytotoxicity in vitro or in vivo , suggesting that its combined ROS-scavenging and TLR4/NF-κB–modulating properties may represent a potential therapeutic strategy, pending further mechanistic and translational validation.

Many neurological and psychiatric disorders stem from maladaptive conditioning and resist treatment. Tinnitus, as one example, is the distressing perception of sound in the absence of an external source. One of the network systems implicated in multiple disorders is the 'salience network', associated with positive/negative reward, habit formation, motivation, valuation and mood. However, it is not known whether directly modulating the 'salience network' at its anatomical and physiological core, in the ventral striatum, more specifically the nucleus accumbens, could be beneficial. Here we show that a novel treatment approach, targeting the salience network, can reduce tinnitus perception in a rat model. We found that bilateral rewarding stimulation of the nucleus accumbens, when paired with non-tinnitus tones, was most effective. A combined approach using rewarding accumbens stimulation and dysrewarding lateral habenula stimulation - paired with non-tinnitus and tinnitus tones, respectively - also suppressed tinnitus but caused negative effects. Our results demonstrate how the rewarding stimulation can recondition brain networks to effectively remove the salience of tinnitus frequencies. We anticipate that our unique reconditioning strategy has broader therapeutic applications for other brain disorders rooted in maladaptive learning.

Cisplatin is widely used in oncology yet causes dose-limiting, irreversible hearing loss through cochlear hair-cell injury. Although mitochondrial dysfunction is central to this ototoxicity, how the outer mitochondrial membrane (OMM) fails in hair cells remains unclear. We identify BAX-associated mitochondrial membrane rupture and abnormal permeabilization as key drivers. In HEI-OC1 cells and murine cochlear explants, super-resolution and transmission electron microscopy revealed cisplatin-induced BAX translocation and oligomerization on the OMM, forming ring-like assemblies with ultrastructural damage (rupture, herniation, fragmentation). Subcellular fractionation and functional assays demonstrated consequent mitochondrial outer membrane permeabilization, cytochrome c release, loss of membrane potential, and accumulation of reactive oxygen species (ROS). Pharmacologic inhibition of BAX oligomerization with BAX inhibitor peptide V5 (BipV5) preserved mitochondrial integrity, reduced ROS, and limited hair-cell loss in vitro. In vivo, repeated transtympanic delivery of BipV5 conferred sustained functional protection and reduced outer hair cell loss. These findings establish a structural mechanism linking mitochondrial membrane rupture to redox imbalance and apoptosis in cochlear hair cells and nominate BAX oligomerization as a drug-targetable node for preventing cisplatin ototoxicity without compromising anticancer therapy.

Traumatic brain injuries (TBIs) are more than mere lesions and generate a persistent secondary pathology. This, combined with functional reorganization of circuits post-injury, may explain the increased risk for psychiatric disorders in patients with TBI. In the current studies, we demonstrate that frontal TBI changed the Pavlovian behavioral response to reinforcer-predicting cues and reduced the motivational value of cues. TBI also chronically impaired decision-making on a gambling-like task with reinforcer-paired cues. To investigate how these changes occur, we evaluated the nucleus accumbens (NAc) core. At a subacute time point (14 days), we confirmed reduced input to the NAc with optogenetics and evaluated electrophysiological and transcriptional changes. TBI increased neuronal excitability and the single nucleus RNA sequencing profile indicated a substantial stress and inflammatory response, but also high indicators of plasticity, particularly in D1- and D2-positive medium spiny neurons. To evaluate how these subacute changes transitioned to chronic NAc dysfunction, we measured immunohistochemical surrogates of activity post-mortem and recorded calcium activity from the NAc after TBI during Pavlovian conditioning. TBI reduced histological markers of activity and reduced cue-evoked calcium activity. Overall, these data indicate that substantial reorganization of the NAc occurs following frontal brain injury. A primary effect of this is to reduce the salience of environmental cues linked to outcomes. The inability to properly process outcomes could contribute to broader psychiatric symptoms after TBI, including impairments in decision-making, behavioral flexibility, and impulsivity but also presents a potential treatment target.

Flexible behavior requires decision-making that integrates both perceptual and mnemonic-related information. While the dorsal premotor cortex (PMd) is known to support perceptual decision-making, its contributions to decisions based on mnemonic information for motor planning remain underexplored. Here, we investigate local field potential (LFP) oscillations in the PMd of monkeys performing a transitive inference task requiring the formation and retrieval of mnemonic representations of an arbitrarily defined rank order among perceptual items. The difficulty of this operation depends on the distance of the items in the mnemonic representation. We tested the hypothesis that this symbolic distance (SD) systematically modulates PMd oscillatory activity in a frequency-specific manner during decisions that combine perceptual identification with mnemonic retrieval. Consistent with this hypothesis, PMd exhibited local and reliable SD-dependent changes across low (Theta, Alpha, Beta) and high-Gamma (h-Gamma) frequency bands, and related to behavioral performance. These findings provide evidence that the PMd integrates perceptual and mnemonic information through coordinated modulations of oscillatory activity, extending its role beyond perceptual mapping to support abstract, memory-guided decisions.

Sensorineural hearing loss (SNHL) induced by noise or aminoglycoside antibiotics is a significant public health concern without any FDA‐approved pharmaceutical therapies. Dysregulation of iron homeostasis and its subsequently induced ferroptosis has increasingly been identified as a key mechanism underlying cochlear hair cell (HC) damage. Nevertheless, the therapeutic targets for restoring iron balance for hearing protection remain poorly investigated. In this study, we uncover a previously unrecognized role of the SMO pathway in regulating iron homeostasis. SMO expression was rapidly upregulated and activated in HCs following injury. Both genetic ablation of Smo and pharmacological inhibition of SMO reduced iron accumulation and lipid peroxidation, promoting HC survival and preserving auditory function in mouse models of ototoxic‐ and noise‐induced hearing loss. Mechanistically, SMO inhibition suppressed ATF2 phosphorylation, resulting in downregulation of IRP1, which decreased iron accumulation via downregulation of Tfrc and upregulation of Fpn , ultimately protecting HCs from ferroptosis. Notably, treatment with the SMO inhibitor SANT‐1 nearly restored auditory thresholds to baseline levels in mice subjected to ototoxic injury. Our findings identify the SMO–ATF2–IRP1–FPN/TFRC axis as a central regulator of cochlear iron homeostasis and propose SMO inhibition as a promising therapeutic strategy for SNHL through precise modulation of iron metabolism.

Interpersonal coordination is fundamental to social evolution. We investigate its phenomenology and neural underpinnings in humans and macaques, examining the behavioral adaptations required for mutual coordination during motor interactions and the extent to which the underlying brain mechanisms are shared across species. Using a common interpersonal coordination paradigm, we conducted functional magnetic resonance imaging (fMRI) in humans and intracranial local field potential (LFP) recordings in macaques. Despite between-species behavioral discrepancies, both monkeys and humans coordinate through adjustments that proved to be based on proactive adaptation of motor planning and execution. Evidence from fMRI and time-resolved decoding analysis of LFPs converged to show modulation of premotor brain activity associated with interpersonal coordination and its effectiveness. Moreover, a dynamic sequential coding emerged, whereby the action context is represented early during planning, and coordination features near movement onset. Our findings reveal an evolutionarily conserved cortical architecture across primates that supports cooperative motor behavior.

Lipid metabolism is an important biological process that maintains the dynamic balance of several key functions, such as intracellular energy metabolism, signal transduction, and membrane remodeling. However, the role of lipid metabolism in auditory function and the underlying mechanisms remain unclear. Our results reveal that the neomycin exposure disrupts lipid metabolism in auditory system. We find that neomycin-induced hair cells (HC) damage leads to abnormal lipid droplets (LD) accumulation. Further research reveals that decreased YAP expression is a key factor that contributes to abnormal LD accumulation. In both in vivo and in vitro studies, Yap overexpression reduces abnormal LD accumulation and mitigated HC damage. To further investigate its downstream mechanisms, we perform a cross-analysis of Yap -related and lipid metabolism–related genes, identifying that Cox2 is a key downstream target of Yap that contributes to LD accumulation and HC damage. Our work provides clear evidence for the role of lipid metabolism in neomycin-induced hearing loss and elucidates underlying mechanism of Yap/Cox2 pathway. These findings provide new perspectives and avenues for the clinical treatment of sensorineural hearing loss.

One of the biggest challenges for neurotechnology is the design of devices that are tolerated well by brain tissue, without sacrificing functionality and implantability. This study examined which design choices mitigate tissue damage and improve longevity by varying probe features implanted in the cerebral cortex of mice. We report on a systematic, quantitative analysis of neuronal and inflammation markers across cortical depth. We implanted a total of 103 stiff silicon or flexible polyimide probes in 32 mice, varying their thicknesses and widths, and either attaching them to the skull or not. A new, automated workflow to quantify immunohistochemical data examines: 1) the tissue loss caused by the implant, 2) the cortical neuronal density, and 3) the immune response expressed by astrocytic and microglial reaction. Flexible polyimide probes exhibited a clear advantage, causing fewer lesions and weaker immune responses than stiff silicon probes. Furthermore, we observed a weak influence of the shank cross‐section. A cortical depth profile of immune reactivity revealed focal reactions at the device entry points in the superficial cortex and at the cortex‐white matter boundary. This study gives important insights on optimizing device design parameters as well as surgical insights for improved tissue integration of intracortical electrode arrays.

Magnetogenetic deep brain stimulation (MG‐DBS) represents a wireless neuromodulation that has demonstrated long‐lasting behavioral benefits in Parkinson's disease models. However, the circuit‐level mechanisms underlying these therapeutic effects have remained uncharacterized due to limitations of conventional neural interfaces. We present a bio‐integrable soft neural interface featuring ultrasoft liquid‐metal probes with bioresorbable stiffeners and customizable interconnects directly printed onto cranial surfaces to match individual skull anatomy and nanoparticle injection sites. This platform enables stable multi‐regional recordings from deep brain structures without chronic tissue damage. We systematically investigate MG‐DBS therapeutic mechanisms in a Parkinson's disease mouse model. Circuit‐level analysis reveals that MG‐DBS modulates pathological beta‐band oscillations and inter‐regional synchrony across the cortico‐basal ganglia‐thalamic circuit. Direct comparison with conventional electrical DBS demonstrates that MG‐DBS effects persisted approximately fifteen‐fold longer after stimulation cessation. Our electrophysiological recordings elucidate the mechanistic basis for this sustained therapeutic effect, providing unprecedented insights into magnetogenetic neuromodulation dynamics.

Cisplatin (CDDP) is an effective chemotherapeutic agent used to treat solid tumors, but it can cause irreversible hearing loss. Currently, there are no specific preventive measures available for this side effect. G protein-coupled receptor 55 (GPR55) exhibits antioxidant, anti-inflammatory, and anti-apoptotic properties and is implicated in various disease processes. Nevertheless, whether GPR55 plays a role in CDDP-induced hearing loss remains unclear. We explored the effects and mechanisms of O-1602, a GPR55 agonist, on CDDP-induced ototoxicity. Our results showed that GPR55 is present in cochlear hair cells and HEI-OC1 cells, with increased expression following CDDP exposure. Moreover, O-1602-induced activation of GPR55 markedly mitigated the ototoxic effects of CDDP in HEI-OC1 cells, cochlear explants, and mouse models by preventing oxidative stress and apoptosis. In addition, GPR55 protected against CDDP-induced damage via inhibiting the MAPK pathway. Therefore, GPR55 is a potential therapeutic target for preventing CDDP-induced ototoxicity.

Background Ménière’s disease (MD) is a disabling inner-ear disorder. Although the key pathologic alteration of MD is characterized as endolymphatic hydrops (EH), the underlying pathogenic mechanism remains unclear, and no definitive curative treatments are available. Emerging evidence implicates oxidative stress and innate immunity as key contributors to MD pathogenesis. Methods Human vestibular end organs were collected to characterize the reactive oxygen species (ROS) levels and the STING signaling activation, findings that were further corroborated in an LPS-induced EH mouse model. Transfection and transwell co-culture were performed to investigate the feedback loop between sensory epithelial cells and macrophages in vitro. Molecular biology experiments were performed to elucidate the underlying regulatory mechanisms. Additionally, STING and CUL4B deficiency mice were used to explore potential therapeutic targets in vivo. Results The oxidative stress, cytoplasmic dsDNA leakage, and STING activation were elevated in both MD patients and LPS-induced EH mouse model. The dsDNA released from ROS-damaged hair cells activates STING in vestibular macrophages. STING-specific knockout in macrophages alleviates EH, audio-vestibular dysfunction, and interferon-stimulated genes expression in mouse model. The CUL4B-DDB1-ROC1 complex ubiquitinates STING at K370, promoting its degradation and inhibiting activation. Notably, CUL4B deficiency exacerbates LPS-induced EH, audio-vestibular dysfunction, and interferon-stimulated genes (ISG) upregulation, while double conditional knockout reverses these effects. Conclusion Our study demonstrates that STING activation in vestibular macrophages contributes to audio-vestibular dysfunction and modulating this pathway has promising beneficial effects on audio-vestibular function in EH mice model, which is a potential therapeutic strategy for MD.

Ménière's disease (MD), a chronic inflammatory disorder with age‐related increased incidence, exhibits poorly understood pathogenesis and limited therapeutic options. Here, we demonstrate that cellular senescence, marked by mitochondrial damage, reactive oxygen species accumulation, and senescence‐associated secretory phenotype (SASP), is prevalent in the vestibular tissue of MD patients and an endolymphatic hydrops mouse model. The transcription factor GATA4 is upregulated in MD and mice, and its genetic deletion in hair cells alleviates LPS‐induced audio‐vestibular dysfunction and cellular senescence in mice and HEI‐OC1 cells. Mechanistically, HDAC6 interacts with GATA4 and restrains its nuclear transport, while RNA‐seq and ChIP‐seq identify HtrA1, a serine protease, as a direct transcriptional target of GATA4. Inhibition of HDAC6 or AAV‐mediated HtrA1 overexpression exacerbates MD‐like symptoms, whereas inhibition of HtrA1 by Galegenimab ameliorates these phenotypes in mice. In aged mice, GATA4 deletion reduces age‐related audio‐vestibular deficits and senescence markers. Collectively, our findings establish GATA4 as a critical regulator of cellular senescence and inflammaging in inner ear pathologies, providing promising therapeutic targets for MD and age‐related audio‐vestibular disorders.

Human vision relies on photoreceptor cells in the outer retina that are sensitive to visible light. However, many people suffer from blindness due to retinal diseases that cause photoreceptor degeneration. Electrical stimulation of retinal neurons can recreate the action potentials associated with seeing that are generated by these cells. Here we report a thin artificial retina that can be adhered to the epiretinal surface and can convert near-infrared (NIR) light into electrical stimuli that selectively stimulate ganglion cells. The artificial retina consists of a NIR-sensitive phototransistor array and three-dimensional liquid metal micropillar electrodes. The liquid metal electrodes enhance proximity to retinal ganglion cells, providing effective charge injection while minimizing tissue damage, owing to their low Young’s modulus. Ex vivo studies demonstrate its biocompatibility, and in vivo studies using healthy and blind mice demonstrate perception of both visible and NIR light, as indicated by cortical recordings and behavioural tests. The retina could, in the future, be used to create a NIR visual channel in patients with photoreceptor degenerative blindness without interfering with their remaining natural vision.

The psychedelic psilocybin has shown therapeutic potential, yet underlying neural mechanisms remain poorly understood. We investigated the impact of psilocin-the active metabolite of psilocybin-on basal activity and reactivity within the paraventricular nucleus of the thalamus (PVT) and PVT projections to central amygdala (CeA) in rats. Psilocin administration increased PVT c-Fos expression and selectively engaged PVT→CeA neurons in females, but not males. Psilocin enhanced PVT reactivity to an aversive air-puff stimulus, with effects primarily driven by passive responders. In PVT→CeA neurons, psilocin prevented time-dependent reductions in stimulus-evoked activity and maintained reactivity across timepoints in females but not males. The sustained engagement of PVT→CeA circuitry was driven by active responders. These findings identify sex-specific modulation of thalamic-limbic circuitry and behavior by psilocin, implicating PVT→CeA circuitry in the neural and behavioral effects of psychedelic compounds, advancing our understanding of how psychedelics modulate emotional brain circuits to further inform potential therapeutic mechanisms.

Ultrasonic vocalizations (USVs) are widely used in rodent social communication, yet the functional significance of male–male vocal interactions in mice remains unclear. Here, we investigated whether USVs produced during specific social behaviors influence the behavior of conspecifics. Using playback experiments, we compared responses to vocalizations recorded during chasing and being chased in male–male interactions. We found that USVs emitted by chased intruders consistently elicited approach behavior in receiver mice, whereas those emitted by chasing individuals did not. Acoustic analyses revealed that these vocalizations differed in syllable composition, with intruder calls containing a higher proportion of upward frequency-modulated syllables and exhibiting higher mean frequencies. In addition, the temporal organization of syllables appeared to contribute to the behavioral response. Together, these results suggest that male mice respond selectively to certain USV patterns associated with specific social contexts, indicating that acoustic features and temporal structure may jointly influence social approach behavior in mice. Highlights Behavioral context (chased vs. chasing) shapes the composition of USV syllable types Male mice selectively approach USVs from chased intruders, but not chasing residents The approach response exhibits high temporal synchrony across individual receivers Temporal organization of syllables modulates approach behavior based on acoustic features

The Gestalt laws of perceptual organization determine which image regions in a visual scene are perceived as figures or background. Convex, enclosed, and symmetric regions are more likely to be perceived as figures, but the underlying neural mechanisms are not well understood. Here, we studied the influence of Gestalt cues on visual perception and on neuronal activity in early visual cortex. We found that, in both humans and macaques, the perceived contrast of Gabor probes was generally higher when placed on Gestalt-defined figures than on background regions, although individuals differed. Neural activity in areas V1 and V4 of the visual cortex of monkeys performing a contrast discrimination task was higher for image elements belonging to Gestalt-defined figures than image-elements of the background, except for symmetry-defined figures. We observed this figure-background modulation in both V1 and V4 even when the distinction between figure and background was irrelevant for the task of the animal. The influence of Gestalt cues on neural activity was stronger in V4 than in V1, suggesting that Gestalt organization arises through modulation of neural activity in higher visual areas, which then modulates neural activity in early visual areas through feedback.

The molecular and cellular mechanisms underlying the function of the cochlear nucleus (CN) remain to be fully elucidated. Using single-nucleus RNA sequencing and single-cell spatial transcriptome analyses, we generated a comprehensive cell type atlas of the mouse CN, identified molecularly defined CN subregions, and quantified changes in gene expression and the spatial organization of CN cells in normal mice during postnatal development and in mutant mice with congenital hearing loss. We further identified a subtype of bushy cells expressing the osteopontin-encoding gene Spp1 as the primary CN cell type that exhibited hearing loss-induced alteration of gene expression. Among the highly affected genes in bushy cells, deletion of the auditory input-regulated gene Spp1 affected CN processing of auditory signals in mice. These results provide the most comprehensive cellular and molecular database to date for understanding auditory processing within the CN and identifying potential therapeutic targets for hearing restoration at the CN level.

Across sensory modalities, peripheral deafferentation can induce maladaptive central plasticity that amplifies sensory responses while distorting affective processing, rendering innocuous stimuli unpleasant, intrusive, or even painful. Here, we examined the affective dimension of compensatory plasticity in a mouse model of hyperacusis by introducing noise-induced focal cochlear lesions and tracking maladaptive plasticity in the lateral amygdala (LA), a key limbic hub for sensory-affective valuation. Whereas control mice habituated to neutral sounds, mice with noise-induced hearing loss (NIHL) showed sustained LA hyperresponsivity and abnormally strong temporal coupling between calcium transients and pupil dilations, an autonomic index of arousal. NIHL also disrupted discriminative auditory threat learning, producing poorly selective, non-extinguishing enhancement of LA responses and freezing to both threatening and non-threatening sounds. We posited that potentiating inhibition in the higher-order auditory cortex (HO-AC), a prominent source of auditory sensory input to the LA, could reinstate normal affective sound processing after NIHL. Brief bouts of 40-Hz optogenetic activation of HO-AC parvalbumin-expressing inhibitory neurons (PVNs) durably reversed LA sensitization, normalized pupil-indexed arousal dynamics, and reinstated discriminative auditory threat memory. These findings identify cortical inhibitory potentiation as a strategy for reversing neural, autonomic, and behavioral signatures of distorted affective sound processing after peripheral sensory injury.

Background: Kölliker’s organ (KO) support cells undergo orderly, time-dependent degeneration that is essential for auditory development and is accompanied by precisely regulated autophagic activity; however, the molecular hierarchy linking autophagy to this remodeling remains obscure. This study aimed to elucidate the regulatory mechanisms connecting autophagic flux to lysosomal biogenesis and auditory function during cochlear development. Method: We established an Atg5flox/flox; Sox2Cre+ mouse model with deletion of the autophagy gene Atg5 in cochlear-supporting cells. Auditory function was assessed via Auditory Brainstem Response (ABR) testing. Transcriptomic profiling of the neonatal basilar membrane was performed to screen for downstream targets. Mechanistic validation included spatiotemporal immunofluorescence mapping (E18–P30) and in vitro functional assays using siRNA-mediated knockdown and lysosomal tracking. Results: At 2 months of age, Atg5flox/flox; Sox2Cre+ mice exhibited moderate-to-severe sensorineural hearing loss accompanied by significant outer hair cell loss. Bulk RNA-seq of the basilar membrane identified fork-head box A3 (Foxa3) as a significantly downregulated transcription factor within the lysosomal–autophagy network. Spatiotemporal immunolabelling from embryonic day 18 to postnatal day 30 revealed that FOXA3 expression becomes progressively restricted to KO cells during postnatal development, with ATG5 loss reducing FOXA3 protein levels by 62.4%. In vitro, deficiency of either Atg5 or Foxa3 in primary KO cells resulted in comparable reductions in LAMP1-positive puncta. Conclusions: These findings support a model wherein the ATG5-FOXA3 axis contributes to lysosomal biogenesis in developing KO cells, with implications for understanding mechanisms of congenital sensorineural hearing loss.