Publications using TDT

Psychedelics lead to profound changes in subjective experience and behaviour, which are typically conceptualised in psychological terms rather than corresponding to an altered brain state or a distinct state of vigilance. Here, we performed chronic electrophysiological recordings from the neocortex concomitant with pupillometry in freely moving adult male mice following an injection of a short-acting psychedelic 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). We report an acute induction of a dissociated state, characterised by prominent slow oscillations in the cortex and marked pupil dilation in behaviourally awake, moving animals. REM sleep was initially markedly suppressed, but was overcompensated in the subsequent 48 hours, while administration of 5-MeO-DMT immediately after sleep deprivation attenuated the subsequent rebound of sleep slow-wave activity. We argue that the occurrence of a dissociated state combining features of waking and sleep may fundamentally underpin the known and hypothesised effects of psychedelics — from dream-like hallucinations to reopening of the critical period for plasticity.

Foraging in the wild requires coordinated switching of critical functions, including goal-oriented navigation and context-appropriate action selection. Nevertheless, few studies have examined how different functions are represented in the brain during naturalistic foraging. To address this question, we recorded multiple single-unit activities from the medial prefrontal cortex (mPFC) of rats seeking a sucrose reward in the presence of an unpredictable attack posed by a robotic predator (Lobsterbot). Simultaneously recorded ensemble activities from neurons were analyzed in reference to various behavioral indices as the animal moved freely across the foraging area (F) between the nest (N) and the goal (E) area. An artificial neural network, trained with simultaneously recorded neural activity, estimated the rat’s current distance from the Lobsterbot. The accuracy of distance estimation was the highest in the middle F-zone in which the dominant behavior was active navigation. The spatial encoding persisted in the N-zone when non-navigational behaviors such as grooming, rearing, and sniffing were excluded. In contrast, the accuracy decreased as the animal approached the E-zone, when the activity of the same neuronal ensembles was more correlated with events related to dynamic decision-making between food procurement and Lobsterbot evasion. A population-wide analysis confirmed highly heterogeneous encoding by the region. To further assess the decision-related activity in the E-zone, a naive Bayesian classifier was trained to predict the success and failure of avoidance behavior. The classifier predicted the avoidance outcome as much as 6 s before the head withdrawal. In addition, two sub-populations of recorded units with distinct temporal dynamics contributed differently to the prediction. These findings suggest that an overlapping population of mPFC neurons may switch between two heterogeneous modes, encoding relevant locations for goal-directed navigation or an imminent situational challenge.

To investigate auditory acclimatization to high-altitude hypobaric hypoxia, we conducted longitudinal transcriptomic analyses in Wistar rats rapidly transported from 500 m to 3,700 m. Auditory brainstem response (ABR) testing and hematoxylin and eosin staining revealed progressive changes, with hearing impairment at 30 days (D30) followed by acclimatization at 60 days (D60). RNA-seq of cochlear tissues identified 1,329 differentially expressed genes (DEGs) during impairment and 1,441 DEGs during acclimatization. STEM analysis linked these temporal patterns to specific biological processes: peripheral nervous system development (acclimatization) and myotube differentiation (impairment), as annotated by GO/KEGG and Metascape. STEM analysis revealed gene expression profiles that significantly correlated with ABR threshold shifts, encompassing biological processes such as sensory organ morphogenesis and gravity-sensing pathways. Subsequent validation through RT-PCR and immunofluorescence staining confirmed the involvement of key candidate genes, including morphogenesis-associated factors (Aqp1, Rbp4), the mechanosensitive hormone Bglap, and critical transcriptional regulators (Maz, Tfap4, Nf1) in the acclimatization response. This study elucidates key transcriptional mechanisms governing both the initial hearing impairment and subsequent acclimatization processes during high-altitude adaptation.

Objective Electrical stimulation of the baroreceptors pathways at the carotid sinus bulb – known as baroreflex activation therapy (BAT) – is intended to change autonomic tone and ultimately reduce blood pressure and heart rate. BAT is pre-market approved by the United States Food and Drug Administration (FDA) for the treatment of heart failure and received an FDA humanitarian device exemption for drug resistant hypertension. However, responder rates are limited by side-effects including numbness in the head and neck, altered speech, respiratory constriction, dry cough, vomiting, and altered sensory and motor function of the tongue. We hypothesized that these side-effects are driven by activation of other nearby nerve fibers of similar or lower threshold than the carotid sinus nerve. In this study, we sought to identify the neural sources responsible for off-target muscle activation contributing to these side-effects. These sources would inform strategies mitigating off-target activation in BAT therapy. Methods Domestic swine were used in this work as the diameter and thickness of the swine carotid artery are closer to human than those of canine models. A monopolar disk electrode mimicking the clinical CVRx® Neo electrode was surgically placed proximal to the carotid bifurcation with the position optimized for stimulation dose responsive changes in blood pressure. Evoked responses were recorded during dose response testing from multiple neck muscles, and the corresponding off-target nerve pathways were identified by sequential transection of nearby nerves. Results The following activated off-target muscle groups and their corresponding nerve pathways were verified which included 1) the cricoarytenoid via recurrent laryngeal nerve, 2) cricothyroid via superior laryngeal nerve, 3) sternocleidomastoid via accessory nerve, and 4) the tongue via hypoglossal nerve. The constrictor muscle group was also activated through a more complex neural pathway. Conclusion We identified multiple sources of therapy-limiting side-effects of BAT in the swine model. These results will help guide the design of improved stimulation electrodes, surgical placement, and parameter programming to reduce BAT-associated side-effects while increasing on-target activation in patients.

Interoceptive predictions are internal models that guide behavior by anticipating physiological needs based on past experiences and environmental cues. The paraventricular nucleus of the thalamus (PVT), which receives both interoceptive and exteroceptive inputs, is well-positioned to integrate these signals. Using fiber photometry and bulk calcium imaging in mice performing a reward-based linear maze task, we found that dopamine receptor 2-expressing PVT neurons (PVTD2R+) are engaged in behaviors leading to physiologically relevant outcomes, with their activity highly dependent on the interoceptive state of the mice and the expected outcome. Furthermore, we show that the chronic inhibition of PVTD2R+ neurons impairs the long-term performance of interoceptive-guided motivated behavior. Collectively, these findings identify PVTD2R+ neurons as critical integrators of internal states, external cues, and experiential factors, all of which contribute to interoceptive predictions that facilitate adaptive, goal-directed behavior.

Dexamethasone-loaded LPNs protect the cochlea from cisplatin.

Parvalbumin-expressing inhibitory neurons (PVNs) stabilize cortical network activity, generate gamma rhythms, and regulate experience-dependent plasticity. We found that PVNs act like a volume knob in the mouse auditory cortex (ACtx), bi-directionally adjusting neural and perceptual sensitivity to sound level over a 20 dB range. PVN-based gain adjustments were "sticky," such that a single bout of PVN activation at 40 Hz-but not at 1 or 70 Hz-sustainably dampened ACtx sound responsiveness, enhanced feedforward inhibition, and behaviorally desensitized mice to loudness. We then developed a mouse model of adult-onset hyperacusis by demonstrating ACtx hyperactivity, PVN hypofunction, and loudness hypersensitivity following a restricted noise-induced cochlear lesion. We found that several minutes of 40-Hz PVN stimulation in noise-exposed mice sustainably dampened ACtx hyperactivity and restored normal loudness sensitivity for 1 week. These findings demonstrate that sensory disorders caused by permanent peripheral injuries can be reversed by patterned stimulation of cortical circuits that directly regulate perception.

The inner hair cells (IHCs) in the inner ear form synapses with auditory nerve fibers (ANFs) that send sound signals to the brain. ANFs have been grouped by their level of spontaneous firing rates (SRs) into high-, medium-, and low-SR ANFs. Based on their molecular profiles evaluated by RNAseq experiments, ANFs have been divided into three groups (1A, 1B, and 1C) that likely correspond to high-, medium-, and low-SR ANFs, respectively. In guinea pigs, the synapses between IHCs and low-SR ANFs have been shown to be more vulnerable to noise exposure compared to other ANF subtypes, but not in a study performed in CBA/CaJ mice, questioning if these results can be generalized. Here, an LYPD1 reporter mouse model on a C57Bl/6J background with specifically labeled group 1C, low-SR ANFs was used to examine whether LYPD1 positive ANF synapses are more vulnerable to noise exposure. Six-week-old mice were exposed to an 8-16 kHz octave band noise presented at 100 dB-SPL for 2 h. One week later, cochlear tissue was harvested to quantify ANF synapses and compare the percentage of LYPD1 positive ANF synapses in noise-exposed and unexposed animals. Auditory brainstem response measurements were performed to assess hearing function after noise exposure. The number of all ANF synapses and the percentage of LYPD1-positive ANF synapses were reduced following noise exposure, concurrent with increased ABR thresholds and decreased ABR wave 1 amplitudes. The reduction in the percentage of LYPD1-positive ANF synapses specifically indicates greater vulnerability of LYPD1 positive ANF synapses to noise exposure compared to other ANFs in C57Bl/6J mice.

Cisplatin-based chemotherapy causes hearing loss in 40-60 % of all patients, yet effective preventative options remain limited. Building on prior animal studies, we demonstrate that oral administration of AZD5438, a potent and selective CDK2 inhibitor, provides dose-dependent protection against hearing loss in a clinically relevant multi-dose cisplatin mouse model. Protective doses (4.7 and 9.4 mg/kg b.i.d.) fall within the human-equivalent maximum tolerated dose range established in AstraZeneca trials, and exhibit plasma pharmacokinetics comparable to those in humans. Importantly, AZD5438 at 9.4 mg/kg b.i.d. does not reduce cisplatin's anti-tumor efficacy in a testicular cancer xenograft model, consistent with in vitro findings. These results support AZD5438 as a promising candidate for clinical trials to prevent cisplatin-induced hearing loss while preserving cancer treatment efficacy.

There is growing evidence that perceptual difficulties associated with age-related hearing loss are not solely due to cochlear damage and are exacerbated by central nervous system changes. We examined electrophysiological (EEG) responses to clicks and diffusion kurtosis imaging in 49 older (29 female) and 26 younger (20 female) adults to determine the extent to which auditory nerve (AN) deficits in older adults contributed to functional and structural changes throughout the auditory system. Older adults exhibited smaller AN responses, similar brainstem responses, and larger auditory cortex (AC) responses, demonstrating progressive "central gain." Audiometric thresholds were not predictive of EEG measures. Reduced AN function predicted deficits in cortical microstructure (lower AC fractional anisotropy) in older adults, consistent with microstructure degeneration. These lower fractional anisotropy values in the AC of older adults also predicted larger AC responses and more central gain. Older adults exhibited significantly lower AC fractional anisotropy and kurtosis fractional anisotropy coupled with higher mean and radial diffusivity compared to younger adults. AC fractional anisotropy, radial diffusivity, axial diffusivity, and mean diffusivity were all significant predictors of speech-in-noise (SIN) recognition in older adults. The results suggest that reduced afferent input in older adults not only results in functional changes throughout the auditory system consistent with progressive gain but also contributes to deficits in AC structure beyond those explained by age alone, contributing to SIN recognition deficits. Understanding the complex effects of age, reduced AN input, central gain, and AC microstructure on SIN recognition may provide potential therapeutic targets for intervention.

Hearing loss is the most common sensory organ disorder, with genetic factors contributing substantially to the disease. Among the 87 genes responsible for autosomal recessive nonsyndromic hearing loss, mutations in MPZL2 have been frequently linked to mild-to-moderate autosomal recessive hearing loss (DFNB111). Here, we present multiple families whose hearing loss arose from biallelic mutations in the MPZL2 gene and found that the MPZL2 p.Q74∗ mutation may be a founder allele among East Asians. Furthermore, we generated an Mpzl2 p.Q74∗ knockin mouse model that exhibited autosomal recessive, progressive, ski-sloping hearing loss with Deiter's cell degeneration. Gene supplementation using AAV-DJ or AAV-PHP.eB to deliver human MPZL2 (hMPZL2) under control of the CAG promoter induced ototoxicity, whereas employing an alternative EF1α promoter with AAV-DJ (DJ-EF1α-hMPZL2) circumvented this issue, restoring long-term auditory function and Deiter's cell survival in Mpzl2Q74∗/Q74∗ mice for up to 24 weeks. Overall, this study provides the foundational steps for developing a safe and effective biological treatment for DFNB111 and underscores the importance of precise regulation of target cells and transgene expression in AAV-based treatments.

Objective: The vibratory source for voicing in children with dysphonia is classified into three categories including a glottal vibratory source (GVS) observed in those with vocal lesions or hyperfunction; supraglottal vibratory sources (SGVS) observed secondary to laryngeal airway injuries, malformations, or reconstruction surgeries; and a combination of both glottal and supraglottal vibratory sources called mixed vibratory source (MVS). This study evaluated the effects of vibratory source on three primary dimensions of voice quality (breathiness, roughness, and strain) in children with GVS, SGVS, and MVS using single-variable matching tasks and computational measures obtained from bio-inspired auditory models. Methods: A total of 44 dysphonic voice samples from children aged 4-11 years were selected. Seven listeners rated breathiness, roughness, and strain of 1000-ms /ɑ/ samples using single-variable matching tasks. Computational estimates of pitch strength, amplitude modulation filterbank output, and sharpness were obtained through custom-designed MATLAB algorithms. Results: Perceived roughness and strain were significantly higher in children with SGVS and MVS compared to children with GVS. Among the computational measures, only the modulation filterbank output resulted in significant differences among vibratory sources; a posthoc test revealed that children with SGVS had greater amplitude modulation than children with GVS, as expected from their rougher voice quality. Conclusions: The results indicate that the output of an auditory amplitude modulation filterbank model may capture characteristics of SGVS that are strongly related to the rough voice quality.

In birds, detection of sound source azimuth begins in the nucleus laminaris (NL), which computes interaural time differences (ITDs). Inhibition has been proposed to protect NL neurons from losing ITD sensitivity with increasing sound level, although the nature of this inhibition is incompletely understood. Anatomical studies show GABAergic synapses throughout NL and first order nuclei, while in vitro studies in chicken NL showed that GABAergic inhibitory postsynaptic potentials (IPSPs) shorten membrane time constants, perhaps to allow the membrane potential to follow rapid synaptic currents accurately over a range of sound levels. Given the importance of inhibition in regulating auditory brainstem activity, we examined the nature of inhibitory input to NL in vivo. The Superior Olivary Nucleus (SON) is the major source of descending GABAergic inhibition to the ipsilateral nucleus magnocellularis (NM), nucleus angularis (NA) and NL, and receives excitatory input from NA and NL. We used viral tracers to reveal projections from SON to NL, and characterized response types within SON. In NL, we isolated inhibitory synaptic contributions from extracellular field potentials through the iontophoretic application of blockers of GABA (gabazine) or glycine (strychnine). These blockers increase onset and offset responses evoked by tonal stimuli, but did not shift best ITD. The co-application of gabazine and strychnine revealed supra-linear summation of GABA and glycine. Profiles of synaptic activation revealed more prominent inhibition following stimulus offset, suggesting inputs to NL originate from both sustained and offset response types of the SON. These heterogeneous responses may represent separate SON neuronal populations. Together, our results support the role of SON inhibition in increasing the dynamic range of ITD tuning of NL neurons.

Objective: The purpose of this paper is to present a chronic, preclinical, pilot study of a multi-electrode auditory nerve implant. To date, the most successful auditory neuroprosthesis is the cochlear implant, but these devices have known limitations. Intraneural stimulation of the auditory nerve is a promising alternative, but preclinical investigations of multi-electrode devices have been limited to acute or semi-chronic studies. Methods: Six cats were chronically implanted in the right auditory nerve with a 15-channel Utah Slant ArrayTM. The array's position in the internal auditory canal was confirmed using computed tomography. Electrode impedance and evoked responses were recorded regularly during the indwelling period to evaluate performance. Results: Two of the six implants met endpoint criteria at 6 months, with stable electrode impedances and robust evoked responses on at least 50% of their channels. Another two implants exhibited stable electrode impedances, but activation thresholds increased over three months. Two implants failed within the first two weeks due to device migration caused by connector-related issues. Conclusion: This study reports the first successful chronic deployment of an multi-electrode auditory nerve implant in a preclinical model. Two implanted cats exhibited stable chronic performance, marked by a consistent set of electrodes capable of eliciting evoked responses. The failure modes of the remaining four cats are discussed and recommendations are made to stabilize implant placement. The study lays a solid foundation for future chronic safety and efficacy investigations as part of an effort to translate this new neuroprosthetic technology into the clinic.

Deep neural network (DNN)-based noise reduction has emerged as a promising advancement in hearing aid signal processing as a means to improve speech intelligibility in noisy environments for hearing aid wearers. The aim of this study was to investigate the impact of the DNN on speech intelligibility in speech-shaped noise (SSN) and multitalker babble (MTB) when the target speech was coming from the front and from the side. Subjective ratings of clarity, total impression, listening effort, and background noise awareness were also collected. Twenty adult participants with mild to moderately severe sensorineural hearing loss were fitted with hearing aids from a single manufacturer, programmed with four different settings that varied across combinations of microphone directionality (omnidirectional and directional beamforming) and noise reduction (off, traditional, DNN). Results showed that DNN, when combined with beamforming, consistently outperformed the other programs across all metrics. Outcomes were influenced by both noise type and spatial configuration. DNN was more effective in SSN than MTB. Beamforming was especially beneficial when the target speech came from the front. Listening in programs that included both DNN and beamforming together resulted in additional benefits shown in the outcome measures, most likely due to the beamforming improving the signal-to-noise ratio and providing a cleaner signal for the DNN to work with.

Everyday listening often requires the auditory system to move beyond the perception of individual sound sources towards a more global representation of acoustic scenes. While auditory behaviour has been well characterised for one or a few sources, it remains unclear how listeners perceive scenes containing many simultaneous sounds. As multiple sound sources combine into a single acoustic mixture, separating individual sources becomes increasingly difficult, potentially requiring listeners to rely on summary representations rather than discrete object-based parsing. Auditory numerosity judgement , the ability to estimate how many distinct sound sources are present, can provide a way to probe how listeners perceive such complex acoustic scenes. Here, we measured numerosity judgements along the three dimensions of auditory space: azimuth, elevation, and distance, allowing each spatial axis to be examined in isolation. As these dimensions rely on markedly different spatial cues and differ strongly in spatial acuity, this design enabled the dissociation of spatial and non-spatial contributions to numerosity perception. Across dimensions, numerosity judgements showed no systematic relationship with individual spatial hearing performance. Speech intelligibility likewise exerted only a weak influence. In contrast, perceived numerosity was significantly modulated by the spectrotemporal coverage of the acoustic mixture, a summary statistic independent of spatial dimension or higher-lever linguistic factors. Together, these findings suggest that auditory numerosity judgement is largely insensitive to spatial hearing precision and instead reflects more general principles of how complex sound mixtures are represented at the scene level.

Basal forebrain cholinergic neurons (BFCNs) densely innervate auditory cortex (ACtx), conveying signals linked to internal brain states and external sensory cues. Acetylcholine (ACh) is known to rapidly modulate cortical circuits through nicotinic ACh receptor (nAChR)-mediated activation of layer 1 inhibitory neurons (L1-INs). However, BFCN terminals are also abundant in deeper layers, where their functional impact has received less attention. Using multi-plex in situ labeling across cortical layers and cell types, we found that layer 6 pyramidal neurons (L6-PNs) are highly enriched in diverse transcripts for nAChR subunits and muscarinic ACh receptors (mAChRs). In vivo optogenetic activation of BFCN axons revealed persistent modulation of regular spiking units in L2-6 but a rapid phasic activation only in L6. In acute slices, optogenetic activation of BFCN axons elicited fast nAChR-mediated excitatory post-synaptic potentials in L6-PNs, comparable to responses in L1-INs, and slower mAChR-mediated inhibitory responses. These findings identify L1-INs and excitatory L6-PNs as two major hubs for BFCN modulation of cortical circuits. By recruiting distinct receptor mechanisms and circuit motifs in L1 and L6, BFCNs may engage parallel pathways of cholinergic control that couple fast, transient modulation with slower, sustained regulation to shape cortical perception and plasticity.

Auditory evoked responses undergo notable changes during childhood, likely reflecting modifications in synaptic signaling in the auditory cortex. Particularly robust response, observed around 200 to 300 ms post stimulus (N/M250), has been consistently reported in children but is absent in adults. This long-latency response, evoked even in passive listening conditions, may indicate heightened sensory pathway responsiveness, facilitating experience-driven cortical plasticity. However, it remains unclear whether this delayed activation pattern is an intrinsic, species-general feature of brain development. We recorded cortical auditory evoked responses to monaural sine-wave tones/click sounds in 3 age groups (preadolescents, adolescents, and young adults) of human subjects and rats. Following short-lived early responses, both species exhibited a long-latency (150 to 450 ms) response in the auditory cortex. In both species, the relative amplitude of the long-latency response, compared to early responses, was increased in younger individuals. In human children, single-trial analysis demonstrated more consistent trial-by-trial timing of the response in this later time window than in the adult-typical 100-ms response in the earlier time window. Given its emergence in purely passive conditions, and across species, the robust current activity in late time window could represent a distinct synaptic event and may serve as a marker of the maturational stage, particularly in GABAergic cortical circuits.

Speech production entails several processing steps that encode linguistic and articulatory structure, but whether these computations correspond to spatiotemporally discrete patterns of neural activity is unclear. To address this issue, we use electrocorticography to directly measure the brains of neurosurgical participants performing an interactive speech paradigm. We observe a broad range of cortical modulation profiles, and subsequent clustering analyses establish that responses comprised distinct classes associated with sensory perception, planning, motor execution, and task-related suppression. These activity classes are also localized to separate neural substrates, indicating their status as specialized networks. We then parse dynamics in the planning and motor networks using unsupervised dimensionality reduction, which reveals subnetworks that are sequentially active throughout preparation and articulation. These results therefore support and extend a localizationist model of speech production where cortical activity "flows" within and across discrete pathways during language use.

Introduction: Learning-induced cortical reorganization is facilitated by neuromodulator release. However, the precise temporal relationship between neuromodulator release and neural activity required to induce plasticity is not well understood. In single synapses, eligibility traces regulate plasticity such that neuromodulator arrival must occur within seconds of activity. Cortical plasticity can also be induced by pairing neuromodulator release with neural activity, but it is unknown whether plasticity in populations of neurons is regulated by the same temporal constraints. Methods: To determine whether the synaptic eligibility trace regulates cortical plasticity, we used vagus nerve stimulation (VNS) to drive neuromodulator release 3 s before, 1 s before, concurrent with, or 3 s after tone-evoked activity in auditory cortex. After 20 days of pairing, we used in vivo electrophysiology to quantify the proportion of auditory cortex responding to the paired tone frequency. Results: We found that VNS 1 s before or concurrent with tone onset significantly expanded the representation of the paired tone frequency (-1s, p = 0.04; 0s, p = 0.02), whereas 3 s before or after did not (-3s, p = 0.87; +3s, p = 0.53). Confirming the role of neuromodulators in this eligibility trace, we found that depletion of norepinephrine prevented VNS-tone pairing-induced plasticity (0s + DSP4, p = 0.23). Discussion: Our study demonstrates that cortical plasticity is regulated by time constraints similar to the synaptic eligibility trace and highlights the importance of considering the timing of neuromodulator release when employing methods to enhance plasticity.