Publications using TDT

Repeated exercise produces robust physiological benefits and is the leading lifestyle intervention for human health. The benefits from exercise training result from the remodeling of skeletomuscular, cardiovascular, metabolic, and endocrine systems. In mice, we find that activation of the central nervous system following exercise is essential for subsequent endurance performance and metabolism benefits. Ventromedial hypothalamic steroidogenic factor-1 (SF1) neurons are activated following exercise, and repeated training results in increased post-exercise SF1 neuron activation. Exercise training increases the intrinsic excitability and density of excitatory synapses on SF1 neurons, suggesting that exercise history is encoded through hypothalamic plasticity. Inhibition of SF1 neuron output blocks endurance gains and metabolic improvements that result from exercise training. Conversely, stimulation of SF1 neurons following exercise enhances gains in endurance. These results demonstrate that exercise-induced hypothalamic SF1 neuron activity is essential for the coordination of physiological improvements following exercise training.

Sound is essential for threat detection. In many animals, salient sounds trigger defensive behaviors, suggesting an innate negative valence. Here, we examined how salient noise is represented in dopaminergic circuits encoding valence and saliency. In the nucleus accumbens (NAc), dopamine decreased during noise presentation in all subjects, with a subset additionally showing a transient increase at noise onset. Dopaminergic fibers from the ventral tegmental area showed corresponding patterns in the NAc. In the tail of the striatum (TS), dopamine increased in response to noise, also suggesting negative valence coding. For ramped and damped noises, dopamine dynamics are related to the temporal profile of sound intensity. Neural activity increased in both NAc and TS during noise. Together, these findings suggest that dopaminergic signaling in the NAc and TS represents noise intensity with negative valence, while NAc dopamine also reflects perceived saliency and may contribute to defensive behaviors evoked by auditory stimuli.

Repetitive transcranial magnetic stimulation (rTMS) is an emerging treatment for brain disorders, but its therapeutic mechanism is poorly understood. We developed a mouse model of rTMS with superior clinical face validity and investigated the neural mechanism by which accelerated intermittent theta burst stimulation (aiTBS), the first rapid-acting rTMS antidepressant protocol, reversed chronic stress-induced behavioral deficits. Using fiber photometry, we showed that aiTBS drives distinct patterns of neural activity in intratelencephalic (IT) and pyramidal tract (PT) projection neurons in dorsomedial prefrontal cortex (dmPFC). However, only IT neurons exhibited persistently increased activity during both aiTBS and subsequent depression-related behaviors. aiTBS reversed stress-related loss of dendritic spines on IT, but not PT neurons, further demonstrating cell type-specific effects of stimulation. Chemogenetically inhibiting dmPFC IT, but not PT neurons, during rTMS blocked the antidepressant-like behavioral effects of aiTBS. Thus, we demonstrate a prefrontal mechanism linking rapid aiTBS-driven therapeutic effects to cell type-specific circuit plasticity.

Low-frequency interaural time differences (ITDs) are the primary human horizontal-plane localization cue. Across-frequency binaural interference tasks, which assess changes in ITD sensitivity in the presence of a remote interferer, reveal how listeners weigh binaural information across frequency regions. Low-frequency (0.5-kHz) targets experience less interference from high-frequency (4-kHz) interferers compared to the reverse, but the role of relative signal level across frequencies remains relatively underexplored. This study measured ITD discrimination thresholds in ten young normal-hearing listeners using target and interferer frequencies of 0.5, 4, and 8 kHz and levels of 35, 55, and 75 dB-A. Binaural interference magnitude depended on both stimulus level and frequency. For a 4-kHz target and 0.5-kHz interferer, interference significantly increased with increasing interferer and decreasing target levels. For a 0.5-kHz target and 4-kHz interferer, interference significantly increased with increasing interferer level when the target level was 35 dB-A, but was unchanged when the target level was 55 or 75 dB-A. The resistance to binaural interference for the low-frequency target at higher target levels confirms the robustness of low-frequency ITD processing and highlights the level-dependent vulnerability of high-frequency targets to interference. This helps advance understanding of spatial hearing for complex stimuli in more realistic auditory scenes.

Quickly adapting behavior to changing environments is key for survival. Brain dopamine signals reinforce actions that procure rewards and avoid adverse outcomes. However, the molecular mechanisms within the circuits that actuate these signals at subsecond timescales remain unexplored. We show that midbrain endocannabinoid mobilization is the conditio sine qua non for behavioral invigoration evoked by external cues. Reward- and punishment-predictive signals require intact retrograde release of the endocannabinoid 2-arachidonoylglycerol (2-AG) from ventral tegmental area dopamine neurons. Moreover, we show that genetic deletion of presynaptic cannabinoid type-1 receptors (CB1Rs), the target for 2-AG, recapitulates behavioral and dopaminergic deficits. Exploiting causal inference tools to interpret continuous brain signals, we describe that 2-AG/CB1R communication is essential for striatal dopamine release to signal salient cues and propel conditioned responding. These findings reveal an endocannabinoid-mediated disinhibition mechanism exploited by dopamine neurons to orchestrate striatal dopamine release events, enabling adaptive action selection informed by cues.

Stimulus-specific adaptation is a key feature of sensory systems, where the repeated presentation of a stimulus results in diminishing neuronal responses specifically to that stimulus, but not to a different stimulus. Cortical neurons display varying degrees of stimulus-specific adaptation, with cortical circuits shaping the dynamics of these responses. Here, we use calcium imaging and optogenetic approaches to assess the contributions of SOM and PV neurons to stimulus-specific adaptation in the mouse auditory cortex. We find opposing and complementary effects of SOM and PV neurons on the adaptation of principal neurons which manifest as context-dependent SOM neuron-mediated enhancement and PV-neuron mediated suppression of responses that depend on the temporal repetition rate of the sounds. Our results suggest that SOM and PV neurons can engage in multiple operating regimes that exist in a continuum during sensory processing.

Post-stroke spasticity (PSS), characterized by hyperreflexia and spastic hypertonia, is a common and debilitating consequence of cerebrovascular injury that impedes motor recovery. Despite its prevalence, the neurophysiological mechanisms underlying PSS remain poorly understood, partly due to the lack of reliable animal models. A known clinical correlate of spasticity is weakened rate-dependent depression (RDD) of the Hoffman reflex (H-reflex), particularly in the upper limbs of chronic stroke patients. However, the mechanistic basis of RDD impairment and its relationship to brain lesion characteristics remain unclear. Here, we characterized the longitudinal progression of H-reflex RDD in a wrist flexor muscle following photothrombotic stroke in mice and examined its association with lesion volume across cortical and subcortical regions using magnetic resonance imaging. RDD was significantly reduced 2-3 weeks after stroke, indicating hyperreflexia. Approximately 60% of stroke mice exhibited weakened RDD. Notably, lesion volumes in contralateral primary (M1) and secondary (M2) motor cortices correlated positively with RDD impairment, linking greater cortical damage to more severe reflex hyperexcitability. These results suggest that damage to motor cortical regions disrupts central reflex-modulating pathways, contributing to post-stroke hyperreflexia. The presented stroke model provides a valuable platform for mechanistic investigations of PSS and for evaluating potential therapeutic interventions.

Background: Firefighters search for survivors in low-visibility environments and have documented expertise in spatial orientation and wayfinding. No studies so far have investigated their ability to make use of auditory spatial cues. Methods: The performance of 41 professional firefighters and 24 control subjects to localise sounds played in a dark environment at 9 azimuthal positions was assessed using (i) meaningless single sounds and (ii) meaningful sounds presented with two simultaneous distractors. Localisation errors were analysed with a 3-way ANOVA Task × Position × Group. Results: The analysis yielded significant main effects of Task, Position and Group. The localisation errors tended to be smaller when localising meaningless single sounds (main effect Task), for items presented at central as compared to peripheral positions (main effect Position), and by firefighters rather than controls (main effect Group). The interactions Position × Group and Task × Position were significant; firefighters performed more accurately at peripheral positions than controls, and meaningless single sounds yielded fewer localisation errors at the periphery than meaningful sounds presented with distractors. Conclusions: Professional firefighters perform better than controls at explicit localisation of sounds, including in conditions where sound objects need to be segregated from distractors by spatial cues. These results suggest that firefighters have acquired expertise in the explicit and implicit use of auditory spatial cues. The proficiency of firefighters needs to be taken into consideration when planning and carrying out interventions.

Interictal epileptiform discharges (IEDs) are pathological bursts of brain activity between seizures in people with epilepsy. Despite their importance in diagnosis, cognitive comorbidities and therapeutic implications as biomarkers for neurostimulation, it is unknown how IEDs arise from structured large-scale neuronal firing across human cortical lamina. We used high-density Neuropixels probes to record from epileptogenic tissue in patients undergoing resective surgery, sampling 1,152 neurons during 1,094 IEDs across nine neocortical sites. We identified microcircuits for IEDs organized by firing pattern, neocortical depth and putative cell type. Regular-spiking cells, concentrated in superficial cortical lamina, initiated and coded the amplitude of the sharp discharge and excitatory–inhibitory imbalances across neocortical lamina preceded IEDs, enabling IED prediction up to 1,000 ms in advance. Most neurons that were modulated during IEDs also encoded cognitive information and adhered to physiological rhythms at baseline. Thus, neocortical IEDs are generated from predictable laminar–cellular interactions, providing the groundwork for new neurostimulation therapies that harness the granularity of single neurons.

SLC26A4 is a major causative gene for hereditary hearing loss, its mutation spectrum shows pronounced population specificity. In Chinese populations, patients predominantly carry biallelic mutations, and compound heterozygous genotypes are prevalent, which results in a wide spectrum of auditory phenotypes. However, how different alleles interact within these contexts to shape phenotypic variability remains poorly understood. We employed cellular and mouse models to explore the allele-specific mechanisms associated with two novel mutations, a frameshift mutation and a missense mutation, in compound heterozygous that share the same splice-site pathogenic allele. In vitro, wild-type (WT) and mutant (c.574delC, c.1211C>A) SLC26A4 constructs were expressed in HeLa cells to assess pendrin localization. Both mutations reduced membrane enrichment and increased intracellular retention. In vivo, compound heterozygous knock-in mouse models (Slc26a4c.574delC/c.919-2A>G and Slc26a4c.1211C>A/c.919-2A>G) were generated using CRISPR/Cas9. The auditory function and cochlear pathology were investigated. Both compound mutants exhibited elevated ABR thresholds, with more severe hearing loss in Slc26a4c.574delC/c.919-2A>G mice. Correspondingly, these mice showed marked hair cell disruption, stereociliary loss, and cochlear structural abnormalities, whereas the Slc26a4c.1211C>A/c.919-2A>G mice displayed milder changes. Transcriptomic profiling examined by bulk RNA-sequencing revealed broader differential expression in Slc26a4c.574delC/c.919-2A>G mice, enriched in structural and developmental pathways, while the missense model showed predominantly immune-related signatures. Our findings demonstrate that allele-specific functional divergence in compound heterozygous SLC26A4 mutations leads to distinct auditory dysfunction, cochlear pathology, and transcriptional programs. These findings provide mechanistic insight into the phenotypic heterogeneity of hearing loss and may indicate future allele-specific interventions or therapeutic strategies.

The cortex generates diverse neural dynamics, ranging from broadband fluctuations to narrowband oscillations at specific frequencies. Here, we investigated whether broadband and oscillatory dynamics play different roles in the encoding and transmission of visual information. We used information-theoretical measures to dissociate neural signals sharing common information (i.e., redundancy) from signals encoding complementary information (i.e., synergy). We analyzed electrocorticography (ECoG) and local field potentials (LFP) in the visual cortex of human and non-human primates (macaque) to investigate the extent to which broadband signals (BB) and narrowband gamma (NBG) oscillations conveyed synergistic or redundant information about images. In both species, the information conveyed by BB signals was highly synergistic within and between visual areas. By contrast, the information carried by NBG was primarily redundant within and between the same visual areas. Finally, the information conveyed by BB signals emerged early after stimulus onset, while NBG sustained information at later time points. These results suggest a potential dual role of BB and NBG cortical dynamics in visual processing, with broadband dynamics supporting nonlinear pattern recognition and oscillations facilitating information maintenance across the cortex.

Oncomodulin (OCM) is the most abundant Ca2+ buffering protein found in mature outer hair cells (OHCs). Cadherin 23 (CDH23) is a crucial component of the tip-links in hair cell stereocilia. The absence or dysfunction of these two proteins contributes to the early onset of age-related hearing loss (AHL). In this study, we investigated the effects of the Cdh23753G→A mutation on OHC function using new Ocm-knockout (KO) mouse models (Ocmtm1a/tm1a) with or without the Cdh23753G→A mutation. Despite having the same genetic background, Ocm-KO mice carrying the Cdh23753G→A mutation displayed a notable decline in OHC function across all measured frequencies as early as three months of age. In contrast, Ocm-KO mice without the Cdh23753G→A mutation did not exhibit comparable hearing loss until they reached twelve months of age. Additionally, we examined the role of OCM in preserving OHC function under ototoxic stress induced by HPβCD (2-hydroxypropyl-β-cyclodextrin). The distortion product otoacoustic emission data show that the administration of HPβCD resulted in a more pronounced decline in OHC function in Ocm-KO mice compared to wild-type (WT) mice. Time-lapse recording also shows that HPβCD treatment led to greater structural deterioration and more rapid rupture events in OHCs from Ocm-KO mice than in those from WT mice. These findings suggest that the Cdh23753G→A mutation, rather than other potential strain-specific genetic factors associated with AHL, significantly exacerbates the early onset of AHL phenotypes in Ocm-KO mice. Furthermore, our data indicates that the OCM protein in OHCs enhances their ability to withstand ototoxic stimuli.

The CUGBP Elav-like family 4 (CELF4), an RNA-binding protein, is dynamically expressed in spiral ganglion neurons (SGNs) in the cochlea over development, but how Celf4 is involved in regulating hearing functions is poorly understood. In this study, we generated a Celf4 ± mouse line and examined changes in the first two synapses along the auditory pathways. Firstly, we found that hearing functions were largely intact in Celf4 ± mice, with exception of reduced amplitude for Wave II of auditory brainstem responses (ABRs) and increased delays for Wave II and IV, both in case of 4 kHz only. Secondly, we found that counts of inner and outer hair cells (IHCs and OHCs) and SGNs remained unchanged in Celf4 ± mice, and that the number and function of ribbon synapses between IHCs and SGNs were comparable between WT and Celf4 ± mice. Lastly, function of the endbulb of Held synapse, formed between auditory nerve fibers (ANFs) of SGNs and bushy cells in the cochlear nucleus, was significantly altered in Celf4 ± mice. Specifically, synaptic vesicle release was subtly reduced, and excitability of bushy cells was significantly dampened, likely due to a hyperpolarized resting membrane potential. Furthermore, we found that spike kinetics was significantly faster in Celf4 ± bushy cells, likely caused by a larger fast-inactivating A-type potassium current (I A ) found in these cells. In conclusion, we found that Celf4 haploinsufficiency altered transmission at the endbulb of Held synapses in the cochlear nucleus in a significant and multifaceted manner, revealing the roles of Celf4 in regulating hearing functions. Graphical Abstract Title: Schematic representation of the experimental approach and major findings. Legend: In mice with Celf4 haploinsufficiency, we found that while function at hair cell ribbon synapses was largely preserved, transmission at the endbulb of Held synapse was significantly altered, including subtly reduced release of synaptic vesicles from the endbulb, dampened excitability in bushy cells, and accelerated spike kinetics caused by enhanced voltage-gated K + current.

Our ability to generalize abstract rules to new situations is a cognitive hallmark, yet its neural basis is unclear. We identified a thalamocortical circuit essential for this process in mice. During a cross-modal rule transfer task, medial prefrontal cortex (mPFC) neurons encoded task rules across sensory modalities to enable generalization. Crucially, mediodorsal thalamus (MD) projections to mPFC were causally required: Inhibiting this pathway destabilized mPFC representations and impaired rule transfer, whereas enhancing it improved performance. Without MD input, mPFC recruited distinct populations for each task, losing cross-context stability. Direct mPFC excitation impaired generalization, underscoring the specificity of thalamic regulation. Thus, the MD stabilizes mPFC activity for flexible rule transfer—a mechanism with implications for cognitive disorders and artificial intelligence.

Parkinson’s disease (PD) is marked by impairments in voluntary movement, including prolonged movement preparation and execution, yet how parkinsonism alters neural processing to produce these deficits remains unresolved. Prior work examining M1 spiking activity in parkinsonian states has largely characterized firing-rate changes and motor representations at the level of individual neurons, with inconsistent results and limited insight into population-level organization. Here we investigated how parkinsonism reshapes the population-level organization of neural activity in M1 during movement. We simultaneously recorded large populations of neurons from M1 in two nonhuman primates performing reaching tasks before and after induction of parkinsonism with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In the parkinsonian state, both preparation and reach durations were significantly prolonged. Population-level analyses revealed that parkinsonism increased the dimensionality of M1 activity during both preparation and movement and reduced the orthogonality between preparatory and movement-related subspaces. Moreover, trial-by-trial variability in reach duration was explained by the alignment of the preparatory and reach subspaces, indicating the functional role of subspace orthogonality. Together, these findings suggest that parkinsonism disrupts the population-level organization of cortical dynamics across computations, providing a population-level framework linking altered cortical dynamics to the movement-related dysfunction observed in PD.

Activity-dependent modulation of presynaptic voltage-gated Ca 2+ channels (Ca V 2) regulates Ca 2+ influx to control neuronal circuit output. Although Ca V 2.1 can undergo robust Ca 2+ dependent facilitation (CDF), whether it occurs in native central nervous system neuronal circuits is disputed. Accurate auditory information processing requires precise and reliable synaptic transmission at high activity rates in the auditory brainstem. To determine if Ca V 2.1 CDF is a key regulator of high-fidelity synaptic transmission, we expressed Ca V 2.1 splice variants capable (Ca V 2.1 37a) or incapable (Ca V 2.1 37b) of CDF at the calyx of Held presynaptic terminal in the auditory brainstem. We found no difference in basal Ca V 2.1 currents or synaptic transmission. However, Ca V 2.1 37b terminals lacked CDF, synaptic facilitation and had a decreased reliability and precision of postsynaptic action-potential firing. Additionally, the Wave III amplitude of the auditory brainstem responses was reduced. We propose that Ca V 2.1 CDF is essential for accurate auditory information processing.

Cochlear implants (CIs) have successfully restored hearing in more than one million patients with severe to profound hearing loss worldwide. Although CIs effectively restore speech perception in quiet environments, sound localization remains challenging for bilateral CI users, particularly their ability to utilize interaural time differences (ITDs). The majority of clinical CI processors use a coding strategy that encodes ITD information only in the envelope of electrical pulse trains rather than their pulse timing, which may contribute to the poorer spatial hearing perception of CI users. We recently demonstrated in a behavioural study on early deafened, bilaterally CI‐implanted rats that pulse timing ITDs completely dominate ITD perception, whereas sensitivity to envelope ITDs is almost negligible in comparison. Building on this, we here investigated the neurophysiological sensitivity of the inferior colliculus (IC) to envelope and pulse timing ITDs at two different pulse rates (900 and 4500 pulses/s) and three different stimulation modulations (5, 20 and 100 Hz) in CI rats with different hearing experiences. Our results indicate that IC neurons exhibit far greater sensitivity to pulse timing ITD than envelope ITD independent of pulse rate, modulation rate or hearing experience. These findings suggest that to improve binaural hearing outcomes in bilateral CI users, clinical stimulation strategies should provide informative pulse timing ITDs. image Key points Current bilateral cochlear implants mostly provide time cues of arriving sound in the envelope of stimulation rather than in the timing of pulses. A behavioural study on cochlear implanted rats has shown that pulse timing dominates binaural hearing. Here we examined the neural sensitivity to independent changes in time cues presented on the envelope or pulse timing, respectively, in rats with bilateral cochlear implants and different hearing experiences. Auditory midbrain neurons were consistently more sensitive to changes in pulse timing rather than envelope, irrespective of stimulus pulse rate, modulation rate or an animal's hearing experience.

Internal states including stress and satiety, affect cue-induced feeding behaviors, yet the underlying neural mechanisms remain poorly understood. The nucleus of the solitary tract (NTS), a key hindbrain hub that integrates interoceptive and viscerosensory signals and projects to reward processing nuclei, is anatomically well-positioned to modulate cue-induced feeding behaviors in response to internal state changes. Using behavioral paradigms combined with chemogenetics and fibre photometry, this study investigated the hypothesis that NTS mediates the effects of stress and satiety on cue-induced feeding behaviors via A2 neurons and modulation of ventral tegmental area (VTA) dopamine signaling. We first showed that both foot shock stress and outcome specific satiety (i.e., sucrose prefeed) reduced cue-induced appetitive behavior. Inhibition of NTS neurons only attenuated the suppressive effect of foot shock stress, but not that of outcome specific satiety, indicating that NTS is required for stress-induced suppression of cue-induced appetitive behavior. Further investigation into the contributing neural phenotype revealed that stimulation of NTS A2 neurons reduced conditioned approach and suppressed cue-evoked VTA dopamine neural activity, without any effects on lateral hypothalamus (LH) neuron activity. Together, these findings suggest that NTS neurons mediate the effects of foot shock stress, but not outcome specific satiety, on cue-induced appetitive behavior, in part through activation of NTS A2 neurons and modulation of cue-evoked VTA dopamine neural activity. These results provide an NTS-mediated mechanism through which stress suppresses cue-induced feeding behavior.

Motor skill learning is a complex and gradual process that involves the cortex and basal ganglia, both crucial for the acquisition and long-term retention of skills. The cerebellum, which rapidly learns to adjust the movement, connects to the motor cortex and the striatum primarily via the ventral and intralaminar thalamus, respectively. Here, we evaluated the contribution of cerebellar neurons projecting to these thalamic nuclei in a skilled locomotion task in mice. Using a targeted chemogenetic inhibition that preserves the motor abilities, we found that cerebellar nuclei neurons projecting to the intralaminar thalamus contribute to learning and expression, while cerebellar nuclei neurons projecting to the ventral thalamus contribute to offline consolidation. Asymptotic performance, however, required each type of neurons. Thus, our results show that cerebellar neurons belonging to two parallel cerebello-thalamic pathways play distinct, but complementary, roles functioning on different timescales and both necessary for motor skill learning.

Background Transcranial electrical stimulation (TES) has limited spatial focus and depth penetration, constraining its therapeutic efficacy. Intersectional Short-Pulse (ISP) stimulation was developed to overcome these limitations by delivering rapidly switching pulses that can be temporally integrated by neuronal membranes. Here, we aimed to establish the biophysical basis of ISP-induced temporal summation and to test whether this mechanism enables effective brain modulation in vivo. Methods We combined finite-element modeling, cadaver measurements ( n = 2 human cadavers), and biophysically realistic NEURON simulations to characterize the spatial and temporal properties of ISP-induced electric fields. In vivo whole-cell patch-clamp recordings were performed in the rat somatosensory cortex (female Wistar rat) to test the membrane-level integration of sequential electric field pulses. Functional efficacy was evaluated using closed-loop ISP stimulation in a hippocampal kindling model of temporal lobe epilepsy in male Long–Evans rats ( n = 11 animals, >500 induced seizures analyzed across conditions). Results Here we show that neurons integrate sequential ISP pulses in a non-vectorial, temporally accumulative manner, consistent with membrane-level charge integration rather than extracellular field superposition. ISP and conventional TES simulations produced similar instantaneous field magnitudes, but ISP stimulation resulted in more uniform neuronal excitability across brain depths. Closed-loop ISP stimulation significantly outperformed conventional TES in reducing seizure duration and severity. ISP reduced hippocampal seizure duration by 45% and 35% compared to SHAM stimulation and conventional TES, and significantly reduced motor seizure severity. Conclusions ISP stimulation provides a non-invasive neuromodulation approach that enhances deep brain engagement through rapid, temporally structured pulse sequences. These findings demonstrate effective seizure suppression in a rodent model and support the translational potential of ISP for disorders involving pathological neural dynamics.