Publications using TDT

Human decision-making involves model-free and model-based reinforcement learning (RL) strategies, largely implemented by prefrontal-striatal circuits. Combining human brain imaging with neural network modelling in a probabilistic reversal learning task, we identify a unique role for the mediodorsal thalamus (MD) in arbitrating between RL strategies. While both dorsal PFC and the striatum support rule switching, the former does so when subjects predominantly adopt model-based strategy, and the latter model-free. The lateral and medial subdivisions of MD likewise engage these modes, each with distinct PFC connectivity. Notably, prefrontal transthalamic processing increases during the shift from stable rule use to model-based updating, with model-free updates at intermediate levels. Our CogLinks model shows that model-free strategies emerge when prefrontal-thalamic mechanisms for context inference fail, resulting in a slower overwriting of prefrontal strategy representations - a phenomenon we empirically validate with fMRI decoding analysis. These findings reveal how prefrontal transthalamic pathways implement flexible RL-based cognition.

Neuronal synchronization refers to the temporal coordination of activity across populations of neurons, a process that underlies coherent information processing, supports the encoding of diverse sensory stimuli, and facilitates adaptive behavior in dynamic environments. Previous studies of synchronization have predominantly emphasized rate coding and pairwise interactions between neurons, which have provided valuable insights into emergent network phenomena but remain insufficient for capturing the full complexity of temporal dynamics in spike trains, particularly the interspike interval. To address this limitation, we performed in vivo neural ensemble recording in the primary olfactory center—the antennal lobe (AL) of the hawk moth Manduca sexta —by stimulating with floral odor blends and systematically varying the concentration of an individual odorant within one of the mixtures. We then applied machine learning methods integrating modern attention mechanisms and generative normalizing flows, enabling the extraction of semi-interpretable attention weights that characterize dynamic neuronal interactions. These learned weights not only recapitulated the established principles of neuronal synchronization but also facilitated the functional classification of two major cell types in the antennal lobe (AL) [local interneurons (LNs) and projection neurons (PNs)]. Furthermore, by experimentally manipulating the excitation/inhibition balance within the circuit, our approach revealed the relationships between synchronization strength and odorant composition, providing new insight into the principles by which olfactory networks encode and integrate complex sensory inputs.

Parkinson’s disease (PD) has been associated with alterations in neuronal activity in the basal ganglia-thalamocortical (BGTC) network. Previous studies have suggested that cortical disinhibition is a feature of PD, but there has been little direct evidence of the changes in cortical neuronal spiking activity to support this hypothesis. To test the hypothesis that activity in the motor cortex is enhanced in PD, we investigated the effects of parkinsonism on movement-related neuronal activity in the primary motor cortex (M1). Microelectrode arrays were chronically implanted in M1 of two nonhuman primates and populations of cells were collected before and after the induction of parkinsonism using the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. In both animals, we found that during the reaching task in the parkinsonian state, the proportion of M1 neurons that were activated (excited) during movement were increased, while those that were suppressed (inhibited) decreased. These data support the concept that dopaminergic loss in parkinsonism promotes a loss of inhibition in the motor cortex, leading to overactivity in M1 and a disruption in spatial-temporal processing of information within the BGTC circuit that contributes to the motor dysfunction observed in PD.

Fragile X Syndrome (FXS) is a leading genetic cause of intellectual disability and autism-like behaviors. Glutamatergic mGluR5 receptors and matrix metalloproteinase-9 (MMP-9) are therapeutic targets to treat FXS, but clinical trials targeting each of these pathways have not been successful. Here, we tested if the electroencephalography (EEG) phenotypes associated with FXS are reversed with a novel combination of treatments affecting the two pathways. Fmr1 knockout (KO) mice were given 10 days of CTEP (mGluR5 antagonist) alone or in combination with minocycline (MMP-9 inhibitor). EEG was recorded during resting (no acoustic stimulation) and during sound presentations (to produce sound-evoked EEG) at 1 day and 10 days after the beginning of treatment administration to test acute effects and potential tachyphylaxis. In pre-treatment WT and KO mice comparisons, we replicated previously published Fmr1 KO mouse EEG phenotypes including elevated power in the resting gamma band, elevated single trial power, and reduced phase-locking to spectrotemporally dynamic auditory stimuli. We found that CTEP treatment alone did not show any benefit compared to vehicle in Fmr1 KO mice after either 1 or 10 days of treatment. CTEP + minocycline reduced resting gamma band power in the Fmr1 KO mice to a greater extent than vehicle at both treatment time points. There were no effects on sound-evoked responses. These data suggest that combined CTEP and minocycline treatment alters resting EEG measures while each treatment administered separately does not yield similar changes. High power in broadband gamma frequency correlates with irritability, stereotyped behaviors, and hyperactivity in FXS patients, suggesting a combination of drugs that reduce mGluR5 and MMP-9 activity may be beneficial in FXS.

Adolescence is a developmental period characterized by heightened plasticity. Yet, how ongoing development affects sensory processing and cognitive function is unclear. We investigated how adolescent (postnatal day 20–42) and adult (postnatal day 60–82) mice differ in performance on a pure tone Go/No-Go auditory discrimination task of varying difficulty. Using dense electrophysiological recordings, we measured spiking activity at single neuron resolution in the auditory cortex while mice were engaged in the task. As compared to adults, adolescent mice showed lower auditory discrimination performance in a difficult task. This difference in performance was due to higher response variability and weaker cognitive control expressed as higher lick bias. Adolescent and adult neuronal responses differed only slightly in representations of pure tones when measured outside the context of learning and the task. However, cortical representations after learning within the context of the task were markedly different. We found differences in stimulus- and choice-related activity at the single neuron level representations, as well as lower population-level decoding of the difficult task in adolescents. Overall, cortical decoding in adolescents was lower and slower, especially for difficult sound discrimination, reflecting immature cortical representations of sounds and choices. Notably, we found age-related differences, which were more pronounced after learning, reflecting the combined impact of age and learning. Our findings highlight distinct neurophysiological and behavioral profiles in adolescence, underscoring the ongoing development of cognitive control mechanisms and cortical plasticity during this sensitive developmental period.

The pre‐hearing mouse cochlea undergoes critical periods of spontaneous Ca 2+ ‐dependent activity that spreads across non‐sensory supporting cells and inner hair cells (IHCs). These signals have been shown to regulate not only the refinement of neural circuits along the auditory pathway towards functional maturity, but also the maturation of the hair cells into sensory receptors. Although the origin and interplay of these Ca 2+ signals during cochlear development have recently been investigated in live mice, the impact of anaesthesia on in vivo functional measurements was not explored. Here, we investigate the effects of different anaesthetic regimes (ketamine and xylazine; 2.5% isoflurane; and 1.0%–1.5% isoflurane with the sedative acepromazine) that provided an effective unconsciousness to perform the surgery and Ca 2+ ‐imaging recordings from the intact cochlea of live mice. The IHCs, supporting cells and spiral ganglion neuron terminals onto the IHCs showed spontaneous Ca 2+ ‐dependent activity under all anaesthetic regimes, with a few significant differences observed between conditions. Calcium waves from supporting cells synchronized the activity of IHCs. Moreover, we found that the endocochlear potential, which is crucial for cochlear function, was unaffected by the different anaesthetics. However, low concentrations of isoflurane produced the most stable recordings of vital physiological signs in mice, including heart rate and breathing rate. Although all anaesthetic regimes tested appeared to be suitable for performing Ca 2+ imaging from the cochlea of pre‐hearing live mice, a low concentration of isoflurane (1.0%–1.5%), combined with the pre‐anaesthetic sedative acepromazine and oxygenation, represents the most suitable approach to maintain a stable and long‐lasting depth of anaesthesia.

Hydrogels have emerged as promising materials for anti‐fibrotic neural interfaces due to their mechanical and chemical similarity to biological tissue. However, their use in multimodal platforms remains limited, owing to fabrication challenges in microstructuring multiple functional hydrogels into compact architectures. Here, a hydrogel thermal drawing process (HG‐TDP) is presented that enables the co‐fabrication of multiple thermoplastically deformable hydrogels into a single, compact, and multifunctional fiber. By optimizing key process parameters, all‐hydrogel neural interfaces are developed that minimize gliosis through tissue‐like mechanical compliance and enable post‐implantation anti‐inflammatory drug delivery via the hydrogel‐based matrix. These fibers feature the compact integration of diverse hydrogel components, including a step‐index optical waveguide, an electrically conductive hydrogel electrode, and a hydrogel‐based microfluidic channel within a unified fiber structure. This integration enables multimodal neural interfacing, as demonstrated by high‐quality neural signal recording, optogenetic stimulation, and localized chemical modulation of neural circuits. This work offers a scalable route toward compact, fully hydrogel‐based neural interfaces that combine multimodal functionality with tissue‐friendly, anti‐fibrotic properties.

Long-term sustained pain following acute physical injury is a prominent feature of chronic pain conditions1. Populations of neurons that rapidly respond to noxious stimuli or tissue damage have been identified in the spinal cord and several nuclei in the brain2-4. Understanding the central mechanisms that signal ongoing sustained pain, including after tissue healing, remains a challenge5. Here we use spatial transcriptomics, neural manipulations, activity recordings and computational modelling to demonstrate that activity in an ensemble of anatomically and molecularly diverse parabrachial neurons that express the neuropeptide Y (NPY) receptor Y1 (Y1R neurons) is increased following injury and predicts functional coping behaviour. Hunger, thirst or predator cues suppressed sustained pain, regardless of the injury type, by inhibiting parabrachial Y1R neurons via the release of NPY. Together, our results demonstrate an endogenous analgesic hub at pain-responsive parabrachial Y1R neurons.

Discrimination of sensory stimuli is fundamentally constrained by the information encoded in neuronal responses. In the barn owl, interaural time difference (ITD) serves as a primary cue for azimuthal sound localization and is represented topographically in the midbrain auditory space map in the external nucleus of the inferior colliculus (ICx). While prior studies have demonstrated a correspondence between spatial tuning and behavioral acuity, it remains unclear how changes in sensory reliability influence this relationship. Here, we examined how behavioral and neuronal ITD discrimination thresholds vary with binaural correlation (BC), which manipulates ITD cue reliability. Using the pupil dilation response as a behavioral metric in head-fixed owls of either sex, we found that ITD just-noticeable differences increased exponentially as BC decreased. In contrast, the widths of ICx ITD tuning curves increased more modestly, indicating that tuning resolution alone does not account for behavioral discrimination performance. By computing the Fisher information from ICx neuronal responses, we showed that the average neuronal discriminability predicts behavioral thresholds across BC values. A habituation-based model incorporating BC-dependent changes in tuning width, firing rate, and response variability successfully accounted for both direction and ITD discrimination. These findings support a model in which perceptual acuity is governed by the combined influence of neuronal tuning and variability and provide a unified framework for understanding how midbrain auditory representations underlie adaptive spatial hearing.

The ability to pick out and attend to one sound in a noisy mixture underpins successful communication in many natural scenarios. Selective attention has been shown to drastically alter sound encoding in the cortex and has been hypothesized to modulate subcortical processing via an extensive efferent network. The body of work investigating this possibility in humans has not resulted in a clear consensus, possibly owing to limitations in the available methodologies. Here, we used new experimental tools that allowed distinct neural responses from across the auditory pathway to be simultaneously acquired from human listeners attending to the sound of one person talking while ignoring a second. Our series of experiments provide convergent evidence that selective attention does not influence sound encoding in the auditory periphery or brainstem, with an effect first appearing in the cortex. Humans’ ability to focus their attention on a single sound even in the presence of many others is as remarkable as it is essential. These findings add needed clarity regarding the mechanisms that make this feat possible.

Cerebral cortex and cerebellum are essential for sensorimotor control, but the dynamics of their interactions remain unclear. Here, we investigated which pathways prevail during preparation and execution of spontaneous whisker movements in mice. During preparation, neuronal activity of primary motor (M1) and somatosensory (S1) cortex precede that of cerebellar crus regions, with a lead that is consistent with relaying a copy of motor commands. After movement onset, the phase of the signal inverts, indicating a dominant vector signaling from cerebellum to cerebrum. At this stage, Purkinje cell activity correlates more with S1 than M1, generating a prediction of sensory consequences during motor actions. A computational cerebello-cortical model could replicate the changes in dynamics and directionality. Optogenetic manipulations of pons and thalamus confirm the modeled predictions on stage-dependent dynamics. Together our data point towards a swap in direction of information flow between cerebrum and cerebellum when motor preparation switches to execution.

Background: Chronic pain affects approximately 20% of the population, with a higher prevalence in females, and presents significant diagnostic and treatment challenges. While opioids are commonly prescribed, they carry risks of addiction and overdose, highlighting the need for reliable pain biomarkers. New Method: To develop such a biomarker, we recorded non-noxious and noxious evoked potentials from the primary somatosensory cortex (S1) in 8 female pigs across 16 sessions. A convolutional neural network (CNN) was trained, validated, and tested on time-frequency maps of these responses. Three interpretability methods, saliency, integrated gradients, and occlusion were applied to identify neural features critical for distinguishing pain states. Results: The CNN achieved an overall accuracy of 73.5%, with higher accuracy for non-noxious stimuli (85%) than for noxious stimuli (62%). Feature attributions consistently highlighted a window 93–173 ms post-stimulus in the 35–75 Hz gamma-band. Comparison with Existing Methods: The CNN automatically extracted features from spectrograms, addressing the overlap between noxious and non-noxious responses. Interpretability methods revealed gamma-band oscillations (GBOs) consistent with nociceptive processing in humans and rodents. While this architecture offers valuable insights, recent studies suggest that hybrid models (e.g., CNN-LSTM) and transformers may further improve performance and robustness. Conclusion: This CNN-based approach identified GBOs as a promising neural marker of pain, with potential applications in translational research, pre-clinical trials, and pain assessment in non-verbal subjects.

Exposure to loud and/or prolonged noise damages the cochlea and triggers downstream brain changes, resulting in hearing loss and altered speech comprehension. It remains unclear however whether noise exposure also compromises the cochlear efferent system; a feedback pathway originates in the brain that fine-tunes hearing sensitivity in the cochlea. Recent evidence suggests that lateral olivocochlear (LOC) efferent system supports hearing recovery by sustaining auditory nerve activity for several weeks after acoustic trauma (Sitko et al., 2025); however, the underlying neural mechanisms have not been fully elucidated. To address this gap, we examined the long-term effects of noise-induced hearing loss (NIHL) on the spontaneous action potential (AP) firing pattern in mouse LOC neurons of either sex. Under normal conditions, these neurons display a characteristic burst firing pattern driven by Ca 2+ channel-mediated membrane voltage oscillations. One week following noise exposure, hearing thresholds were significantly elevated, and the duration of AP bursts was increased, as a result of an enhanced Ca 2+ current. Moreover, LOC neurons exhibit Ca 2+ -dependent inactivation (CDI) of Ca 2+ currents—a key process that shapes the duration of voltage oscillations—whose properties were also modified following noise exposure. Interestingly, our data suggest that the interplay between Ca 2+ channel activation, CDI, and outward leak currents is sufficient to sustain the oscillating behavior of LOC neurons. We propose that NIHL increases efferent activity, thereby enhancing the release of neurotransmitters and neuropeptides, which may support long-lasting restoration of sensory coding in the damaged cochlea.

Classical neuromodulators regulate arousal states, spanning deep sleep to vigilant wakefulness, primarily by activating cortical neurons. However, cortical astrocytes also express neuromodulatory G-protein-coupled receptors (GPCRs). While astrocytic noradrenergic receptors have been shown to modulate two critical regulators of arousal—cortical synchrony and extracellular adenosine levels—how other neuromodulatory signaling pathways similarly shape arousal remains unclear. Astrocytes in mammalian cortex express particularly high levels of the wake-promoting, Gq-coupled histamine-1-receptor (H1R), yet little is known about how astrocytic H1R contributes to regulation of arousal. To address this gap, we used pharmacological and genetic approaches in murine cortex to test how astrocyte-H1R signaling affects astrocyte calcium (Ca 2+ ), cortical neural activity across sleep/wake, and extracellular adenosine—an astrocytic output that regulates cortical arousal. Using ex vivo two-photon Ca 2+ imaging in acute cortical slices, we show that H1R mediates cell-autonomous astrocyte Ca 2+ responses to histamine (HA) and attenuates responses to norepinephrine (NE). Next, in vivo fiber photometry and electrophysiology results show that H1R deletion in cortical astrocytes disrupts local astrocyte Ca 2+ during wake and extracellular adenosine dynamics specifically around REM sleep transitions, when HA release is minimal. Further, astrocyte-specific H1R deletion in cortex promotes wakefulness and reduces REM sleep time. Our results indicate that H1R activity modulates astrocyte responses to non-histaminergic inputs by inducing lasting changes in astrocyte physiology that modulate extracellular adenosine and REM sleep. Our findings contribute to an emerging model in which neuromodulator GPCRs synergistically shape astrocyte physiology to regulate arousal behavior and adenosine signaling in the cortex.

Objective: This study aims to establish an economically viable and easily accessible adult animal model for optogenetic activation of auditory neurons using adeno-associated viruses (AAVs) carrying ChR2(H134R) to explore the potential of cochlear optogenetics as a hearing restoration technology. Methods: Healthy adult guinea pigs were used in the experiments. The viral vector AAV2/8-ChR2(H134R)-hSyn-eYFP was administered to the right cochlea via the round window membrane. The confocal microscopy and reverse transcription polymerase chain reaction (RT-PCR) were utilized to analyze the ChR2(H134R) expression localized to spiral ganglion neurons (SGNs). The auditory pathway activation was assessed by recording the optical compound action potential (oCAP) and acoustic compound action potential (aCAP) at various laser intensities. Results: The ChR2(H134R)-eYFP expression was confirmed in 90% of the tested animals, localized to the SGNs of the injected ear. Higher mRNA levels of ChR2(H134R) and eYFP were observed in the injected ear compared to the non-injected ear, while actin (Actb) mRNA levels were not significantly different. The oCAP was successfully elicited by a 470 nm blue light laser stimulus, with similar amplitudes and latency periods to those of aCAPs when the oCAP was evoked by 5.80 mW blue light and the aCAP was evoked by a 40 dB SPL click. The amplitudes of oCAPs increased with increasing laser intensity. Conclusion: This study demonstrates the viability of optogenetic activation of the auditory system in adult guinea pigs through the transduction of AAV-ChR2(H134R) in SGNs. Cochlear optogenetics demonstrates potential as a hearing restoration technology, providing a basis for further clinical research and opening new avenues for investigation.

This study aimed to characterize maturation of the binaural intelligibility level difference (BILD) for school-age children in the context of speech-in-speech recognition. Children (5–17 years) and adults completed an adaptive, open-set sentence recognition task in a two-talker masker in two binaural conditions: (1) target and masker speech in-phase across the two ears, and (2) target speech presented 180° out-of-phase across the two ears and masker speech presented in-phase. Estimates of the BILD, computed as the difference score between the two binaural conditions, were mature by ten years of age, consistent with previous data on the BILD for speech-in-noise recognition.

Absence epilepsy is frequently associated with cognitive impairments, yet the direct or indirect involvement of cognitive circuits remains poorly understood, as spike-and-wave discharges are rarely reported in these regions. Here, we investigate the role of a thalamic–prefrontal pathway in a mouse model of absence epilepsy (Scn8a +/- ). We find that Scn8a +/- mice exhibit deficits in reversal learning, along with impaired recruitment of medial prefrontal cortex (mPFC) neurons by the Reuniens nucleus of the thalamus. This deficit is accompanied by an altered excitation–inhibition balance and reduced excitability of layer I interneurons in the mPFC, which constitutes the main recipient zone of reuniens inputs to the mPFC. Remarkably, stimulation of Reuniens at 20 Hz significantly reduces seizure incidence and improves performance in reversal learning. Our findings reveal previously unrecognized cognitive circuit dysfunctions in absence epilepsy and highlight the thalamo–prefrontal axis as a promising target for both cognitive and seizure-related interventions.

Spiny projection neurons (SPNs) in the dorsal striatum play crucial roles in locomotion control and value-based decision-making. SPNs, which include both direct-pathway striatonigral and indirect-pathway striatopallidal neurons, can be further classified into subtypes based on distinct transcriptomic profiles and cell body distribution patterns. However, how these SPN subtypes regulate spontaneous locomotion in the context of environmental valence remains unclear. Using Sepw1-Cre transgenic mice, which label a specific SPN subtype characterized by a patchy distribution of cell bodies in the dorsal striatum, we found that these patchy striatonigral neurons constrain motor vigor in response to valence differentials. In a modified light/dark box test, mice exhibited differential walking speeds between the light and dark zones. Genetic ablation of these patchy SPNs disrupted restful slowing in the dark zone and increased zone discrimination by speed. In vivo recordings linked the activity of these neurons to zone occupancy, speed, and deceleration, with a specific role in mediating deceleration. Furthermore, chemogenetic activation of patchy SPNs—and optical activation of striatonigral neurons in particular—reduced locomotion and attenuated speed-based zone discrimination. These findings reveal that a subtype of patchy striatonigral neurons regulates implicit walking speed selection based on innate valence differentials.

Sympathetic hyperactivity is a common feature observed in both primary and secondary hypertension, and neuromodulation-based therapies targeting this overactivity are under active investigation. The intermediolateral nucleus (IML) in the spinal cord plays a central role in sympathetic regulation, and its direct stimulation induces a transient, frequency-dependent reduction in blood pressure. However, this effect gradually diminishes as the baroreflex restores blood pressure to baseline. Therefore, this study aims to develop a closed-loop (CL) stimulation system that adjusts parameters in real-time based on neural activity recorded from the IML and to enhance and prolong the transient antihypertensive effect. This strategy was evaluated in normotensive and angiotensin II-induced hypertensive rat models and compared to open-loop (OL) stimulation of equal intensity. In both models, CL stimulation produced a more sustained blood pressure reduction than that of OL stimulation. These findings suggest that CL spinal cord stimulation offers a more effective and durable therapeutic option for treating hypertension.

Cross-modal responses are common in primary sensory cortex, yet a recent study showed that signals in primary visual cortex (V1) once labeled multisensory were instead more closely related to face movements. To what extent can multisensory processing in other modalities also be explained by face movements? We measured face movements and neural activity in awake mouse primary auditory cortex (A1) and V1 in response to visual and auditory stimulation as well as during spontaneous activity. We find that visual stimuli rarely evoke face movements, A1 responses to visual input remain robust even in the absence of face movement, and optogenetic silencing of V1 reduces A1 visual responses. Taken together, these results confirm that cross-modal responses in the auditory system are primarily sensory, not state driven, in origin.