Publications using TDT

Dopaminergic signaling is essential for regulating movement, learning, and reward. Disruptions in this system are linked to neuropsychiatric disorders such as ADHD. ADGRL3, an adhesion G protein-coupled receptor highly expressed in the brain, is genetically associated with increased ADHD risk. ADGRL3 knockout in animals alters expression of dopaminergic markers and induces dopamine-related behavioral changes. However, its precise role in modulating dopamine signaling remains unclear. We investigated how ADGRL3 knockout affects striatal dopamine release in mice using ex vivo fast-scan cyclic voltammetry and in vivo fiber photometry with a dopamine sensor. Ex vivo measurements showed increased electrically-evoked dopamine release across the striatum. Conversely, in vivo recordings revealed reduced task-induced dopamine signals in the nucleus accumbens during an operant fixed interval task. This reduction was not due to impaired dopamine availability, as amphetamine-evoked release was unchanged. These findings suggest ADGRL3 modulates dopamine release in complex ways via different pre- and postsynaptic mechanisms.

The insular cortex is involved in a wide range of auditory functions in the mammalian brain. We studied the organization and basic response properties of auditory neurons in the insular cortex and adjacent areas by recording responses to sound stimuli in anesthetized female rats. Auditory neurons were present in an insulo-parietal auditory field that spans the boundary between the posterior insula, particularly in the granular insular cortex, and the ventral part of the adjacent nonprimary somatosensory fields. Confirming previous reports, neurons in this field had narrow tuning and were preferentially tuned to relatively low frequencies (<16 kHz). Intriguingly, auditory units in this field displayed shorter minimal latencies than units in the primary auditory cortex, as well as weaker sensitivity to deviance. These results establish the existence of a rapid auditory information stream with distinct properties through the insulo-parietal cortex that may parallel the pathway through the primary and anterior auditory fields.

Objective. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established therapy for Parkinson’s disease (PD). Yet, optimizing lead placement and stimulation programming remains challenging. Current techniques rely on imaging and intraoperative microelectrode recordings (MER), while programming relies on trial-and-error clinical testing, which can be time-consuming. DBS-induced local evoked potentials (DLEP), also known as evoked resonant neural activity, have emerged as a potential alternative electrophysiological marker for mapping. However, direct comparisons with traditional spectral features, such as beta-band, high-frequency oscillations (HFOs), and aperiodic component are lacking. Approach. We evaluated DLEP across 39 STN DBS leads in 31 subjects with PD undergoing DBS surgery, using both a single-pulse and high-frequency (HF) burst stimulation paradigms. We developed a novel artifact-removal method to enable monopolar DLEP recovery, including estimating the DLEP amplitudes at stimulated contacts, further enhancing spatial sampling of DLEP. We evaluated spectral features and DLEP in respect to imaging-based and MER-based localization, and its predictive power for post-operative programming. Main results. DLEP showed great spatial consistency, maximizing within STN with 100% accuracy for single-pulse and 84.62% for burst stimulation, surpassing spectral measures including beta (89.74%) and HFO (82.05%). DLEP better correlated with clinical outcomes (single-pulses ρ = −0.33, HF bursts ρ = −0.26), than spectral measures (beta ρ = −0.25, HFO ρ = 0.05). Furthermore, single-pulses at low-frequencies are sufficient for DLEP-based mapping. Significance. We show how DLEP provide higher STN-spatial specificity and correlation with postoperative programming compared to spectral features. To support clinical translation of DLEP, we developed two methods aimed to recover artifact-free DLEP and estimating DLEP amplitudes at stimulating contacts. DLEP appear distinct from beta and HFO activity, yet strongly tied to aperiodic spectral components, suggesting that DLEP amplitude reflects underlying STN excitability. This study highlights that DLEP are a robust and clinically valuable marker for DBS targeting and programming.

The stress axis is always active, even in the absence of any threat. This manifests as hourly pulses of corticosteroid stress hormone secretion over the day. Corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (CRH PVN ) control both the neuroendocrine stress axis as well as stress-associated behaviors. However, it is currently unclear how the resting activity of these neurons is coordinated with both spontaneous behavior and ultradian pulses of corticosteroid secretion. To investigate this, we performed fiber photometry recordings of CRH PVN neuron activity in Crh-Ires-Cre mice and a newly generated line of Crh-Ires-Cre rats. In both mice and rats, CRH PVN neurons displayed an ultradian rhythm of activity with reoccurring upstates of activity approximately once per hour over the 24-h day. Upstates in activity were coordinated with increases in animal activity/arousal. Chemogenetic activation of CRH PVN neurons was also sufficient to induce behavioral arousal. In rats, increases in CRH neural activity preceded some pulses of corticosteroid secretion but not others. Thus, while CRH PVN neurons display an ultradian rhythm of activity over the 24-h day that is coordinated with behavioral arousal, the relationship between CRH PVN activity and pulses of corticosteroid secretion is not one-to-one.

In dynamic environments where stimuli predicting reward or punishment unexpectedly change, it is critical to flexibly update behavior while preserving recollection of previous associations. Dopamine and gamma-aminobutyric acid (GABA) neurons in the ventral tegmental area (VTA) are implicated in reward and punishment learning, yet little is known about how each population adapts when the predicted outcome valence changes. To address this, VTA GABA and dopamine population calcium activity fluctuations were measured with fiber photometry while male and female rats learned to associate three discrete auditory cues with three distinct outcomes: reward, punishment, or no outcome within the same session. Contingency learning was determined by quantifying conditioned responding and probability of approach behaviors. After learning, the reward and punishment cue-outcome contingencies were reversed and subsequently re-reversed. The dopamine population displayed the expected adaptation to learning and contingency reversals by increasing the response to appetitive stimuli and decreasing the response to aversive stimuli. By contrast, the GABA population increased activity to all sensory events regardless of valence. Reversing learned contingencies selectively influenced GABA responses to the reward-predictive cue, prolonging increased activity both within and across sessions. Trial-by-trial analysis further confirmed that sustained GABA activity tracks contingency reversal. The valence-specific dissociations in the directionality and temporal progression of VTA GABA and dopamine neuronal activity suggest that these populations serve distinct roles during reward or punishment associative learning and reversal. These findings also describe a novel role for VTA GABA in behavioral flexibility.

Although the globus pallidus internus (GPi) plays a central role in the cardinal symptoms of Parkinson’s disease (PD), how parkinsonism alters the movement-related activity of GPi neurons remains understudied. Using a monkey model of PD, we found that: 1) the timing of GPi responses became uncoupled from movement onset; and 2) responses, especially decrease-type responses, became attenuated and prolonged. These abnormalities in GPi perimovement activity may contribute to the generation of parkinsonian motor signs.

Brain-machine interfaces (BMIs) offer a viable option for restoring function in patients with motor disabilities post-stroke. Most BMI systems rely on signals from the motor cortex (M1), which is often compromised after stroke. The cerebellum, a subcortical structure involved in motor control, remains an underexplored source for neuroprosthetic control. Using chronic electrophysiological recordings in a rat stroke model, we show that cerebellar neural activity can effectively drive BMI control, performing comparably to M1-driven control. We observed this even in animals with motor impairments post-stroke. Simultaneous M1-cerebellum recordings during cerebellar BMI control revealed that cerebellar "direct" neurons driving the interface were influenced by both local cerebellar and distant M1 neurons. While cerebellar influence remained stable, M1's interaction with cerebellar direct neurons shifted from longer to shorter timescales after stroke. These findings highlight that cerebellar direct neural control is possible in the stroke brain and reveal changes in M1-cerebellar network dynamics post-stroke.

Nucleus accumbens dopamine signaling is an important neural substrate for decision-making. Dominant theories generally discretize and homogenize decision-making, when it is in fact a continuous process, with evaluation and re-evaluation components that extend beyond simple outcome prediction into consideration of past and future value. Extensive work has examined mesolimbic dopamine in the context of reward prediction error, but major gaps persist in our understanding of how dopamine regulates volitional and self-guided decision-making. Moreover, there is little consideration of individual differences in value processing that may shape how dopamine regulates decision-making. Here, using an economic foraging task in mice, we found that dopamine dynamics in the nucleus accumbens core reflected decision confidence during evaluation of decisions as well as both past and future value during re-evaluation and change-of-mind. Optogenetic manipulations of mesolimbic dopamine release selectively altered evaluation and re-evaluation of decisions in mice whose dopamine dynamics and behavior reflected future value.

Intracortical microelectrode arrays (MEAs) are vital tools for brain‐machine interface applications and basic neuroscience research, with the potential to advance treatments for neurological disorders and enhance the understanding of the nervous system. However, implanting intracortical electrodes can damage native tissue along the insertion path and trigger inflammatory responses characterized by neuronal loss and glial activation. While flexible electrodes reduce some of these adverse effects compared to rigid counterparts, their mechanical compliance often leads to buckling during insertion, necessitating the use of insertion aids such as stiff shuttles or dissolvable coatings. These aids, however, introduce additional complexity and can cause further tissue damage. In this work, microfabricated polyimide MEAs featuring a buckling‐resistant, trace‐stacked (BRATS) design are presented. It is demonstrated that BRATS MEAs can penetrate agarose brain phantoms and the rat cerebral cortex without the need for insertion aids. Once implanted, BRATS MEAs established a stable and functional electrical interface with the brain, enabling high‐fidelity, single‐unit electrophysiological recordings. Compared to conventional flexible MEAs inserted with a stiff shuttle, BRATS MEAs elicited significantly lower inflammatory responses and preserved a higher density of neurons near the implant site one week post‐implantation.

The central nervous system controls movement by combining neuromotor modules, known as muscle synergies. Previous studies suggest that spinal premotor interneurons (PreM‐INs) contribute to the encoding of stable muscle synergies for voluntary movement. But descending and sensory inputs also influence motor outputs through the spinal interneuronal network, which may be configured by its inputs to encode different sets of muscle synergies depending on the network state, thereby recruiting different selections of synergies. Here we tested this possibility of state‐dependent synergy encoding by examining the muscle synergies represented by the same upstream spinal interneurons under different activity states induced by various optogenetic stimulation patterns. Lumbosacral spinal units and electromyographic (EMG) activities of hindlimb muscles were simultaneously recorded from anaesthetized Thy1‐ChR2 mice as the spinal cord was stimulated by one or two optic fibres at different intensities. The synergy encoded by each unit was revealed as a ‘muscle field’ derived from spike‐triggered averages of EMG, whereas the entire muscle synergy set was factorized from the EMG. We found that although the muscle synergy set remained stable across stimulation conditions, the muscle fields of the same units were matched to different synergies within the set in different states. Thus the interneurons may flexibly adjust their connectivity with the motoneurons of the muscles as descending and sensory afferents impose different states on the spinal network. State‐dependent encoding of muscle synergies may allow different synergies to be selected for producing stable movement in an ever‐changing workspace environment. image Key points Muscle synergies for locomotion can be represented by spinal interneurons, as revealed by the interneurons’ muscle fields derived from spike‐triggered averages of EMG. The muscle field of a single spinal interneuron may vary under different stimulation conditions, as demonstrated by optogenetic stimulation. Encoding of muscle synergies is dependent on the state of spinal activities, thus facilitating the selection of appropriate synergies in different dynamic environments.

Background: Although several evidence demonstrates a "gut-microbiota-brain axis", suggesting a bidirectional communication between gut microbiota and the central nervous system, less is known about a possible link between the gut and the peripheral nervous system, including the inner ear. Methods: Here, we investigated the impact of intestinal inflammation and the modulation of gut microbiota through fecal microbiota transplantation on hearing sensitivity. Female C57BL/6 mice were assigned to four groups: control (Ctrl), DSS-induced colitis (DSS), FMT from patients with active ulcerative colitis (FMT aUC), and FMT from patients with ulcerative colitis in remission (FMT rUC). Auditory function was evaluated by auditory brainstem responses (ABR). Morphological and molecular analyses on cochlear tissues were performed using immunofluorescence, histological staining, and Western blot to assess inflammation, oxidative stress, and blood-labyrinth barrier integrity. Donor microbiota composition was characterized by 16S rRNA sequencing, and systemic inflammation was evaluated by measuring serum lipopolysaccharide (LPS) levels. Results: We found that intestinal dysbiosis is associated with functional, morphological, and molecular alterations in the cochlea, such as increased oxidative stress, inflammation, and altered blood-labyrinth barrier permeability. This leads to macrophage infiltration and immune response activation through the MyD88/NF-κB pathway. Notably, these effects were exacerbated by FMT from subjects with aUC, while FMT from patients with rUC provided a protective effect on cochlear functions. Conclusions: Overall, our findings suggest that gut inflammation, microbiota alteration, or its therapeutic modulation can impact inner ear pathology: worsening gut inflammatory status negatively affects hearing sensitivity, while the restoration of gut microbiota positively impacts auditory function.

The discrete events of our narrative experience are organized by the neural substrate that underlies episodic memory. This narrative process is segmented into distinct units by event boundaries, which facilitate a replay process that acts to consolidate each event into a narrative memory. High-frequency oscillations (HFOs) may synchronize neural activity during these processes. We use intracranial recordings from participants viewing and freely recalling a continuous, audiovisual stimulus. We find that hippocampal HFOs increase following event boundaries and hippocampal-cortical coincident HFOs (co-HFOs) occur in cortical regions that underlie event segmentation (inferior parietal, precuneus, lateral occipital, and inferior frontal cortices). Event-specific co-HFO patterns that occur during event viewing reoccur following event boundaries for the subsequent three events and during recall. This is consistent with models that support replay as a mechanism for memory consolidation. Therefore, HFOs may coordinate activity across brain regions that facilitate event segmentation, encode memory of discrete events, and bind representations to assemble memory of a coherent, continuous experience.

The basolateral amygdala (BLA) assigns valence to sensory stimuli, with a dedicated nociceptive ensemble encoding the negative valence of pain. However, the effects of chronic pain on the transcriptomic signatures and projection architecture of this BLA nociceptive ensemble are not well understood. Here, we show that optogenetic inhibition of the nociceptive BLA ensemble reduces affective-motivational behaviors in chronic neuropathic pain. Single-nucleus RNA sequencing revealed peripheral injury–induced changes in genetic pathways involved in axonal and presynaptic organization in nociceptive BLA neurons. Next, we identified a previously uncharacterized nociceptive hotspot in the nucleus accumbens shell that is innervated by BLA nociceptive neurons. Axonal calcium imaging of BLA projections to the accumbens and chemogenetic inhibition of this pathway revealed pain-related transmission from the amygdala to the medial nucleus accumbens, facilitating both acute and chronic pain affective-motivational behaviors. Together, this work defines a critical nociceptive amygdala-striatal circuit underlying pain unpleasantness across pain states.

Purpose Best practices in audiology recommend assessing speech understanding in noisy environments, especially for those with communication difficulties. Speech-in-noise (SiN) assessments such as the QuickSIN are used for validating signal processing in hearing aids (HAs) and are linked to HA satisfaction. This project seeks to enhance QuickSIN test efficiency by applying recent advancements in automatic speech recognition (ASR) technologies. Method Twenty-three adults with sensorineural hearing loss were fitted bilaterally with Unitron Moxi HAs and were administered the QuickSIN test in low and high reverberation environments. Testing was performed with two different HA programs: an omnidirectional program and a fixed directional microphone program. QuickSIN sentences were presented from 0° azimuth and competing babble from either 0°, laterally from 90° or 270°, or simultaneously from 90°, 180°, and 270° azimuths. Participants’ verbal responses to QuickSIN stimuli were scored by an audiologist and were recorded in parallel for offline transcription and scoring by ASR models from Amazon, Microsoft, NVIDIA, and Picovoice. The ASR-derived QuickSIN scores were compared to the corresponding audiologist-derived scores. Results Repeated Measures ANOVA results revealed that all ASR models overestimated the QuickSIN scores across most test conditions. Bland-Altman analyses showed that the Amazon ASR model had the least bias and the narrowest range for the limits of agreement, in comparison to the manual scoring by an experienced audiologist. Conclusions Some ASR models, such as Amazon, demonstrated performance comparable to that of an audiologist in automatically scoring QuickSIN tests. However, further refinements are necessary to increase the robustness of the ASR models in scoring low SNR loss test conditions.

Introduction Deep brain stimulation (DBS) is a neuromodulation method for treatment of various neurological disorders. Research on DBS has often focused on local inhibition or excitation effects, at the site of stimulation. However, it is well-known that DBS can lead to robust evoked potentials (EP) not only at the stimulation site, representing the local effect, but also in distant brain regions, representing the effects on distant targets. While the significance of these EPs for therapeutic outcomes is not known, it appears that the electrical effects of DBS have a partial modulatory impact on downstream targets. Nonetheless, it partly remains unclear through what mechanism DBS pulses travel to the distant targets or what portion of the pulses travel along the normal pathways from the stimulation site. The possible scenarios include orthodromic or antidromic pathways, accessory pathways, normally inhibited pathways, and direct electromagnetic activation of distant sites. We hypothesize that the pathways that transmit DBS pulses include the pathways that transmit intrinsic neural signals. Methods To test this, we performed a transfer function analysis on deep brain recordings from children with dystonia, during DBS-off condition and compared its impulse response with the transmission of signals from electrical stimulation during DBS-on condition. We compared impulse responses derived from intrinsic neural signals during voluntary movement (DBS-off) to evoked potentials (EPs) recorded during electrical stimulation (DBS-on), focusing on directional transmission (orthodromic vs. antidromic). Results DBS EPs were more accurately predicted by impulse responses corresponding to direct axonal activation rather than somatic relay. Significant correlations between intrinsic signal transfer functions and EPs, particularly in orthodromic directions ( p -value < 0.01) from pallidum to thalamus and subthalamic nucleus, support our hypothesis that DBS travels along physiological pathways. Discussion These results suggest that DBS engages existing motor pathways to reach distant targets, offering mechanistic insight into its network effects. This supports future approaches that could tailor treatment plans based on individual connectivity maps to improve clinical efficacy of DBS.

MDMA is a promising adjunct to psychotherapy and has well-known abuse liability, although less than other amphetamine analogs. While the reinforcing dopamine (DA)-releasing properties of MDMA are on par with methamphetamine (METH), MDMA is a far more potent serotonin (5-HT) releaser, via the 5-HT transporter (SERT). MDMA-mediated 5-HT release in a major reward center, the nucleus accumbens (NAc), drives prosocial behaviors via 5-HT1BR activation. We hypothesized that this prosocial mechanism contributes to the reduced reinforcing properties of MDMA compared to METH and used a platform of assays to predict the balance of prosocial and abuse-linked effects of (R)-MDMA, a novel entactogen in clinical development. NAc DA release, measured by GRAB-DA photometry in vivo, increased in proportion to MDMA (7.5 and 15 mg/kg, i.p.) and METH (2 mg/kg i.p.)-conditioned place preference (CPP). Using conditional knockouts (cKOs) for DAT and SERT, microdialysis, and photometry, we found that MDMA-released 5-HT limited MDMA-released DA through actions in the NAc, rather than at ventral tegmental area DAergic cell bodies. SERT cKO reduced the MDMA dose required for CPP three-fold. This enhanced MDMA-CPP and increased DA release were replicated by intra-NAc infusion of either a 5-HT reuptake inhibitor (escitalopram) to prevent MDMA interaction with SERT, or a 5-HT2CR antagonist (SB242084), but not by the 5-HT1BR antagonist NAS-181. These data support separate mechanisms for the low abuse potential versus prosocial effect of MDMA. Using this platform of assays, (R)-MDMA is predicted to have prosocial effects and low abuse potential.

The transplantation of regionally specific spinal neural progenitor cells (sNPCs) has shown promise for functional restoration after spinal cord injury (SCI) by forming connections with host neural circuits. Here, 3D‐printed organoid scaffolds for transplantation using clinically relevant human induced pluripotent stem cell‐derived regionally specific sNPCs is developed. Scaffolds with microscale channels are printed, and sNPCs are subsequently printed within these channels. The scaffolds direct axonal projections along the channels and guide the cells to simulate in vivo‐like conditions, leading to more effective cell maturation and the development of neuronal networks crucial for restoring function after SCI. The scaffolds, with organoids assembled along their lengths, are transplanted into the transected spinal cords of rats. This significantly promotes the functional recovery of the rats. At 12 weeks post‐transplantation, the majority of the cells in the scaffolds differentiate into neurons and integrate into the host spinal cord tissue. These results demonstrate their potential to create a relay system along the spinal cord and form synapses in both the rostral and caudal directions relative to the scaffold. It is envisioned that combining sNPCs, organoid assembly, and 3D printing strategies can ultimately lead to a transformative treatment approach for SCI.

Age-related hearing loss is common in the human population but it is highly heterogeneous in aetiology which has hampered efforts to develop ways of stopping its progression. Three major sites of the initial dysfunction are the sensory hair cells, their innervation, and the stria vascularis which generates the high potassium endolymph maintained at a high endocochlear potential bathing the apical surface of hair cells. Treatments aimed at the initial site-of-lesion may be useful, and diagnostic tools to distinguish the primary site would help stratify clinical trials and facilitate selection of the most suitable treatment for each person. Here we report a new non-invasive test that distinguishes mutant mice with known stria vascularis dysfunction and reduced endocochlear potential from mice with sensory hair cell or neural defects but with normal endocochlear potential. It is based on measuring inter-trial coherence in auditory brainstem responses to individual stimuli. Mice with reduced strial function show good inter-trial coherence compared with the amplitude of the averaged response, while mice with sensory or neural deficits show poor coherence. This method might be useful in humans to predict whether they have reduced strial function, which cannot be measured directly, and identify who would benefit from treatments aimed at boosting strial function.

Middle age represents a critical period of accelerated brain changes and provides a window for early detection and intervention in age-related neurological decline. Hearing loss is a key early marker of such decline and is linked to numerous comorbidities in older adults. Yet, ~10% of middle-aged individuals who report hearing difficulties show normal audiograms. Cochlear neural degeneration (CND) could contribute to these hidden hearing deficits, though its role remains unclear due to a lack of objective diagnostics and uncertainty regarding its perceptual outcomes. Here, we employed a cross-species design to examine neural and behavioral signatures of CND. We measured envelope following responses (EFRs) – neural ensemble responses to sound originating from the peripheral auditory pathway – in young and middle-aged adults with normal audiograms and compared these responses to young and middle-aged Mongolian gerbils, where CND was histologically confirmed. We observed near-identical changes in EFRs across species that were associated with CND. Behavioral assessments revealed age-related speech-in-noise deficits under challenging conditions, while pupil-indexed listening effort increased with age even when behavioral performance was matched. Together, these results demonstrate that CND contributes to speech perception difficulties and elevated listening effort in midlife, which may ultimately lead to listening fatigue and social withdrawal.

Dopamine (DA)-producing neurons of the ventral tegmental area (VTA) regulate consummatory behavior in a state-dependent manner (e.g. when hungry or thirsty). The mechanisms by which and extent to which DA neurons are regulated by these interoceptive signals are poorly understood. Here, we identify transient receptor potential canonical type 6 (TRPC6) channels as selective mediators of neuropeptide receptor-induced calcium signaling in VTA-DA neurons. These channels regulate DA neuron activity and consummatory behavior in a state-dependent manner. We find that TRPC6 channels regulate distinct aspects of neuropeptide-induced calcium signals in DA neurons but make little contribution to calcium dynamics associated with metabotropic neurotransmitter receptor signaling. We further show that TRPC6 channels regulate scalable reward valuation and consummatory behavior in hungry but not thirsty mice. These findings demonstrate that neuropeptide-and neurotransmitter-activated G-protein coupled receptors (GPCRs) regulate cellular calcium dynamics through distinct mechanisms, and that TRPC6 channels are important determinants of how animals respond to different homeostatic demands.