Publications using TDT

Understanding how downstream brain areas decode sensory information represented by neural populations remains a central problem in neuroscience. While decoders that are optimized to extract the maximum amount of information have been extensively used in research, whether these are physiologically realistic remains at best unclear. Here we show that a physiologically realistic decoding scheme based on correlations between neural activities in the absence of stimulation can predict downstream neural responses as well as the optimal decoder. Simultaneous recordings were made from primary sensory neural populations and their downstream midbrain targets in the electrosensory system of Apteronotus leptorhynchus . We found that neural populations exhibited significant correlations in the absence of stimulation (i.e. ‘baseline’), with downstream neural activity lagging primary sensory neural activity with a short latency. We then investigated how primary sensory neural activities were combined downstream. Overall, a decoder that assigned weights to each primary sensory neuron and was trained solely on baseline correlations performed as well as the optimal decoder trained on neural responses to stimulation. Interestingly, both decoders greatly outperformed schemes for which every neuron was assigned the same weight or when the weights were shuffled, indicating that neural identity is critical. Taken together, our results suggest that the brain uses decoding strategies that perform at optimal levels but are qualitatively different from those predicted from optimal solutions. image Key points How neural signals are decoded to give rise to perception remains poorly understood. We recorded from primary sensory neural populations and their downstream targets. A physiologically realistic decoder performed as well as the optimal solution to predict downstream responses. We found important qualitative differences between how information is decoded and the optimal solution. Our results demonstrate that the brain can do as well as an optimal decoder but uses a different strategy.

Foraging theory predicts animal behavior in many contexts. In patch-based foraging behaviors, the marginal value theorem (MVT) gives the optimal strategy for deterministic environments whose parameters are fully known to the forager. In natural settings, environmental parameters exhibit variability and are only partially known to the animal based on its experience, creating uncertainty. Models of uncertainty in foraging are well established. However, natural environments also exhibit unpredicted changes in their statistics. As a result, animals must ascertain whether the currently observed quality of the environment is consistent with their internal models, or whether something has changed, creating meta-uncertainty. Behavioral strategies for optimizing foraging behavior under meta-uncertainty, and their neural underpinnings, are largely unknown. Here, we developed a novel behavioral task and computational framework for studying patch-leaving decisions in head-fixed and freely moving mice in conditions of meta-uncertainty. We stochastically varied between-patch travel time, as well as within-patch reward depletion rate. We find that, when uncertainty is minimal, mice adopt patch residence times in a manner consistent with the MVT and not explainable by simple ethologically motivated heuristic strategies. However, behavior in highly variable environments was best explained by modeling both first- and second-order uncertainty in environmental parameters, wherein local variability and global statistics are captured by a Bayesian estimator and dynamic prior, respectively. Thus, mice forage under meta-uncertainty by employing a hierarchical Bayesian strategy, which is essential for efficiently foraging in volatile environments. The results provide a foundation for understanding the neural basis of decision-making that exhibits naturalistic meta-uncertainty.

The ability to evaluate valence of a social agent based on social experience is essential for an animal's survival in its social group1. Although hippocampal circuits have been implicated in distinguishing novel and familiar conspecifics2-7, it remains unclear how social valence is constructed on the basis of social history and what mechanisms underlie the heightened valence versatility in dynamic relationships. Here we demonstrate that the ventral (v)CA1 integrates serotonin (5-HT) inputs from the dorsal raphe and neurotensin inputs from the paraventricular nucleus of the thalamus (PVT) to determine positive or negative valence of conspecific representations. Specifically, during an appetitive social interaction 5-HT is released into the vCA1 and disinhibits pyramidal neurons through 5-HT1B receptors, whereas neurotensin is released during an aversive social interaction and potentiates vCA1 neurons directly through NTR1s. Optogenetic silencing of dorsal raphe 5-HT and PVT neurotensin inputs into the vCA1 impairs positive and negative social valence, respectively, and excitation flexibly switches valence assignment. These results show how aversive and rewarding social experiences are linked to conspecific identity through converging dorsal raphe 5-HT and PVT neurotensin signals in the vCA1 that instruct opposing valence, and represent a synaptic switch for flexible social valence computation.

Dopamine release in the nucleus accumbens (NAc) plays a critical role in the motivation to perform actions that promote survival. However, the NAc dopamine response to innately threatening visual stimuli, such as predators descending from above, and the innate behaviors they promote has not been fully characterized. Using the genetically encoded sensor dLight1, we investigated looming visual threat–evoked dopamine release in the lateral (LNAc) and medial NAc shell (NAcS) regions in freely moving mice during performance of a looming stimulus assay. We found that dopamine release related to visual threat perception in the NAcS, but not in the LNAc, predicts the timing and vigor of a future defensive action, yet dopamine released during the performance of the action itself does not. Optogenetic inhibition of dopaminergic terminals in the NAcS at visual stimulus onset prevented escape, confirming a role for ventral striatal dopamine in promoting threat-related behaviors.

Autologous nerve grafting remains the gold standard for treating peripheral nerve injuries; however, it is constrained by limited donor nerve availability, the need for secondary surgeries, and sensory loss at the donor site. Biodegradable material‐based nerve conduits have emerged as a promising alternative to address these limitations and enhance nerve regeneration. Among these materials, magnesium stands out due to its exceptional biocompatibility, biofunctionality, and neuroprotective properties. Despite its potential, magnesium's rapid corrosion rate and the need for controlled ion release necessitate advanced modifications, such as the development of Mg alloys. However, these approaches often face challenges, including viability concerns and material hardness, which can hinder nerve repair and damage surrounding tissues. In this study, a novel solution is introduced by sputtering magnesium onto a soft collagen sheet, achieving controlled magnesium ion release while preserving the material's nerve‐like softness. This Mg‐sputtered collagen sheet demonstrates excellent biocompatibility and significantly improves axon regeneration, muscle reinnervation, and functional recovery in a sciatic nerve defect model. These findings highlight the potential of an innovative Mg‐based biodegradable nerve conduit, offering transformative applications across various medical fields.

Objective Cortical delta band (1–4 Hz) activity is considered a biomarker for states of altered consciousness, with increased delta power observed during anesthesia, sleep, coma, and delirium. The current study sought to characterize delta power following electrode implantation with respect to patient demographics and clinical characteristics as well as type and duration of surgery. Methods Participants were 25 adult neurosurgical patients implanted with intracranial electrodes for clinical monitoring of their epilepsy. Resting state cortical activity was recorded at multiple occasions over the course of the monitoring period. The initial time point was defined as the first recording within 72 h following surgery. Analyses of cortical activity were conducted using a linear mixed effects modeling approach to account for within‐participant correlations and between‐participant heterogeneity. Results Throughout the monitoring period, delta power decreased in frontal, occipital, parietal, and temporal regions, indicating a global phenomenon. By contrast, beta (14–30 Hz) power remained stable. Delta power was higher following surgical cases that required craniotomy compared to stereoelectroencephalography cases. Surgery duration and anesthesia emergence duration were associated with higher delta power. Recordings from depth electrodes showed higher delta power compared to subdural electrodes. No significant effects of patients' age, sex, white blood cell count, antiseizure medication, and opioid medication dosage on postoperative delta power were found. Significance The results are consistent with a postoperative elevation in delta power that resolves over the course of the monitoring period and indicate an association between increased delta power and craniotomy surgery, as well as longer surgery and emergence durations. The current work provides a comprehensive analysis of surgical, clinical, and physiological factors, suggests risk factors, and lays fundamental groundwork for future studies.

Objectives Ferroptosis, a regulated form of cell death, has attracted significant attention in hearing loss research; however, the role of ferroptosis-related genes remains unclear. This study aimed to clarify diagnostic and therapeutic targeting of ferroptosis-related genes in hearing loss. Methods Differentially expressed genes related to hearing loss from the GEO database were intersected with ferroptosis-related genes. The Lasso and SVM-RFE models were applied to reduce the gene set, identifying model genes. Biological functions, pathways, and gene-drug associations related to these model genes were analyzed. Age-related hearing loss (ARHL) genes within the model genes were obtained from a genome-wide association study (GWAS) dataset. Further validation was conducted in HEI-OC1 cells and the cochleae of C57BL/6J mice, including auditory brainstem response (ABR) testing, qRT-PCR, Western blotting, Fe 2+ detection, and immunofluorescence analysis. Results The study identified 20 ferroptosis-related genes associated with hearing loss. Using Lasso and SVM-RFE models, a novel model was constructed, consisting of nine genes ( SCD, ENPP2, PANX2, NEDD4, MEF2C, ABCC5, KLHDC3, CYP4F8 and IFNA2 ). Among these, MEF2C and NEDD4 were found to be associated with ARHL. Conclusion Ferroptosis is a potential pathological mechanism in hearing loss research, and the nine ferroptosis-related genes identified provide promising targets for exploring new diagnostics and treatments for hearing loss. Notably, MEF2C and NEDD4 are associated with ARHL.

Presbycusis or age-related hearing loss (ARHL) affects millions of people worldwide, increasing their risk of cognitive decline and poor quality of life. However, ARHL remains an irreversible condition due to our inability to induce inner-ear hair cell regeneration. Nevertheless, multisession epidural stimulation of the auditory cortex (AC) at the onset of ARHL prevents hearing threshold elevation in naturally aging Wistar rats. Accordingly, we hypothesized that anodal direct current (DC) stimulation of the AC may also compensate for age-related maladaptive, activity-dependent changes. Here, we examined immunocytochemical markers in the AC, including early genes (c-fos and Arc), AMPA receptors (GluR2/3), parvalbumin (PV), and GAD67, along with auditory-evoked potentials (CAEPs) recorded in both auditory and visual (VC) cortices. When comparing 6 and 18.13-month-old rats without AC simulation, we observed loss of c-fos and Arc-positive neurons and decreased GluR2/3 expression, confirming altered AC neuronal network plasticity and activation. In addition, we noted changes in PV and decreased GAD67 immunoreactivity suggesting disrupted inhibition and significantly increased wave amplitudes in CAEPs, altered AC latencies, and decreased VC responses. By contrast, electrically stimulated rats showed no significant variations in early gene markers, GluR2/3, PV, or GAD67 with age, and the amplitudes and latencies of CAEPs recorded in their AC and VC resembled those of young rat. These findings indicate that anodal DC stimulation at the onset of ARHL delays AC aging by minimizing the loss of inhibition and preventing increases in cortical excitability in Wistar rats.

Social novelty preference is an important aspect of social interaction for evaluating new threats and opportunities for survival, but the underlying neuronal mechanism remains unclear. Here, we identify a molecularly defined medial prefrontal cortex (mPFC) excitatory neuron subtype, located in layer 5 expressing Il1rapl2 , which is highly associated with social deficit disorders in genome-wide association studies and might be responsible for regulating social novelty preference. Using an Il1rapl2 -Cre mouse line, we show that chemogenetic activation of the mPFC Il1rapl2 -expressing neurons impairs social novelty preference but with little effect on sociability. In addition, fiber photometry recording indicates that this neuron subtype is inhibited when mice interact with novel but not with familiar mice. Furthermore, viral tracing and terminal manipulation reveal that basolateral amygdala (BLA)–projecting Il1rapl2 + neurons mediate the social novelty preference. Thus, our study uncovers a molecularly defined mPFC-BLA circuit that specifically regulates social novelty preference, highlighting that specific neuron subtypes and circuits could modulate distinct aspects of social behaviors.

The hippocampus (HPC) supports spatial working memory (SWM) through its interactions with the prefrontal cortex (PFC). However, it is not clear whether and how the dorsal (dHPC) and ventral (vHPC) poles of the HPC make distinct contributions to SWM and whether they differentially influence the PFC. To address this question, we optogenetically silenced the dHPC or the vHPC while simultaneously recording from the PFC of mice performing a SWM task. We found that whereas both HPC subregions were necessary during the encoding phase of the task, only the dHPC was necessary during the choice phase. Unexpectedly, silencing of either subregion did not affect PFC neurons’ ability to represent the animal’s position, but did alter how it was represented. In contrast, only silencing of the vHPC affected their coding of spatial goals. These results thus reveal distinct contributions of the dorsal and ventral HPC poles to SWM and the coding of behaviorally relevant spatial information by PFC neurons.

Neurostimulation for cardiovascular control faces challenges due to the lack of predictive modeling for stimulus-driven dynamic responses, which is crucial for precise neuromodulation via quality feedback. We address this by employing a digital twin approach that leverages computational mechanisms underlying neuro-hemodynamic responses during neurostimulation. Our results emphasize the computational role of the nucleus tractus solitarius (NTS) in the brainstem in determining these responses. The intrinsic neural circuit within the NTS harbors collective dynamics residing in a low-dimensional latent space, which effectively captures stimulus-driven hemodynamic perturbations. Building on this, we developed a digital twin framework for individually optimized predictive modeling of neuromodulatory outcomes. This framework potentially enables the design of closed-loop neurostimulation systems for precise hemodynamic control. Consequently, our digital twin based on neural computation mechanisms marks an advancement in the artificial regulation of internal organs, paving the way for precise translational medicine to treat chronic diseases.

The auditory brainstem response (ABR) is an acoustically evoked EEG potential that is an important diagnostic tool for hearing loss, especially in newborns. The ABR originates from the response sequence of auditory nerve and brainstem nuclei, and a click-evoked ABR typically shows three positive peaks (“waves”) within the first six milliseconds. However, an assignment of the waves of the ABR to specific sources is difficult, and a quantification of contributions to the ABR waves is not available. Here, we exploit the large size and physical separation of the barn owl first-order cochlear nucleus magnocellularis (NM) to estimate single-cell contributions to the ABR. We simultaneously recorded NM neurons’ spikes and the EEG in owls of both sexes, and found that ≳ 5000 spontaneous single-cell spikes are necessary to isolate a significant spike-triggered average (STA) response at the EEG electrode. An average single-neuron contribution to the ABR was predicted by convolving the STA with the cell’s peri-stimulus time histogram. Amplitudes of predicted contributions of single NM cells typically reached 32.9 ± 1.1 nV (mean ± SE, range: 2.5–162.7 nV), or 0.07 ± 0.02 % (median ± SE; range from 0.01% to 1%) of the ABR amplitude. The time of the predicted peak coincided best with the peak of the ABR wave II, independent of the click sound level. Our results suggest that individual neurons’ contributions to an EEG can vary widely, and that wave II of the ABR is shaped by NM units.

Rationale: The GJB2 gene, which encodes connexin 26 (Cx26), is recognized as the leading cause of non-syndromic hereditary hearing loss. In clinical settings, a total of 131 Cx26 mutations have been identified in association with hearing loss. Certain Cx26 mutants display normal structural and functional properties but fail to translocate to the plasma membrane. Enhancing the membrane localization of these mutants may provide a promising strategy for rescuing hearing loss and hair cell degeneration. Methods: This study investigated the membrane localization of Cx26 using in vitro cell lines, cultured cochlear explants, and in vivo murine models. Key proteins involved in the membrane localization of Cx26 were identified and validated through immunoprecipitation-mass spectrometry (IP-MS) and co-immunoprecipitation (Co-IP). Additionally, cell lines and murine models harboring Cx26 mutants were developed to evaluate the effects of Narciclasine on enhancing the membrane localization of these mutants, as well as its potential to rescue hearing loss. Results: The membrane localization of Cx26 was dependent on the integrity of the intracellular transport network consisting of microtubules, actin microfilaments, and the Golgi apparatus. Additionally, SPTBN1 played a significant role in this process. The transmembrane domain 4 (TM4) region exhibited a strong association with the membrane localization of Cx26, and Cx26 mutants located in TM4 region retained in the cytoplasm. Narciclasine promoted cytoskeletal development, thereby enhancing the membrane localization of Cx26 mutants retained in the cytoplasm. This process helped to reconstruct the inner ear gap junction network and rescue hearing loss and hair cell degeneration. Conclusion: These findings present that enhancing the membrane localization of Cx26 mutants can significantly improve auditory function. This strategy offers a potential therapeutic approach for addressing hereditary sensorineural hearing loss associated with GJB2 mutations.

Early studies on orientation selectivity in the visual cortex have suggested that sensory systems generate new feature representations at specific processing stages. Many observations challenge this view, but in the absence of systematic, multistage measurements, the logic of how feature tuning emerges remains elusive. Here, using a generic approach based on representational similarity analysis with a noise-corrected population metric, we demonstrate in the mouse auditory system that feature representations evolve gradually with, in some cases, major, feature-specific improvements at particular stages. We observe that single frequency tuning is already fully developed in the cochlear nucleus, the first stage of processing, while tuning to higher-order features improves up to the auditory cortex, with major steps in the inferior colliculus for amplitude modulation frequency or noise bandwidth tuning and in the cortex for frequency modulation direction and for complex sound identity or direction. Moreover, we observe that intensity tuning is established in a feature-dependent manner, earlier for pure frequencies than for more complex sounds. This indicates that auditory feature computations are a mix of stepwise and gradual processes which together contribute to decorrelate sound representations.

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive method that has been used to treat various brain disorders. The modulatory effects of rTMS can be adjusted by changing the repetition patterns. Theta-burst magnetic stimulation (TBS) is a magnetic stimulation pattern that can induce long-lasting modulatory effects with a short stimulation period. However, its effects on auditory brain regions remain unclear because of a lack of animal studies in which invasive techniques allow for a detailed exploration of the underlying neural mechanisms. In the current study, we investigated the effects of TBS on the C57BL/6J mouse auditory cortex using a custom-built 7 mm magnetic stimulation coil. Extracellular recordings were made before, during, and after the application of intermittent TBS (iTBS), continuous TBS (cTBS), or sham stimulation. Local field potential amplitudes were increased for 5–20 min post-iTBS compared with the sham condition and were decreased at 10 min post-cTBS compared with the sham condition. The bidirectional modulatory effects observed in our study are consistent with previous findings from other brain regions. Additionally, multiunit activities were significantly altered in cortical layers 2/3 and 4 but not layer 5, indicating that the modulatory effects were localized to the surface region of the auditory cortex. Interestingly, in the iTBS group, the amplitude of average spike waveforms increased with a 15 min delay. Our findings provide physiological evidence of TBS modulation of the rodent auditory cortex and may guide future research seeking to optimize rTMS for modulating hearing abilities.

Lateralized auditory processing is essential for specialized functions such as speech processing, typically dominated by the Left Auditory Cortex (ACx) in humans. Hemispheric specializations also occur in the adult mouse ACx, but their developmental origins are unclear. Our study finds that the Left and Right ACx in mice reach developmental milestones at different ages. Thalamocortical responses and maturation of synaptic dynamics develop earlier in the Right ACx than the Left. We show that this timing offset predicts hemisphere-dependent differences in sensory-driven plasticity. Juvenile tone exposure at specific times results in imbalanced adult tone frequency representations in the Right and Left ACx. Additionally, sex influences the timing of plasticity; female Right ACx plasticity occurs before male Right ACx, and female Left ACx aligns with male Right ACx plasticity. Our findings demonstrate that sex and hemispheric identity drive asynchronous development and contribute to functional differences in sensory cortices.

Purpose In the receptor organs of the inner ear, hair cells detect mechanical stimuli such as sounds and accelerations by deflection of their hair bundles. Myosin regulatory light chain (RLC) and non-muscle myosin II (NM2) are expressed at the apical surfaces of hair cells, and NM2 and the phosphorylation of RLC by myosin light chain kinase (MLCK) have earlier been shown to regulate the shapes of hair cells’ apical surfaces in rodents. The aim of our study was to elucidate the function of myosin molecules on hair cell physiology. Methods We investigated the expression of NM2 and RLC in the bullfrog’s saccule by immunostaining. Using NM2 and MLCK inhibitors, we measured the stiffness, spontaneous oscillation, and resting open probability of frog hair bundles. Six to ten saccules from pleural animals were used in each experiment. In addition, we recorded auditory brainstem responses in ten mice after transtympanic injection of an MLCK inhibitor. Results We confirmed the expression of NM2A/B and MYL9 on the apical surfaces of hair cells and of NM2A and MYL12A in hair bundles. We found that NM2 and MLCK inhibitors reduce the stiffness of hair bundles from the bullfrog's saccule. Moreover, MLCK inhibition inhibits the spontaneous oscillation of hair bundles and increases the resting open probability of transduction channels. In addition, MLCK inhibition elevates hearing thresholds in mice. Conclusion We conclude that NM2 and the phosphorylation of RLC modulate the physiological function of hair cells and thereby help to set the normal operating conditions of hair bundles.

Introduction Tinnitus is the perception of non-meaningful sound in the absence of external stimuli. Although tinnitus behavior in animal models is associated with altered central nervous system activity, it is not currently possible to identify tinnitus using neuronal activity alone. In the mouse inferior colliculus (IC), a subpopulation of neurons demonstrates a sustained increase in spontaneous activity after a long-duration sound (LDS). Methods Here, we use the “ LDS test ” to reveal tinnitus-specific differences in sound-evoked plasticity through IC extracellular recordings and the auditory brainstem response (ABR LDS ) in CBA/CaJ mice after sound exposure and behavioral tinnitus assessment. Results Sound-exposed mice showed stronger and shorter tone-evoked responses in the IC compared to unexposed controls, but these differences were not strong predictors of tinnitus. In contrast, in the LDS test, non-tinnitus mice had a significantly stronger suppression in tone-evoked spike rate compared to tinnitus and unexposed control mice. ABR peak amplitudes also revealed robust differences between tinnitus and non-tinnitus mice, with ABR peaks from non-tinnitus mice exhibiting significantly stronger suppression in the LDS test compared to tinnitus and control mice. No significant differences were seen between cohorts in ABR amplitude, latency, wave V:I ratio, wave V:III ratio, I-V intra-peak latency, and I-VI intra-peak latency. We found high-frequency tone stimuli better suited to reveal tinnitus-specific differences for both extracellular IC and ABR recordings. Discussion We successfully used the LDS test to demonstrate that tinnitus-specific differences in sound-evoked plasticity can be shown using both multi-unit near-field recordings in the IC and non-invasive far-field recordings, providing a foundation for future electrophysiological research into the causes and treatment of tinnitus.

Simultaneous fiber photometry and optogenetics is a powerful emerging technique for precisely studying the interactions of neuronal brain networks. However, spectral overlap between photometry and optogenetic components has severely limited the application of an all-optical approach. Due to spectral overlap, light from optogenetic stimulation saturates the photosensor and occludes photometry fluorescence, which is especially problematic in physically smaller model organism brains like mice. Here, we demonstrate the multi-frequency interpolation X-talk removal algorithm (MuFIX or μFIX) for recovering crosstalk-contaminated photometry responses recorded with lock-in amplification. μFIX exploits multifrequency lock-in amplification by modeling the remaining uncontaminated data to interpolate across crosstalk-affected segments (R2 ≈ 1.0); we found that this approach accurately recovers the original photometry response after demodulation (Pearson's r ≈ 1.0). When applied to crosstalk-contaminated data, μFIX recovered a photometry response closely resembling the dynamics of noncrosstalk photometry recorded simultaneously. Upon further verification using simulated and empirical data, we demonstrated that μFIX reproduces any signal that underwent simulated crosstalk contamination (r ≈ 1.0). We believe adopting μFIX will enable experimental designs using simultaneous fiber photometry and optogenetics that were previously not feasible due to crosstalk.

Age-related hearing loss (ARHL) is a highly prevalent, burdensome sensorineural hearing loss closely associated with impaired autophagic influx. Our previous studies revealed that neuritin, a neurotrophic factor primarily expressed in the central nervous system, could alleviate drug-induced damages in hair cells (HCs) and spiral ganglion neurons. However, its effects on ARHL and whether these effects are closely related to autophagy remain unclear. Using the Nrn1 knock-in mice and cultured cochlear basilar membrane (CBM) of the neonatal mouse, we show that neuritin could restore aging-associated hearing loss and alleviate senescence-associated damage in the cochlea. Overexpression of neuritin in support cells (SCs) alleviates the loss of cochlear HCs and nerve fibers, reducing the damage to spiral ganglion neurons and the shifts in ABR’s high-frequency threshold. Furthermore, conditional overexpression of neuritin in SCs improves autophagic influx by upregulating the expression of microtubule-associated protein 1 light chain 3 type B (LCB3) protein and downregulating the expression of p21 protein. In cultured neonatal mouse CBM, neuritin administration significantly inhibits D-galactose-induced HC loss, cellular apoptosis, and ROS production and promotes autophagic influx. These effects were weakened when the autophagy inhibitor 3-MA was added. In summary, our results confirm the therapeutic potential of neuritin treatment for ARHL.