Journal of Neuroscience最新文献

Most general anesthetics have long been believed to work by exerting a wide range of inhibitory impacts on the central nervous system, yet accumulating evidence has highlighted their excitatory effects-particularly that multiple anesthetics activate a common neural target to induce anesthesia. However, it remains unclear whether three widely used volatile anesthetics (isoflurane, sevoflurane, desflurane) with similar pharmacokinetic and pharmacodynamic properties share a common brain region for their anesthetic effects, and most receptors mediating the excitatory effects of general anesthetics remain unidentified. To explore the shared excitatory neural targets of common volatile anesthetics, we combined c-Fos staining, targeted recombination in active populations (TRAP), fluorescence in situ hybridization (FISH) in adult male and female mice, and molecular docking prediction to characterize anesthetic-activated neurons, their cell types, and potential mediating receptors. We found that desflurane and sevoflurane, except isoflurane, significantly increased c-Fos expression in Edinger-Westphal (EW) neurons with high urocortin 1 (UCN1) expression. Chemogenetic inhibition of sevoflurane-activated EW neurons shortened the emergence time from desflurane anesthesia without significantly changing the induction time. Furthermore, growth hormone secretagogue receptor (GHSR) was substantially enriched in both sevoflurane-and desflurane-activated EW neurons, and local knockdown of GHSR in EW neurons accelerated recovery from both anesthetics. These findings suggest that UCN1⁺ EW neurons and GHSR contribute greatly to recovery from desflurane and sevoflurane anesthesia.Significance Statement Intraoperative use of reversal agents is a standard strategy to accelerate post-anesthetic recovery, yet no specific reversal agents for volatile anesthetics are currently available in clinical practice. Here, we found that desflurane and sevoflurane activated Urocortin 1-positive neurons in the Edinger-Westphal nucleus (EW UCN1⁺ neurons)-an area implicated in alcohol addiction, stress responses, and nesting behavior-that highly express growth hormone secretagogue receptor (GHSR). On the cellular level, chemogenetic inhibition of sevoflurane-activated EW neurons accelerated emergence from desflurane anesthesia. On the molecular level, local knockdown of EW GHSR sped up arousal from desflurane and sevoflurane anesthesia. Thus, these findings provide a potential common target for developing anesthetics with faster recovery and reversal agents for sevoflurane and desflurane.

A central question in sensorimotor neuroscience is how sensory inputs are mapped onto motor outputs to enable swift and accurate responses, even in the face of unexpected environmental changes. Here, we leverage corticomotor coherence as a window into the dynamics of sensorimotor loops and explore how it relates to online visuomotor control. We recorded brain activity using electroencephalography, while human participants (of either sex) performed an isometric tracking task involving transient, unpredictable visual perturbations. Our results show that coherence between cortical activity and motor output (force) in the alpha band (8-13 Hz) is associated with faster motor responses, while beta-band coherence (18-30 Hz) promotes more accurate control, which is in turn linked to a higher likelihood of obtaining rewards. Both effects are most pronounced near the onset of the perturbation, underscoring the predictive value of corticomotor coherence for sensorimotor performance. Single-trial analyses further reveal that deviations from the preferred corticomotor phase relationship are associated with longer reaction times and larger errors, and these phase effects are independent of power effects. Thus, beta-band coherence may reflect a cautious, reward-efficient control strategy, while alpha-band coherence enables quicker, though not necessarily efficient, motor responses, indicating a complementary, reactive control mode. These results highlight the finely tuned nature of sensorimotor control, where different aspects of sensory-to-motor transformations are governed by frequency-specific neural synchronization on a moment-to-moment basis. By linking neural dynamics to motor output, this study sheds light on the spectrotemporal organization of sensorimotor networks and their distinct contribution to goal-directed behavior.

The unfolded protein response (UPR) sensor PERK exists in haplotypes A and B. PERK-B confers increased risk for tauopathies like progressive supranuclear palsy (PSP), but the mechanisms distinguishing its function from PERK-A and contributing to its association with tauopathy remain unknown. Here, we developed a controlled cellular model for a pair-wise comparison of the two PERK haplotypes, finding their UPR functions nearly indistinguishable. Puromycin-based proteomics highlighted a subset of mRNA translation events was permissible under the PERK-B, but not the PERK-A, dependent UPR. One of the targets that escaped PERK-B suppression was the transcription factor DLX1, which is genetically linked to PSP risk. We found that DLX1 solubility shifted to a detergent-insoluble fraction in human brain tissue from male and female PSP donors. Furthermore, silencing the fly homolog of DLX1 was sufficient to decrease tau-induced toxicity, in vivo. Our results detail the haplotype-specific PERK-B/DLX-1 pathway as a novel driver of tau pathology in cells, flies, and likely human brain, revealing new insights into PSP pathogenesis and potential therapeutic targets.Significance Statement Progressive supranuclear palsy (PSP) is a devastating neurodegenerative tauopathy with no effective treatments. This study identifies how a genetic risk factor for PSP, the PERK-B haplotype, contributes to disease pathogenesis. Using novel cellular and animal models, we demonstrate that PERK-B selectively promotes translation of DLX1, a transcription factor genetically linked to PSP. Importantly, DLX1 accumulates in a detergent insoluble fraction in human PSP brains, and reducing DLX1 mitigates tau-induced toxicity in vivo. These findings reveal a previously unknown PERK-B/DLX1 pathway that drives tauopathy. By elucidating this mechanism, our work opens new avenues for therapeutic intervention in PSP and related tauopathies. More broadly, this research highlights the importance of haplotype-specific effects and selective translational regulation in neurodegenerative disease, with implications for personalized medicine approaches.

Our daily interactions with the world are shaped by sensory expectations informed by context and prior experiences, which in turn influence how we allocate our attention. Prominent predictive coding models suggest that sensory expectancy and attention interact but disagree on the precise mechanisms. One possibility is that the ventral attention network (VAN) may play a role by facilitating attentional reorienting when expectancy is violated. To test this in humans (23 males and 43 females), we employed an auditory-visual trial-by-trial cueing paradigm in three experiments integrating EEG and fMRI to investigate the VAN's role in violations of cross-modal expectancy. Behavioral results showed faster responses to expected targets, confirming the efficacy of cue-induced expectations in orienting attention to the expected target modality. EEG analyses revealed differences in early (∼100 ms latency) event-related potentials (ERPs) to both auditory and visual stimuli when expectations were violated. Unexpected stimuli elicited significantly larger early-latency negative ERPs, across both modalities. Source localization of these ERPs and subsequent fMRI evidence revealed activation in the right VAN. Functional connectivity analyses showed greater coupling between VAN regions and sensory cortices, with modality-specific pathways involving superior temporal gyrus for auditory and fusiform gyrus for visual targets. These findings demonstrate that expectancy violations recruit the VAN to reorient attention and resolve sensory conflict. By coordinating top-down control and bottom-up sensory input, the VAN supports adaptive responses to unexpected stimuli. This work advances our understanding of predictive processing in multisensory perception and highlights the VAN's central role in flexible cognitive control.

In addition to providing outputs from the cerebellar cortex, Purkinje cell (PC) axon collaterals target other PCs, molecular layer interneurons (MLIs), and Purkinje layer interneurons (PLIs). It was assumed that PC collaterals to MLI synapses provide positive feedback to PCs via the PC-MLI-PC pathway, because it was thought that MLIs primarily inhibit PCs. However, it was recently shown that MLIs consist of two subtypes: MLI1s primarily inhibit PCs, whereas MLI2s mainly inhibit MLI1s and disinhibit PCs. Clarifying PC connectivity onto these MLI subtypes is vital to understanding the influence of feedback from PC collaterals. Here we use a combination of serial electron microscopy (EM) and optogenetic studies to characterize PC synapses onto MLI subtypes in mice of either sex. EM reconstructions show that PCs make 53% of their synapses onto other PCs, 32% onto PLIs, 6% onto MLI1s, and 7% onto MLI2s. Since there are far more MLI1s than MLI2s, each MLI2 is expected to receive many more synapses than each MLI1. In slice experiments, optogenetic activation of PCs evokes inhibitory currents in most MLI2s but primarily disinhibits MLI1s. We also find that candelabrum cells, a type of PLI, form many more synapses onto MLI1s than MLI2s. These findings suggest that PC-MLI synapses do not primarily disinhibit PCs and that the PC-MLI2-MLI1-PC and PC-PLI-MLI1-PC pathways might provide negative feedback to PCs that acts in concert with PC-PC synapses to counter elevations in PC firing.

A spatial filter combines signals from multiple sensors to create a virtual channel that emphasizes specific brain activity while reducing interference. Spatial filters range from simple, fixed configurations-such as rereferencing, gradient, or Laplacian filters-to more sophisticated, data-driven approaches like beamforming or independent component analysis (ICA). Although the underlying principle is simple, understanding a spatial filter's behavior can be challenging because of the high dimensionality of the data and the multiple "spaces" involved-those of sources, sensors, fields, and signals. This paper examines the properties and limitations of spatial filters, focusing on the idea of a virtual electrode-a synthetic signal formed by combining channels from noninvasive techniques such as EEG or MEG. While a spatial filter can fully suppress some sources, it cannot perfectly isolate a single source while rejecting all others, as a real electrode could. This places clear limits on what a virtual electrode can represent. I here suggest an alternative view of it as a virtual scalpel-a tool for refining recorded data rather than capturing activity of a single neural source. Just as temporal filters shape signals over time, spatial filters are key tools for improving the clarity and interpretability of brain recordings.

The brain and spinal cord originate from a neural tube that is preceded by a flat structure known as the neural plate during early embryogenesis. In humans, failure of the neural plate to convert into a tube by the fourth week of pregnancy leads to neural tube defects (NTDs), birth defects with serious neurological consequences. The signaling mechanisms governing the process of neural tube morphogenesis are unclear. Here we show that in Xenopus laevis embryos glutamate is released during neural plate folding in a Ca²⁺ and vesicular glutamate transporter-1 (VGluT1)-dependent manner. Vesicular release of glutamate elicits Ca²⁺ transients in neural plate cells that correlate with activation of Erk1/2. Knocking down or out VGluT1, globally or neural tissue-specifically, leads to NTDs and increased expression of Sox2, neural stem cell transcription factor, and neural plate cell proliferation. Exposure during early pregnancy to neuroactive drugs that disrupt these signaling mechanisms might increase the risk of NTDs in offspring.Significance Statement Neural tube defects are serious and common birth defects that occur when the neural tube fails to form and close at four weeks of pregnancy. Use of antiepileptic drugs during early pregnancy increases the risk of these defects by unclear mechanisms. Here we show that vesicular release of glutamate occurs during and is necessary for neural tube formation in Xenopus laevis embryos. This study motivates discussion on the presynaptogenic signaling mechanisms in the nervous system and their role during these early developmental stages, challenging the prevailing paradigm that neurotransmission is not apparent until neurons fully differentiate and synapses are formed.

The binocular circuitry in mammals (e.g., mice, cats, and primates) integrates two distinct visual cortical circuitries-the contralateral and ipsilateral eye circuitries-into a cohesive functional system for three-dimensional vision. These two circuitries, differing in their developmental timing and trajectories, demonstrate the intricate interplay between innate genetic programs and experience. The contralateral eye cortical circuitry, largely laid down by intrinsic mechanisms and maturing earlier, establishes an initial framework, whereas the later-developing ipsilateral eye circuitry, established and refined through visual experience, aligns with and is integrated into this framework to achieve precise functional connectivity. We propose that this mechanism of binocular circuitry development, wherein distinct circuits are progressively refined and integrated under the influence of environmental stimuli, exemplifies a fundamental organizing principle governing the development of the entire cortical architecture. Such integration enables different cortical areas to combine diverse streams of information, improving processing capabilities and optimizing neural circuits to support more sophisticated functions, ultimately facilitating advanced sensory-motor coordination and complex behaviors.

The prefrontal cortex (PFC) and hippocampus (HPC) reportedly play crucial roles in the flexible use of stored information according to context. However, it remains unclear whether and how their neural representations differ during the context-guided retrieval. To solve this problem, we examined neural activity in the lateral PFC (lPFC, 470 neurons), medial PFC (mPFC, 322 neurons), and HPC (456 neurons) of two male macaques performing an item-location association memory task. The task required the animals to remember the location of a firstly-presented item-cue relative to a background image that was later shown with a tilt as a context-cue. Population-decoding analyses using all recorded neurons suggested that the lPFC and HPC (but not the mPFC) represented substantial task-related information. However, the represented contents differed between the two areas, both before and after the context-cue. Before the context-cue, the lPFC represented only the location retrieved from the item-cue, while the HPC also represented the item-cue itself. After the context-cue, the lPFC demonstrated a selective representation of the target-location regardless of the context-cue. In contrast, the HPC represented the three task-related pieces of information equivalently. These results suggest that the lPFC selectively represents goal-directed information at that moment among task-related information while the HPC automatically represents a task event and its mnemonically-linked information, implying complementary functional roles of the two brain regions as "regulator" and "supplier" in the context-guided memory process.Significance statement Population decoding analysis of macaque single-unit data revealed neural representations in both the prefrontal cortex (PFC) and hippocampus (HPC), suggesting distinct and complementary roles in the flexible use of past memory within the current context. Previous studies have emphasized the goal-directed information represented by the HPC. However, the present study suggests that the HPC may simply sustain preceding events and associated memory traces regardless of task relevance, although some memory traces may correspond to goal-directed information. In contrast, the PFC, particularly the lateral PFC, selectively maintains goal-directed information. These findings depict neural operations of the HPC and PFC as "supplier" and "regulator" in the context-guided memory process.

Perception is increasingly viewed as an inferential process wherein sensory inputs are integrated with prior expectations. We employed time-resolved decoding on electroencephalography (EEG) data (n = 30 male participants) to investigate how expectations modulate sensory processing across varying levels of stimulus complexity, and tested the effect of attention and NMDA receptor blockade. We designed a visual stimulus containing features of different complexity whose processing relies on distinct neural mechanisms: local contrast, collinearity, and the Kanizsa illusion, involving primarily feedforward, lateral, and feedback processes, respectively. EEG decoding revealed that expectations modulated lateral and feedback processing (better decoding for unexpected stimuli) but not feedforward processing. These expectation effects were confined to attended (task-relevant) features and were not observed for task-irrelevant features. The NMDA receptor antagonist memantine selectively enhanced decoding of the Kanizsa illusion, implicating NMDA-mediated feedback mechanisms in perceptual inference, but it did not modulate the effects of expectation or attention. These findings highlight the differential impact of expectations across different stages of sensory processing and reveal a distinct role of NMDA receptor-mediated feedback mechanisms.Significance statement Perception integrates sensory inputs with prior expectations. Using EEG decoding, we examined how expectations shape sensory processing at different levels of complexity and tested the effects of attention and NMDA receptor blockade. Our visual stimuli were designed to capture EEG markers of feedforward, lateral, and feedback mechanisms. Expectations influenced lateral and feedback processing (better decoding for unexpected stimuli) but not feedforward processing, and these effects were selective to task-relevant stimulus features. Memantine, an NMDA receptor antagonist, selectively improved decoding of the Kanizsa illusion, implicating NMDA-mediated feedback in perceptual integration, but it did not shape expectation or attention effects.