搜索结果：circuits

This study aimed to develop a novel PET reporter gene imaging system based on modified wheat germ agglutinin (mWGA) and tyrosinase (TYR) for tracing trans‑monosynaptic neural circuit in vivo. Mouse neural stem cells NE4C were engineered via lentiviral transduction to express mWGA-TYR and GFP. TYR expression was confirmed by western blot and RT-qPCR. Melanin production was assessed using Masson-Fontana staining, gamma counting, and 18F-FPABZA PET imaging. In vitro trans-synaptic transfer was evaluated by co‑culturing transduced NE4C cells with naive cells. To validate the system in the normal brain, an rAAV vector encoding mWGA-TYR was delivered into the right sensorimotor cortex. In vivo melanin transport along neural circuits was traced by 18F-FPABZA PET imaging and confirmed by ex vivo immunofluorescent staining. Finally, the system was tested in an ischemic stroke model following NE4C transplantation. Lentiviral transduction of NE4C cells led to successful expression of mWGA, TYR and GFP. Masson‑Fontana staining confirmed melanin production, while gamma counting and 18F‑FPABZA PET imaging showed significantly higher radiotracer uptake in TYR‑expressing cells in vitro. In co‑culture experiments, mWGA‑TYR underwent trans‑synaptic transfer from transduced to naive NE4C cells. Following rAAV injection into the right sensorimotor cortex, 18F‑FPABZA PET signals were detected in multiple brain regions, with ex vivo immunofluorescence corroborated these connectivity patterns. In the ischemic stroke model with NE4C transplantation, elevated PET signals were observed at both the transplantation site and distal sites two weeks after transplantation, which was further validated by ex vivo analyses. Furthermore, HSV‑1‑H129 tracing confirmed the anterograde trans‑monosynaptic capability of mWGA‑TYR system. This study developed a novel mWGA-TYR PET reporter gene system for non-invasive in vivo tracing of anterograde trans-monosynaptic neural circuits. This system can be extended to monitor graft-host neural circuit connections in stem cell therapy for ischemic stroke.

Presynaptic neurexins are key regulators of synapse properties that arguably represent the best-studied synaptic adhesion molecules. Despite thousands of papers, however, no direct comparison of overall neurexin functions in different types of synapses is available. A decade ago, we provided such an analysis but we recently retracted this paper because four images contained microduplications that, although without discernible impact on the paper's conclusions, could not be corrected. As a result, the scientific community lost access to primary data that established the fundamental principle that neurexins perform profound but distinct functions in different types of synapses. In the present study, we have therefore reanalyzed the original raw data and expanded their conclusions with new experiments to document in a single study the basic contributions of neurexins to different synapses. Using triple conditional knockout mice that target all neurexins except for Neurexin-1γ and applying neuron-specific manipulations combined with slice electrophysiology, two-photon Ca 2+ imaging and immunohistochemistry, we focussed on excitatory climbing-fiber synapses in the cerebellum and on inhibitory synapses formed by parvalbumin-or somatostatin-positive neurons in the cerebellum, hippocampus, and medial prefrontal cortex. Our results show that pan-neurexin deletions produce dramatically different phenotypes in synapses, ranging from modest to massive impairments in synapse assembly (climbing-fiber and parvalbumin-positive synapses) to severe but selective decreases in presynaptic action potential-induced Ca 2+ -transients (somatostatin-positive synapses). Thus, neurexins perform powerful but distinct context-dependent roles in different synapses that shape the brain's circuits. Neurexins are abundant presynaptic adhesion molecules expressed from three genes in more than a thousand splice variants. Although neurexins are well studied, no analysis that compares neurexin deletions in multiple types of synapses is currently available. Here, we provide such an analysis by examining triple conditional knockout mice that delete all neurexins except for Neurexin-1γ. Using neuron-specific manipulations combined with slice electrophysiology, two-photon Ca 2+ imaging and immunohistochemistry, we show that pan-neurexin deletions produce distinct phenotypes in different synapses, ranging from impairments in synapse assembly (climbing-fiber and parvalbumin-positive cortical synapses) to severe selective decreases in presynaptic action potential-induced Ca 2+ -transients (somatostatin-positive cortical synapses). Our data reveal context-dependent distinct functions of neurexins in different synapses whose properties shape the input-output relations of neural circuits.

The human brain exhibits extraordinary computational capabilities, enabled by its intricate network of neuronal interconnections and parallel signal transmission pathways. Nanofluidic memristors, which dynamically modulate ionic conductance through controlled ion transport, have shown promise in emulating synaptic functions. Here, we report an integratable nanofluidic memristor based on a hydrogel covered SiNx nanopore, which modulates its ionic conductance via voltage induced ion concentration polarization. By tuning the diameter of SiNx nanopore, the ionic device functionalities can switch from memristor to capacitor. Moreover, this nanofluidic memristor are capable of mimicking diverse synaptic plasticity behaviors, such as paired-pulse facilitation/depression and synaptic weight potentiation/depression. Notably, it can serve as a neuromorphic synaptic element for information processing, storage, and encoding, achieving an accuracy of 93.8% in the MNIST handwritten digit classification task. Finally, fluidic memristors are integrated to construct fluidic ionic circuits, which are applied for logic functions. This architecture based on hydrogel covered SiNx nanopore devices offers an innovative strategy for the design of integrated iontronic circuits and provides an experimental foundation for neuromorphic computing in liquid environments.

Realizing tunable charge carrier polarity is essential for programmable complementary logic circuits. While two-dimensional (2D) semiconductors have demonstrated polarity controllability through Schottky barrier modulation or contact engineering, their high interfacial sensitivity limits scalability and integration. Here, we present a robust polarity-conversion strategy for tin oxide (SnO) semiconductors based on electrolyte-gated transistors (EGTs). In situ electrochemical doping enables the conversion of p-type SnO to n-type SnO2 via Sn2+ to Sn4+ oxidation. Both p- and n-type EGTs exhibit outstanding electrical characteristics, including low-voltage operation, high ON/OFF current ratios, sharp switching behavior, and reliable long-term stability. Furthermore, we demonstrate the monolithic integration of complementary logic gates, including inverter, NAND, and NOR gates, through spatially selective electrochemical doping of a single SnO layer. Overall, this work provides a scalable and versatile pathway toward oxide-based programmable complementary circuits.

The controlled synthesis of transition metal dichalcogenide (TMD) ribbon arrays represents a promising route toward integrating 2D semiconductors into large-scale circuits. However, in ribbon synthesis, excessively large diameters of transition metal source droplets lead to a dominant non-directional surface driving force, which disrupts directional droplet migration and consequently hinders the growth of ribbon arrays. In this work, we leverage the surface energy difference to provide a driving force for the molten precursor droplets, while the atomic steps of the sapphire substrate impart directionality to this force. The introduction of Ni substantially reduced the droplet size, which significantly enhanced the efficacy of this directional driving force. Based on this approach, we successfully guided the directional migration of molten transition metal precursor droplets, thereby enabling the fabrication of highly aligned ribbon arrays. In situ visual chemical vapor deposition enables in situ observation of droplet-mediated growth, while density functional theory calculations and force analyses elucidate the underlying driving mechanisms. This work provides both a mechanistic framework and a versatile synthesis strategy for the scalable fabrication of well-aligned TMD ribbon arrays suitable for next-generation 2D semiconductor integration.

The brain does not process the present in isolation. Its responses are shaped by the accumulating weight of prior states, yet existing frameworks treat large-scale brain dynamics as sequences of transient configurations, leaving the constraining influence of history formally unspecified. Here we show that the brain possesses an intrinsic, representation-agnostic organizing constraint, the degree to which accumulated prior states resist ongoing reorganization, which we term functional inertia. Using an inertial state-space model replicated across two independent observational frameworks, we demonstrate that functional inertia operates coherently across three levels of brain organization: it structures activity into dynamical regimes, links these regimes to clinical and cognitive expression through a system-level inertial magnitude, and distributes across circuits in patterns that reconcile the longstanding coexistence of associative rigidity and sensory volatility in schizophrenia. Critically, removing the cumulative integration collapses this multilevel organization. Strikingly, the system-level inertial magnitude carries opposite cognitive signatures across diagnostic contexts, predicting better performance in healthy individuals but greater symptom severity in schizophrenia, reflecting context-dependent expression of a single constraint. These findings position functional inertia as a unifying, multilevel constraint on brain reorganization, recasting stability and volatility not as opposing properties but as context-dependent expressions of a single constraint.

Fistulizing Crohn's disease represents a severe and disabling complication characterized by transmural inflammation and aberrant tissue remodeling. Although fissures are considered precursors of fistulas, the cellular and molecular mechanisms driving this transition remain poorly defined. We aimed to characterize the spatial immune-stromal interactions underlying fissure formation and progression toward fistula. Spatial transcriptomics was performed on intestinal surgical specimens from Crohn's disease patients with inflamed tissue, fissures of increasing depth, and entero-enteric fistulas. Spatial data were integrated with single-cell reference and ligand-receptor analysis to define cellular programs and signaling networks across tissue niches. Fissure-associated regions were enriched in inflammatory fibroblasts and inflammatory monocytes, identifying fissures as active immune-stromal niches rather than passive structural defects. Integration with independent single-cell datasets confirmed the association of these signatures with Crohn's disease fistulae, while comparison with non-Crohn's fistulas and ulcerative colitis supported disease specificity. Single-cell-informed pseudotime analysis identified coordinated stromal and myeloid remodeling programs associated with inflammatory fibroblast enrichment and macrophage/LAMP3 + dendritic cell states. Ligand-receptor analysis demonstrated a progressive shift from CXCL12-CXCR4-mediated immune recruitment toward Complement activation and adhesion-mediated retention circuits involving ADGRE5-CD55 and THY1-integrin pathways, defining a spatially organized fistula-associated immune-stromal niche. Fissures represent active immune-stromal niches in which coordinated remodeling programs support the development of the fistula microenvironment. These findings identify early fissure-associated remodeling as a potential therapeutic window and highlight CXCR4, complement, and immune-stromal adhesion pathways as candidate targets to intercept fistula progression in Crohn's disease.

Animals must constantly calibrate the costs and benefits of exploration of an environment based on expectations of danger. These decisions are strongly shaped by past experience of perceived threats within that environment and by internal state, which is strongly modulated by circulating gonadal hormones. Although the circuits underlying threat detection are relatively well characterized, how sex hormones shape the long-term behavioral consequences of prior threat experience, and whether this differs across sexes, remains unknown. Here, we show that female mice, like males, exhibit robust long-term threat avoidance (LTTA), avoiding a location where they previously experienced a single visual threat. However, we find that in females this behavior shows strong modulation by the estrous cycle. Surprisingly, we find that though male and female LTTA is driven through glutamate release by the melanopsin-projecting intrinsically photosensitive retinal ganglion cells (ipRGCs) in the thalamic perihabenular nucleus, disruption of this circuit drives completely opposing effects on male versus female LTTA. Moreover, hormonal modulation of LTTA in females requires functional ipRGC input. Thus, despite similar circuit architecture and behavioral outcomes, the individual components of the LTTA circuit play opposing roles in shaping this behavior in males and females, and female LTTA is further tuned by hormonal status.

Psychological adaptability hinges on the dynamic balance between cognitive regulation (self-control) and emotional reactivity (impulsivity, reward/punishment sensitivity). However, traditional variable-centered approaches often fail to capture how these traits holistically co-occur, and the neural architectures predicting their longitudinal transitions in early adulthood remain under-explored. This longitudinal study (N = 1,229 baseline; N = 432 2-year follow-up) integrated a person-centered behavioral approach with resting-state fMRI. We employed Latent Profile Analysis (LPA) to identify trait configurations based on self-control, impulsivity, and sensitivity to reward/punishment. Network-Based Statistic (NBS) analysis with family-wise error (FWE) correction was utilized to evaluate functional connectivity differences among groups. Finally, hierarchical regression and formal interaction models were conducted to test the prospective predictive validity of the identified neural circuits. LPA delineated three distinct baseline profiles: Adaptive, Moderate, and Maladaptive. NBS analysis revealed that the 'Adaptive' profile is underpinned by robust cortico-striatal functional connectivity, integrating the medial prefrontal cortex and striatum. Longitudinally, initial regression models demonstrated that the baseline integrity of this circuit prospectively predicted behavioral adaptation at the 2-year follow-up. Furthermore, hierarchical regression and formal interaction analyses confirmed that this cortico-striatal circuit provided significant incremental predictive validity - above and beyond massive baseline behavioral stability - specifically in males. These findings highlight cortico-striatal integration as a significant, gender-specific prospective predictor of longitudinal adaptation. By bridging person-centered profiling with network neuroscience, this study elucidates the neural correlates supporting future adaptive functioning and psychological resilience during the early adult transition.

The cerebellum has historically been underrepresented in language research. However, converging evidence from lesion and neuroimaging studies supports its crucial involvement in phonological and semantic aspects of language processing, highlighting the relevance of cerebro-cerebellar circuits in language-related functions. Likewise, cerebellar neurostimulation has emerged as a promising tool for modulating sensorimotor and higher-order cognitive processes. A systematic search was conducted in PubMed and Web of Science following PRISMA guidelines and the present review synthesizes findings from 30 neurostimulation studies probing the causal role of the cerebellum for language processing. It summarizes transcranial electric and magnetic stimulation studies in neurotypical speakers and readers, and individuals with higher-order language disorders. Special emphasis is placed on studies combining cerebellar stimulation with behavioral interventions to assess the potential of improving language-related outcomes in clinical populations. Collectively, these studies support the role of the right posterolateral cerebellum as a key modulator of language functions, especially meaning-related operations.

DNA methylation of the ELOVL2 (Elongation of Very Long Chain Fatty Acids Protein 2) promoter is one of the most robust molecular biomarkers for chronological age; however, whether ELOVL2 plays a functional role in brain aging and immunosenescence, and whether the APOE genotype modulates these effects, has not been fully explored. This study investigated the associations among ELOVL2 methylation, APOE genotype, and neurophysiological changes in the brain, as well as indicators of immunosenescence of peripheral blood T cells during aging. We examined 72 non-demented volunteers aged 20-88 years, stratified by APOE genotype (41 APOE-, 31 APOE+). ELOVL2 methylation levels were measured via bisulfite conversion and pyrosequencing. Participants underwent cognitive screening, auditory P3 event-related potential (ERP) recordings, and resting-state MRI functional connectivity (rsFC) assessments. In a subgroup of 18 healthy subjects, we examined peripheral blood T-cell subsets and analyzed the association of CD3+HLA-DR+ T cells with ELOVL2 methylation and neurophysiological characteristics. ELOVL2 CpG promoter methylation (chr 6:11044880. GRCh37) was associated with P3 ERP latency in both the overall sample and APOE4+ carriers, remaining significant even after adjusting for age; however, this association was not significant in APOE4- individuals. DNA methylation of ELOVL2 was inversely correlated with fMRI rsFC in the salience-, and memory-related, and central autonomic networks, indicating disrupted connectivity within these networks. An increased proportion of CD3+ cells expressing the immune activation marker HLA-DR was correlated with elevated ELOVL2 methylation level and with decreased fMRI rsFC in brain networks, including circuits related to the DMN medial prefrontal cortex, amygdala, and cerebellum. The results imply a close link between ELOVL2 methylation, inflammaging and brain dysfunction, which is modulated by APOE4+ genotype.

Basal ganglia-thalamo-cortical circuits are essential for learning complex motor sequences, yet their roles in controlling flexible motor behavior remain poorly understood. The homologous songbird Anterior Forebrain Pathway (AFP) drives song motor learning and was previously thought not to play a role in song performance, as early lesion studies reported no detectable effect. This perspective is now debated, as newer results demonstrate effects in subsets of songbirds. Here, we revisit this question in adult canaries by performing bilateral excitotoxic lesions targeting the lateral and medial subdivisions of the AFP. To quantify behavioral changes across thousands of recorded canary songs, we developed a high-throughput annotation pipeline that extends a self-supervised vision transformer (TweetyBERT) with a supervised classification head, eliminating the memory bottleneck of UMAP-based clustering. This model enables phrase-level analysis across thousands of songs per bird. We find that lesions involving the medial AFP produce a stuttering-like behavior, defined here as a prolonged and variable syllable repetition before transition, resulting in a significant increase in the variability of phrase duration. This effect was strongest in birds with medial+lateral AFP involvement, and was not observed in birds with lateral-only AFP lesions. Phrase duration variability remained elevated across much of the post-lesion recording period and was accompanied by detectable changes in syllable acoustic structure. Our results implicate the medial AFP in the ongoing control of phrase duration in adult canary song, challenging the view that the AFP is dispensable once song is learned. These findings position the medial AFP as a tractable model for understanding how basal ganglia and cortical dynamics jointly maintain complex learned motor sequences.

Animals can initiate movements either in response to external cues or from internal drive, yet how the brain flexibly supports both remains unclear. Disorders such as Parkinson's disease disrupt these modes differently, suggesting distinct underlying mechanisms. These differences could arise from specialized circuits or from shared neuronal populations that shift their dynamics across contexts. To distinguish between these possibilities, we performed two-photon calcium imaging in the dorsolateral striatum as mice executed the same lever press either spontaneously or in response to a cue. Unsupervised clustering identified neurons modulated during cue, movement, or postaction periods. Critically, the same neurons encoded movement across initiation contexts, but their population dynamics diverged before movement. Both D1- and D2-expressing spiny projection neurons contributed to these dynamics, with D1-SPNs more active at the time of the sensory stimulus. These results show that context shapes neural dynamics within a shared movement-encoding population, revealing a context-generalizable striatal code that supports flexible movement initiation across internal and external drives.

Regenerative engineering harnesses materials science and stem cell biology to develop strategies to repair damaged and diseased tissue. Despite advances in designer materials, few techniques effectively provide auto-regulated feedback mechanisms that govern how cells sense and respond to discrete microenvironmental changes. Here, we demonstrate that the artificial, juxtacrine-like receptor synthetic Notch (synNotch) can be activated by endogenous multimeric cytokines in solution, without immobilizing materials, revealing a previously unreported activation modality and yielding up to 24-fold dynamic range. To broaden synNotch sensing to monomeric cytokines, we developed nMATRIX, a co-engineered material-cell platform that detects endogenous, soluble ligands and routes them to programmed gene circuits with spatially confined effects. nMATRIX can be tuned to recognize the interleukins IL-1β and IL-6 using synNotch receptors plus cognate biomaterials, yielding more than 68-fold dynamic range and converting these inflammatory inputs into orthogonal outputs that reprogram nearby cell phenotypes. nMATRIX functions across multiple cell types and can incorporate the synNotch-related SNIPR synthetic receptor platform. nMATRIX repurposed inflammatory signals and converted them into anti-inflammatory cues to modulate macrophage surface marker expression. Thus, nMATRIX couples native soluble cues to customized cellular responses with tunable sensitivity, offering a flexible materials-based approach for self-regulating regenerative therapies.

Frontolimbic circuits connecting the frontal cortex with the amygdala and the hippocampus are critical for emotion and learning. These connections undergo major changes throughout childhood and adolescence, yet the principles guiding their maturation remain unclear. Analyzing large developmental cohorts, we show that fronto-hippocampus connectivity develops rapidly in early childhood and stabilizes thereafter. In contrast, fronto-amygdala connectivity becomes progressively differentiated from fronto-hippocampus connectivity, with development most pronounced during adolescence. This entailed hippocampus and amygdala respectively becoming preferentially tethered to association-related regions and sensorimotor-related regions. Greater adversity exposure was associated with more differentiated fronto-amygdala connectivity for a given age. Higher cognitive ability was associated with less differentiated fronto-hippocampus connectivity. These findings suggest that frontolimbic connectivity development follows a principle of differentiation, with circuit-specific timing and sensitivity to stress and learning. This work provides a foundation for understanding typical and atypical frontolimbic circuitry development from birth to emerging adulthood. The frontolimbic circuit, especially the fronto-hippocampus and fronto-amygdala circuitry, is integral for cognitive and affective processes. Yet its maturation has been challenging to characterize due to variable connectivity growth across the frontal cortex. Here, we reveal that this variability follows a principle of differentiation, where the hippocampus and the amygdala acquire respectively unique connectivity profiles with the frontal cortex at disparate developmental stages. Deviations from these normative trajectories were linked to cognitive ability and cumulative adversity, respectively. This approach provides a framework to unify inconsistent findings while serving as a foundation for identifying circuit-specific windows of plasticity and vulnerability.

The murine model is a standard system in translational microbiome research, yet its functional equivalence to the human microbiome remains debated. To evaluate its translational validity, we conducted a comparative whole-genome shotgun (WGS) metagenomic meta-analysis, integrating an initial retrieval of 520 datasets from 5 independent cohorts (BioProjects) across Homo sapiens (n = 202), Mus musculus (n = 75), and Drosophila melanogaster (n = 243) samples. Taxonomic and functional profiles were evaluated using strict bioinformatic quality control and batch-effect mitigation. Taxonomic profiling revealed pronounced divergence driven by host-specific ecological constraints and filtering. However, metabolic reconstruction demonstrated substantial functional equivalence, supporting the functional redundancy hypothesis for core mammalian metabolic circuits. We also noted a methodological vulnerability in our dataset: a low-depth murine sample clustered with invertebrate profiles, suggesting that technical noise or insufficient depth might artificially compress mammalian functional diversity. Comparative analysis identified sex-biased metabolic pathways conserved across mammalian hosts. Specifically, we observed a consistent enrichment of steroid metabolism in females and mineralocorticoid regulation in males. These findings indicate that functional conservation between humans and mice is modular rather than global. Consequently, the translational value of the murine model lies in domain-specific functional equivalence rather than taxonomic imitation. Moreover, the conservation of sex-specific metabolic signatures suggests that biological sex is a fundamental organising principle of microbiome function. This study highlights the necessity of mapping conserved metabolic modules and rigorously controlling inter-study variance to effectively deploy murine models in biomedical research.