Biology subjects

Dai, K.

Publications and source records attributed to Dai, K..

11 recordsLinked to original sources

bioRxiv2026

Deep-learning-assisted simulation of a cortical circuit: integrating anatomy, physiology and function

Mechanistic understanding of the brain requires models constrained by anatomy, physiology, and functional activity. We present a differentiable simulator and a ~67,000-neuron model of mouse primary visual cortex that integrates multimodal data, including electron-microscopy connectomics, multipatch synaptic physiology, cell-type-resolved intrinsic electrophysiology, and large-scale Neuropixels recordings from diverse cell types. End-to-end training completes on a single GPU in ~6.5 hours while preserving biological constraints. Networks trained only on brief drifting-grating responses reproduce cell-type-specific benchmarks and generalize to new contrasts and natural scenes. We uncover heterogeneous cell-type- and tuning-dependent synaptic organization and show that training preferentially sculpts inhibitory connectivity into distinct cohorts that exert outsized control over network activity. Targeted ablations show that removing biological priors on synaptic weight distributions can preserve functional activity yet disrupt emergent wiring rules. The freely shared models and code facilitate differentiable simulations as a computationally practical framework for studying brain circuit function and mechanisms under biological constraints.

neuroscience↗

bioRxiv2025

RIP2 inhibits DOCK8-mediated platelet dense granule release and alleviates experimental myocardial infarction

ObjectiveReceptor-interacting protein 2 (RIP2) is an essential mediator of inflammation and innate immunity downstream of pattern recognition receptors (PRRs). Platelets express RIP2, while its role in platelet activation, thrombosis, and myocardial infarction (MI) is unknown. Approach and ResultsHere we show that RIP2 deficiency enhances platelet dense granule secretion in response to GPIb and GPVI activation; platelet aggregation in whole blood and adhesion under arterial shear are also increased. Consistently, RIP2 inhibitor WEHI-345 potentiates human platelet dense granule secretion and inhibits RIP2 phosphorylation induced by thrombin and collagen. These phenotypes are translated into shorter bleeding time, accelerated FeCl3-induced arterial thrombosis. Importantly, platelets from patients with coronary artery disease and mice with atherosclerosis express lower RIP2, and RIP2 deficiency deteriorates MI and cardiac function in a mouse ischemia/reperfusion model. Mechanistically, we found that platelets express dedicator of cytogenesis protein 8 (DOCK8), which is sequestered by phosphorylated RIP2 (p-RIP2), causing inhibition of Cdc42 activation and subsequent dense granule release. ConclusionsIn conclusion, RIP2 inhibits platelet activation, thrombosis, and ameliorates MI. Our results also suggest that a novel PRR-independent pathway, p-RIP2-DOCK8-Cdc42, negatively regulates platelet activation downstream of GPIb and GPVI. Platelet RIP2 pathway may be promising for therapeutic intervention of atherothrombotic diseases from early atherosclerosis stage to arterial thrombosis and MI. HighlightsO_LIRIP2 inhibits platelet dense granule release NOD2-independenly via pRIP2-DOCK8-Cdc42. C_LIO_LIThe negative regulation of RIP2 on platelet activation is translated into enhanced thrombosis, exacerbated myocardial infarction (MI). C_LIO_LIRIP2 pathway booster may be an approach for therapeutic intervention of atherothrombotic diseases. C_LI

molecular biology↗

bioRxiv2024

Cytotoxicity and Characterization of 3D-Printable Resins Using a Low-Cost Printer for Muscle-based Biohybrid Devices

Biohybrid devices integrate biological and synthetic materials. The selection of an appropriate synthetic material to interface with living cells and tissues is crucial due to cellular chemical and mechanical sensitivities. As such, the stiffness of the material and its biocompatibility while in direct contact must be considered. In this study, the material properties and biocompatibility of six commercially available, 3D printable resins (three rigid and three elastomeric) were assessed for their suitability for biohybrid actuators. To characterize the material, uniaxial tension and compression tests with post-hoc Hookean and Yeoh model analyses were conducted for both nonsterile and sterilized (ethanol-soaking or autoclaved) samples. The mechanical properties of the elastomeric resins were minimally impacted by the different sterilization techniques. However, both Phrozen AquaGray 8K and Liqcreate Bio-Med Clear rigid resins were significantly softer in tensile tests after sterilization, and AquaGray became far more ductile. Asiga DentaGUIDE was much more stable in its mechanical properties than the other rigid resins. It was also shown that long-term exposure to saline solutions leads to a decrease in the Youngs moduli of these rigid resins before any sterilization has occurred. The print fidelity was also assessed for nonsterile and sterilized samples via manual scoring to determine the impacts of the sterilization processes on the part fidelity. Sterilization techniques had a minimal impact on print fidelity for both elastomeric and ridged resins with two exceptions. In both Formlabs Silicone 40A IPA/BuOAc post-treatment and Phrozen AquaGrey 8K groups, ethanol/UV-sterilization caused more degradation compared to autoclave-sterilization. In addition to the material analyses, cytotoxicity analyses using calcein AM and ethidium homodimer-1 fluorescence markers were conducted by directly culturing C2C12, a common myoblast cell line used in bioactuators, with sterilized resin samples. Of the elastomeric resins, only Formlabs Silicone 40A was shown to have minimal impacts on cell viability. For the rigid resins, Asiga DentaGUIDE, Liqcreate Bio-Med Clear, and ethanol-sterilized Phrozen AquaGray 8K demonstrated minimal impacts on cell viability. Based on these analyses, Asiga DentaGUIDE and Formlabs Silicone 40A demonstrate potential for applications in biohybrid muscle-based actuators when using low-cost 3D printers.

bioengineering↗

bioRxiv2022

Uncovering circuit mechanisms of current sinksand sources with biophysical simulations ofprimary visual cortex

Local field potential (LFP) recordings reflect the dynamics of the current source density (CSD) in brain tissue. The synaptic, cellular and circuit contributions to current sinks and sources are ill-understood. We investigated these in mouse primary visual cortex using public Neuropixels recordings and a detailed circuit model based on simulating the Hodgkin-Huxley dynamics of numerous cortical neurons belonging to 17 cell types. The model simultaneously captured spiking and CSD responses and demonstrated a two-way dissociation: Firing rates are altered with minor effects on the CSD pattern by adjusting synaptic weights, and CSD is altered with minor effects on firing rates by adjusting synaptic placement on the dendrites. We describe how thalamocortical inputs and recurrent connections sculpt specific sinks and sources early in the visual response, whereas cortical feedback crucially alters them in later stages. Our findings show that CSD analysis provides powerful constraints for modeling beyond those from considering spikes.

neuroscience↗

bioRxiv2020

Targeted Degradation of Transcription Factors by TRAFTACs: Transcription Factor Targeting Chimeras

Many diseases, including cancer, stem from aberrant activation and overexpression of oncoproteins that are associated with multiple signaling pathways. Although proteins with catalytic activity are able to be successfully drugged, the majority of other protein families, such as transcription factors, remain intractable due to their lack of ligandable sites. In this study, we report the development of TRAnscription Factor TArgeting Chimeras (TRAFTACs) as a generalizable strategy for targeted transcription-factor degradation. Herein, we show that TRAFTACs, which consist of a chimeric oligonucleotide that simultaneously binds to the transcription-factor of interest (TOI) and to HaloTag fused dCas9 protein, can induce degradation of the former via the proteasomal pathway. Application of TRAFTACs to two oncogenic TOIs, NF-{kappa}B and brachyury, suggests that TRAFTACs can be successfully employed for the targeted degradation of other DNA-binding proteins with minor changes to the chimeric oligonucleotide.

bioengineering↗

bioRxiv2020

Brain Modeling ToolKit: an Open Source Software Suite for Multiscale Modeling of Brain Circuits

Experimental studies in neuroscience are producing data at a rapidly increasing rate, providing exciting opportunities and formidable challenges to existing theoretical and modeling approaches. To turn massive datasets into predictive quantitative frameworks, the field needs software solutions for systematic integration of data into realistic, multiscale models. Here we describe the Brain Modeling ToolKit (BMTK), a software suite for building models and performing simulations at multiple levels of resolution, from biophysically detailed multi-compartmental, to point-neuron, to population-statistical approaches. Leveraging the SONATA file format and existing software such as NEURON, NEST, and others, BMTK offers consistent user experience across multiple levels of resolution. It permits highly sophisticated simulations to be set up with little coding required, thus lowering entry barriers to new users. We illustrate successful applications of BMTK to large-scale simulations of a cortical area. BMTK is an open-source package provided as a resource supporting modeling-based discovery in the community.

neuroscience↗

bioRxiv2019

A survey of spiking activity reveals a functional hierarchy of mouse corticothalamic visual areas

The mammalian visual system, from retina to neocortex, has been extensively studied at both anatomical and functional levels. Anatomy indicates the cortico-thalamic system is hierarchical, but characterization of cellular-level functional interactions across multiple levels of this hierarchy is lacking, partially due to the challenge of simultaneously recording activity across numerous regions. Here, we describe a large, open dataset (part of the Allen Brain Observatory) that surveys spiking from units in six cortical and two thalamic regions responding to a battery of visual stimuli. Using spike cross-correlation analysis, we find that inter-area functional connectivity mirrors the anatomical hierarchy from the Allen Mouse Brain Connectivity Atlas. Classical functional measures of hierarchy, including visual response latency, receptive field size, phase-locking to a drifting grating stimulus, and autocorrelation timescale are all correlated with the anatomical hierarchy. Moreover, recordings during a visual task support the behavioral relevance of hierarchical processing. Overall, this dataset and the hierarchy we describe provide a foundation for understanding coding and dynamics in the mouse cortico-thalamic visual system.

neuroscience↗

bioRxiv2019

Systematic Integration of Structural and Functional Data into Multi-Scale Models of Mouse Primary Visual Cortex

AO_SCPLOWBSTRACTC_SCPLOWStructural rules underlying functional properties of cortical circuits are poorly understood. To explore these rules systematically, we integrated information from extensive literature curation and large-scale experimental surveys into a data-driven, biologically realistic model of the mouse primary visual cortex. The model was constructed at two levels of granularity, using either biophysically-detailed or point-neurons, with identical network connectivity. Both variants were compared to each other and to experimental recordings of neural activity during presentation of visual stimuli to awake mice. While constructing and tuning these networks to recapitulate experimental data, we identified a set of rules governing cell-class specific connectivity and synaptic strengths. These structural constraints constitute hypotheses that can be tested experimentally. Despite their distinct single cell abstraction, spatially extended or point-models, both perform similarly at the level of firing rate distributions. All data and models are freely available as a resource for the community.

neuroscience↗

bioRxiv2019

The SONATA Data Format for Efficient Description of Large-Scale Network Models

Increasing availability of comprehensive experimental datasets and of high-performance computing resources are driving rapid growth in scale, complexity, and biological realism of computational models in neuroscience. To support construction and simulation, as well as sharing of such large-scale models, a broadly applicable, flexible, and high-performance data format is necessary. To address this need, we have developed the Scalable Open Network Architecture TemplAte (SONATA) data format. It is designed for memory and computational efficiency and works across multiple platforms. The format represents neuronal circuits and simulation inputs and outputs via standardized files and provides much flexibility for adding new conventions or extensions. SONATA is used in multiple modeling and visualization tools, and we also provide reference Application Programming Interfaces and model examples to catalyze further adoption. SONATA format is free and open for the community to use and build upon with the goal of enabling efficient model building, sharing, and reproducibility.

neuroscience↗

bioRxiv2018

Molecular Nearest Neighbors Determine Generalization of Odorant Mixtures

Most natural odors arise from mixtures of multiple odorants. Some such mixtures are perceived \"elementally\", with each odorant component clearly identifiable, while others are perceived \"configurally\", with the mixture adopting a perceptual quality distinct from any of the components. While the perceptual similarity of two mixtures is presumably related in some way to the similarity of the corresponding components, given the elemental/configural dichotomy it is unclear if any formal principle can be used to predict mixture similarity. To investigate this problem, we trained mice to respond to a binary reference mixture of structurally similar odorants (S+) and then tested generalization of this response to other structurally related binary test mixtures. Across 5 experiments, we parametrically varied these mixtures in distinct ways to test candidate models for the perceptual similarity of mixtures. The best-performing model predicted behavioral responses by considering, for each component of the S+, only the similarity of the most structurally similar (\"nearest neighbor\") component of each test mixture. We conclude that for mixture generalization tasks the olfactory system may deemphasize or discard information about mixture components not perceptually \"near\" enough to any of those in the S+, consistent with a sparse and elemental rule for perception of structurally-related binary mixtures.

neuroscience↗

bioRxiv2018

h-channels contribute to divergent electrophysiological properties of supragranular pyramidal neurons in human versus mouse cerebral cortex

Gene expression studies suggest that differential ion channel expression contributes to differences in rodent versus human neuronal physiology. We tested whether h-channels more prominently contribute to the physiological properties of human compared to mouse supragranular pyramidal neurons. Single cell/nucleus RNA sequencing revealed ubiquitous HCN1-subunit expression in excitatory neurons in human, but not mouse supragranular layers. Using patch-clamp recordings, we found stronger h-channel-related membrane properties in supragranular pyramidal neurons in human temporal cortex, compared to mouse supragranular pyramidal neurons in temporal association area. The magnitude of these differences depended upon cortical depth and was largest in pyramidal neurons in deep L3. Additionally, pharmacologically blocking h-channels produced a larger change in membrane properties in human compared to mouse neurons. Finally, using biophysical modeling, we provided evidence that h-channels promote the transfer of theta frequencies from dendrite-to-soma in human L3 pyramidal neurons. Thus, h-channels contribute to between-species differences in a fundamental neuronal property.

neuroscience↗