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Biology subjects

Wang, W. Y.

Publications and source records attributed to Wang, W. Y..

4 recordsLinked to original sources

Neuronal Population Statistics, Computations, and Mechanisms of a Feedforward Convolutional Neural Network that Learns to Covertly Attend

Covert visual attention allows the brain to select different regions of the visual world without eye movements. Predictive cues of a target location orient covert attention and improve perceptual performance. In most computational models, researchers explicitly incorporate an attentional mechanism that alters processing at the attended location (gain, noise reduction, divisive normalization, biased competition, Bayesian priors). Here, we assess the emergent neuronal mechanisms of Convolutional Neural Networks (CNNs) that exhibit behavioral signatures of covert attention, despite lacking a built-in attention mechanism. We use neuroscience-inspired approaches to analyze 1.8M units of CNNs trained on the cueing paradigm. Consistent with neurophysiology, we show early layers with retinotopic neurons separately tuned to the target or cue, and later layers with neurons with joint tuning and increased cue influence on target responses. CNN computational stages mirror a Bayesian ideal observer (BIO), but with more gradual transitions. The cue influences the target sensitivity through four mechanisms. A BIO-like cue-weighted location summation, and three mechanisms absent in the BIO: an opponency across locations, a summation/opponency location combination, and interaction with the thresholding Rectified Linear Unit (ReLU). Re-analyses of mices superior colliculus neuronal activity during a cueing task show CNN-predicted but previously unreported cue-inhibitory, location- summation, and location-opponent cells in addition to the commonly reported cue (attention) excitatory cells. The novel single-unit CNN analysis approach establishes a likely system-wide characterization mediating covert attention and a framework to identify new neuron types and emergent computational mechanisms contributing to perceptual behavior. Significance StatementCues predictive of a target location orient covert attention and improve perceptual performance. Studies have focused on how attention influences neural activity, but how cues activate attention and how entire neuronal populations result in behavioral signatures of attention is not understood. Using neuroscience-inspired approaches to characterize properties of 1.8M CNN neurons, we predict new neuron types and emergent mechanisms. A re-analysis of mices superior colliculus activity shows new neuron types predicted by the CNN. The findings might explain how organisms, from primates and crows to insects, show behavioral signatures of covert attention using a variety of cue-target-location neuronal properties. The new CNN single-neuron analysis can guide neurophysiological studies to identify potential new neuron types and their computational contributions to perception.

neuroscience↗

Mechanical intercellular communication via matrix-borne cell force transmission during vascular network formation

Intercellular communication is critical to the development and homeostatic function of all tissues. Previous work has shown that cells can communicate mechanically via transmission of cell-generated forces through their surrounding extracellular matrix, but this process is not well understood. Here, we utilized synthetic, electrospun fibrous matrices in conjunction with a microfabrication-based cell patterning approach to examine mechanical intercellular communication (MIC) between endothelial cells (ECs) during the assembly of microvascular networks. We found that cell force-mediated matrix displacements in deformable fibrous matrices underly directional migration of neighboring ECs towards each other prior to the formation of stable cell-cell connections. We also identified a critical role for intracellular calcium signaling mediated by focal adhesion kinase and TRPV4 during MIC that extends to multicellular assembly of vessel-like networks in 3D fibrin hydrogels. The results presented here are critical to the design of biomaterials that support cellular self-assembly for tissue engineering applications.

bioengineering↗

Fiber density and matrix stiffness modulate distinct cell migration modes in a 3D stroma mimetic composite hydrogel

The peritumoral stroma is a complex 3D tissue that provides cells with myriad biophysical and biochemical cues. Histologic observations suggest that during metastatic spread of carcinomas, these cues influence transformed epithelial cells, prompting a diversity of migration modes spanning single cell and multicellular phenotypes. Purported consequences of these variations in tumor escape strategies include differential metastatic capability and therapy resistance. Therefore, understanding how cues from the peritumoral stromal microenvironment regulate migration mode phenotypes has prognostic and therapeutic value. Here, we utilize a synthetic stromal mimetic in which matrix fiber density and bulk hydrogel stiffness can be orthogonally tuned to investigate the contribution of these two key matrix attributes on MCF10A migration mode phenotypes, epithelial-mesenchymal transition (EMT), and invasive potential. We developed an automated computational image analysis framework to extract migratory phenotypes from fluorescent images and determine 3D migration metrics relevant to metastatic spread. Using this analysis, we find that matrix fiber density and bulk hydrogel stiffness distinctly contribute to a variety of MCF10A migration modes including amoeboid, single mesenchymal, multicellular clusters, and collective strands. Taking advantage of the tunability of this material platform, we identify a combination of physical and soluble cues that induces distinct heterogeneous migration modes originating from the same MCF10A spheroid and use this setting to examine a functional consequence of migration mode - apoptotic resistance. We find that cells migrating as part of collective strands are more resistant to staurosporine-induced apoptosis than either disconnected multicellular clusters or individual invading cells. Improved models of the peritumoral stromal microenvironment that help elucidate relationships between matrix attributes and cell migration mode can contribute to ongoing efforts to identify efficacious cancer therapeutics that address migration plasticity-based therapy resistances.

bioengineering↗

Functional angiogenesis requires microenvironmental cues balancing endothelial cell migration and proliferation

Angiogenesis is a complex morphogenetic process that involves intimate interactions between multicellular endothelial structures and their extracellular milieu. In vitro models of angiogenesis can aid in reducing the complexity of the in vivo microenvironment and provide mechanistic insight into how soluble and physical extracellular matrix cues regulate this process. To investigate how microenvironmental cues regulate angiogenesis and the function of resulting microvasculature, we multiplexed an established angiogenesis-on-a-chip platform that affords higher throughput investigation of 3D endothelial cell sprouting emanating from a parent vessel through defined biochemical gradients and extracellular matrix. We found that two fundamental endothelial cell functions, migration and proliferation, dictate endothelial cell invasion as single cells vs. multicellular sprouts. Microenvironmental cues that elicit excessive migration speed incommensurate with proliferation resulted in microvasculature with poor barrier function and an inability to transport fluid across the microvascular bed. Restoring the balance between migration speed and proliferation rate rescued multicellular sprout invasion, providing a new framework for the design of pro-angiogenic biomaterials that guide functional microvasculature formation for regenerative therapies.

bioengineering↗