Biology subjects

Tan, Y. L.

Publications and source records attributed to Tan, Y. L..

7 recordsLinked to original sources

bioRxiv2026

Rapid simulation of organ-scale oxygen transport for tissue ischemia prediction

A densely vascularized tissue can still be starved of oxygen. Tissue oxygenation depends heavily on vessel arrangement, blood flow distributions, and cellular metabolism. Resolving these effects from individual constituent vessels to whole organs has historically been computationally prohibitive. We introduce the Cardiovascular Analysis and Simulation of Circulatory Advection, Diffusion, and Exchange (CASCADE) toolkit, which makes vessel-resolved oxygen transport tractable at the organ scale through a novel screened Green's-function formulation. On laptop-class hardware, CASCADE simulates networks containing thousands of vessels in under one second and a full biventricular human heart model in about two minutes. We validate spatial oxygen and cell-survival predictions against experiments in perfused engineered tissues and matched finite-element simulations. In engineered tissues, sweeps across thousands of network designs and physiological conditions reveal when vessel density, oxygen supply, or network architecture limits viability, establishing design rules for sustaining thick constructs. In a human heart model, CASCADE translates coronary occlusion, anemia, polycythemia, and hypoxemia into distinct myocardial oxygenation patterns, revealing where oxygen delivery fails and how much tissue is at risk.

bioengineering↗

bioRxiv2026

A cellular midbrain mechanism for executing fast and reliable escape

Escape from threat is one of the most ancient and conserved sensorimotor transformations and must satisfy two competing demands. It must be fast and reliable, because failing to escape genuine threats risks death, yet also selective, because escaping indiscriminately costs energy and missed resources 1,2. Speed and reliability favour a system with a low threshold that responds to the slightest indication of danger, whereas selectivity demands a high threshold that filters out innocuous stimuli -- yet both must be achieved simultaneously. While previous work has identified mechanisms for implementing selectivity 3-6, it is not known how the mammalian brain achieves speed and reliability once genuine threats have been identified. Here we use whole-cell recordings from dorsal periaqueductal gray (dPAG) neurons in behaving mice to show that the escape circuit resolves this tension via high intrinsic excitability at the single cell level. We find that while the membrane potential of dPAG neurons does not reach action potential threshold during exploratory behaviour, they require only a small amount of current to fire. Threat stimuli cause a sparse increase in synaptic input rate that, because of the high excitability, produces a sustained depolarizing voltage step that drives spiking and escape behaviour. Individual dPAG neurons respond similarly on escape and non-escape trials --what determines escape is the fraction of the dPAG population that is recruited, a finding we confirm with single-unit recordings in freely moving mice. The membrane voltage step response is also invariant to threat type, in contrast to superior colliculus neurons where membrane potential dynamics reflect stimulus identity. These findings reveal a single neuron mechanism for fast and reliable escape, in which the high intrinsic excitability of dPAG neurons transforms sparse, threat-evoked synaptic input into a rapid and stereotyped voltage signal, converting diverse threat representations into a uniform escape command.

neuroscience↗

bioRxiv2026

Presynaptic temporal dynamics flexibly set input weights in the mouse escape circuit

Animals facing threat must integrate multiple streams of information -- about danger, environment, and internal state -- into a time-pressured escape decision. In mice, this computation is performed by glutamatergic neurons of the dorsal periaqueductal grey (dPAG), but how their convergent long-range inputs combine to drive flexible decisions is unknown. Here we find that the functional weight of each input is set predominantly by the temporal statistics of its presynaptic activity, rather than by pathway identity or synaptic placement. We first used multi-region single unit recordings during naturalistic behaviour and generalised linear models to estimate the functional connectivity from midbrain, hypothalamic, and cortical inputs onto dPAG neurons. We then combined synapse-resolution circuit tracing, two-photon dendritic stimulation with whole-cell somatic and dendritic recordings, and biophysical modelling to identify the mechanisms setting these weights. We found that dPAG neurons are electrotonically compact, generating broadly uniform somatic responses to inputs across the dendritic tree. As a result, presynaptic firing dynamics -- burstiness within neurons and population synchrony -- are the dominant determinants of input efficacy. This temporal-statistics framework accounts for the measured differences in functional connectivity across input regions and predicts that input weights should change dynamically whenever presynaptic temporal structure shifts -- which we confirm by showing rapid, context-dependent reweighting of cortical input during motivational conflict. We propose that the subcellular specialisations of dPAG neurons allow them to integrate signals from distributed sources into a single decision, with input weights that can be flexibly adjusted on behavioural timescales -- a principle that may extend to other brain hubs that compute survival decisions.

neuroscience↗

bioRxiv2026

Photopatterned Sacrificial Vascular Architectures for Large Tissue-Scale Oxygenation

The engineering of thick, metabolically active tissues is constrained by the lack of scalable methods to create perfusable vasculature. This hinders effective metabolite transport in large tissue volumes, posing a critical barrier for regenerative tissue applications. In this study, we introduce photopatterned Channel Architectures with Sacrificial Templates (pCAST), an additive manufacturing strategy for generating three dimensional (3D), interconnected vascular networks with precisely defined negative space. Water-soluble sacrificial templates were fabricated using scalable Continuous Liquid Interface Production (CLIP), embedded within tissue constructs, and flushed away to yield 50 {micro}m perfusable channels spanning centimeter-scale tissue constructs. We then apply experimental oxygen mapping and viability analysis to pCAST constructs to build finite-element models that predict patterns of oxygen availability and tissue survival are governed by the balance between metabolic demand and vascular architecture, consistent with reaction-diffusion theory. This computational framework quantitatively predicts oxygen distributions and viability boundaries across vascular geometries and is validated experimentally. Together, these results establish pCAST as a scalable design framework linking vascular architecture, perfusion, and metabolic support for engineering large, 3D perfused tissue constructs. SignificanceThe ability to engineer thick, living tissues is limited by poor oxygen and nutrient delivery, which causes cell death before tissues can function or integrate with the body. This work addresses that fundamental barrier by introducing photopatterned Channel Architecture with Sacrificial Templates (pCAST), a scalable manufacturing strategy that creates precisely defined, perfusable vascular networks inside 3D tissues. By combining high-resolution 3D printing, sacrificial templating, and quantitative oxygen mapping, this research establishes design rules that link vascular geometry, perfusion, and tissue viability. These insights provide a general framework for building large, metabolically active tissues, with direct relevance to cardiac patches and other regenerative medicine applications.

bioengineering↗

bioRxiv2025

A Microneedle Device for Rapid Dermal Interstitial Fluid Sampling

Dermal interstitial fluid (ISF) offers a promising alternative to invasive blood tests and opportunities for novel skin diagnostics. Progress in both the understanding and adoption of ISF tests is hindered by sampling challenges, including lengthy collection times, non-negligible failure rates, variable collection volumes, and inconsistent bioanalyte levels. The causes of many of these issues are not well understood. We demonstrate a microneedle device that is several times faster than state-of-the-art, collecting an average of 15.5 mg of ISF in 5 minutes in humans with near-zero failure rate. This improvement was achieved by designing the spatial pressure gradient driving ISF flow. The influence of penetration depth, collection time, pressure, and age on ISF collection was elucidated, with Darcys law explaining multiple observations. A data-driven acceptance criterion of <1% blood contamination for ISF is proposed. The device and findings presented will empower researchers to better conduct robust studies in the development of ISF diagnostics.

bioengineering↗

bioRxiv2020

A cortico-collicular circuit for accurate orientation to shelter during escape

When faced with predatorial threats, escape towards shelter is an adaptive action that offers long-term protection against the attacker. From crustaceans to mammals, animals rely on knowledge of safe locations in the environment to instinctively execute rapid shelter-directed escape actions 1,2. While previous work has identified neural mechanisms of escape initiation3-5, it is not known how the escape circuit incorporates spatial information to execute rapid flights along the most efficient route to shelter. Here we show that mouse retrosplenial cortex (RSP) and superior colliculus (SC) form a circuit that encodes shelter direction vector and is specifically required for accurately orienting to shelter during escape. Shelter direction is encoded in RSP and SC neurons in egocentric coordinates and SC shelter-direction tuning depends on RSP activity. Inactivation of the RSP-SC pathway disrupts orientation to shelter and causes escapes away from the optimal shelter-directed route, but does not lead to generic deficits in orientation or spatial navigation. We find that the RSP and SC are monosynaptically connected and form a feedforward lateral inhibition microcircuit that strongly drives the inhibitory collicular network due to higher RSP input convergence and synaptic integration efficiency in inhibitory SC neurons. This results in broad shelter direction tuning in inhibitory SC neurons and sharply tuned excitatory SC neurons. These findings are recapitulated by a biologically-constrained spiking network model where RSP input to the local SC recurrent ring architecture generates a circular shelter-direction map. We propose that this RSP-SC circuit might be specialized for generating collicular representations of memorized spatial goals that are readily accessible to the motor system during escape, or more broadly, during navigation when the goal must be reached as fast as possible.

neuroscience↗

bioRxiv2019

Complementary roles for parvalbumin and somatostatin interneurons in the generation of hippocampal gamma oscillations

Gamma-frequency oscillations (30-120 Hz) can be separated into fast (>60 Hz) and slow oscillations, with different roles in neuronal encoding and information transfer. While synaptic inhibition is important for synchronization across the gamma-frequency range, the role of distinct interneuronal subtypes in fast and slow gamma states remains unclear. Here, we used optogenetics to examine the involvement of parvalbumin (PV+) and somatostatin (SST+) expressing interneurons in gamma oscillations in the mouse hippocampal CA3 ex vivo. Disrupting either PV+ or STT+ interneuron activity, via either photo-inhibition or photo-excitation, led to a decrease in the power of cholinergically-induced slow gamma oscillations. Furthermore, photo-excitation of SST+ interneurons induced fast gamma oscillations, which depended on both synaptic excitation and inhibition. Our findings support a critical role for both PV+ and SST+ interneurons in slow hippocampal gamma oscillations, and further suggest that STT+ interneurons are capable of switching the network between slow and fast gamma states.

neuroscience↗