Biology subjects

Li, H.-H.

Publications and source records attributed to Li, H.-H..

15 recordsLinked to original sources

bioRxiv2026

Probabilistic neural code supports metacognition in value-based decisions in the human brain

Subjective value underlies many everyday decisions, yet the neural representations supporting these valuations are inherently noisy and inevitably subject to uncertainty. Whether humans have metacognitive access to this uncertainty, and how such access is supported neurally, remains unclear. Here, we provide converging behavioral and neural evidence that subjective value is represented probabilistically in the human brain. Behaviorally, participants explicit uncertainty reports tracked trial-by-trial fluctuations in valuation variability. Neurally, we decoded full probability distributions over value from fMRI population activity in ventromedial prefrontal cortex (vmPFC) and superior parietal lobe and intraparietal sulcus (SPL-IPS). Decoded neural uncertainty predicted behavioral reported uncertainty at the trial, item, and individual levels. These findings indicate that neural populations jointly encode value and uncertainty, extending probabilistic population coding from perception and working memory to subjective value, and providing a neural basis for metacognitive access to uncertainty in value-based decisions.

neuroscience↗

bioRxiv2026

Multiple Oscillatory Neural Rhythms Support Metacognitive Access of Working Memory

Working memory enables the maintenance of information to guide behavior, yet its representations are inherently noisy and variable. To act effectively, observers must track the uncertainty of their own memory. However, the neural mechanisms supporting uncertainty representations in working memory remain poorly understood, particularly at the level of neural dynamics. Here, we combined electroencephalography (EEG) with a spatial visual working memory task that elicited trial-by-trial uncertainty reports to investigate how oscillatory activity encodes memory uncertainty. We identified two forms of uncertainty supported by distinct oscillatory neural activity. Using a probabilistic encoding-decoding model, we found that memory content can be reconstructed from alpha-band activity, and that the precision of these representations predicts subsequent uncertainty reports, consistent with probabilistic mnemonic representations. In parallel, beta-band activity contained a scalar, magnitude-based, representation of uncertainty. This signal exhibited slow, persistent dynamics across task epochs and tracked uncertainty reports for both the current and previous trials. Together, these findings show that the human brain multiplexes two neural codes for memory uncertainty, representational precision and a scalar confidence signal, across distinct oscillatory rhythms, providing a neural dynamical account of metacognitive access to working memory.

neuroscience↗

bioRxiv2026

UBA1 Mitigates Myocardial Ischemia/Reperfusion Injury by Attenuating Endoplasmic Reticulum-Mitochondria Contacts via Pdzd8 ubiquitination

BACKGROUNDMyocardial ischemia/reperfusion injury (I/RI) represents a serious clinical complication in patients after acute myocardial infarction. Ubiquitin-activating enzyme 1 (UBA1) catalyzes the initial step of ubiquitination and plays a fundamental role in regulating protein homeostasis and related diseases. This study aims to elucidate the functional contribution of UBA1 to the pathogenesis of myocardial I/RI and to uncover its underlying mechanisms. METHODSSingle-cell RNA sequencing was employed to characterize UBA1 expression in human ischemic heart tissues. Myocardial I/R injury was examined in myocardial-specific UBA1 knockout (UBA1cko) mice, UBA1-overexpressing mice (rAAV9-UBA1), and corresponding controls. Neonatal rat cardiomyocytes underwent hypoxia/reoxygenation in vitro. Cardiac function and infarction were evaluated by echocardiography and pathological staining. Protein-protein interactions were analyzed via immunoprecipitation combined with mass spectrometry. The endoplasmic reticulum-mitochondrial contact sites (ERMCSs) and mitochondrial ultrastructure were evaluated through transmission electron microscopy and confocal imaging. RESULTSUBA1 expression was significantly downregulated in human and murine ischemic myocardium, especially in cardiomyocytes. UBA1cko mice exhibited aggravated I/RI with greater infarct size, impaired function, apoptosis, elevated intracellular Ca2+ levels, mitochondrial dysfunction, and ER stress, whereas UBA1 overexpression conferred cardioprotective effects. Mechanistically, UBA1 directly bound to and ubiquitinated Pdzd8, a key ERMCS-tethering protein, thereby promoting its degradation, which inhibited ERMCS formation and improved mitochondrial dysfunction and ER stress. Moreover, knockdown of Pdzd8 via rAAV9-siRNA effectively mitigated UBA1 knockout-induced myocardial damage. Additionally, administration of auranofin (AF), a U.S. Food and Drug Administration-approved drug for treating rheumatoid arthritis, markedly alleviated myocardial I/RI via activating UBA1 in vivo and in vitro. CONCLUSIONSUBA1 confers protection against myocardial I/RI by limiting ERMCS formation through Pdzd8 ubiquitination. Activating UBA1 or targeting Pdzd8 as a potential therapeutic strategy for the treatment of ischemic heart disease. GRAPHIC ABSTRACTA graphic abstract is available for this article. Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIUBA1 expression is downregulated in human and murine ischemic myocardium, especially in cardiomyocytes. C_LIO_LICardiac deletion of UBA1 significantly exacerbates myocardial ischemia/reperfusion injury (I/RI), whereas cardiac UBA1 overexpression confers a marked protective effect. C_LIO_LIUBA1 interacts with Pdzd8 (PDZ domain containing 8) and facilitates its ubiquitination and subsequent degradation, which then reduces endoplasmic reticulum-mitochondria contact sites (ERMCSs) and ameliorates mitochondrial dysfunction and ER stress, protecting myocardial I/RI. C_LIO_LIPharmacological activation of UBA1 with the FDA-approved drug auranofin attenuates myocardial I/R injury and improves heart dysfunction. C_LI What Are the Clinical Implications?O_LIUBA1 represents a new therapeutic target for myocardial I/RI. C_LIO_LIActivating UBA1 or targeting Pdzd8 may offer a promising therapeutic strategy for mitigating myocardial I/RI and heart failure, underscoring its potential for clinical translation. C_LI

pathology↗

bioRxiv2025

Drift-like dynamics and information flow across the cortical hierarchy during working memory

Working memory is supported by widespread and distributed brain regions spanning across the cortical hierarchy. However, how working memory content evolves and is transmitted across cortical regions remains largely unknown. Here, we investigated the flow of working memory information across the cortex using time-resolved fMRI decoding. Across multiple regions in visual and parietal cortex, we found that decoded working memory content drifted over time from the memoranda towards the later errors in memory reports, consistent with drift-like dynamics predicted by attractor models. These behaviorally predictive neural memory errors emerged earliest in higher-order dorsal visual area (V3AB) and intraparietal sulcus (IPS0), and then later in early visual cortex (V1), suggesting a propagation of mnemonic information originated in higher-level visual area. Inter-areal correlation analyses revealed that during memory maintenance, information flowed predominantly in a top-down manner--from higher to lower visual areas whereas during passive viewing feedforward dynamics prevailed. Together, our findings demonstrate that working memory maintenance involves temporally structured drift dynamics and feedback-dominated information flow across cortical hierarchy, providing a mechanistic link between neural population dynamics and the formation of memory errors.

neuroscience↗

bioRxiv2025

Attention induced perceptual traveling waves in binocular rivalry

Cortical traveling waves -smooth changes of phase over time across the cortical surface- have been proposed to modulate perception periodically as they travel through retinotopic cortex. Yet, little is known about the underlying computational principles. Here, we make use of binocular rivalry, a perceptual phenomenon in which perceptual (illusory) waves are perceived when a shift in dominance occurs between two rival images. First, we assessed these perceptual waves using psychophysics. Participants viewed a stimulus restricted to an annulus around fixation, with orthogonal orientations presented to each eye. The stimulus presented to one eye was of higher contrast thus generating perceptual dominance. When a patch of higher contrast was flashed briefly at one position in the other eye, it created a change in dominance that started at that location of the flash and expanded progressively, like a wave, as the previously suppressed stimulus became dominant. We found that the duration of the perceptual propagation increased with both distance traveled and eccentricity of the annulus. Diverting attention away from the annulus reduced drastically the occurrence and the speed of the wave. Second, we developed a computational model of traveling waves in which competition between the neural representations of the two stimuli is driven by both attentional modulation and mutual inhibition. We found that the model captured the key features of wave propagation dynamics. Together, these findings provide new insights into the functional relevance of cortical traveling waves and offer a framework for further experimental investigation into their role in perception.

neuroscience↗

bioRxiv2024

Neural mechanisms of resource allocation in working memory

To mitigate capacity limits of working memory, people allocate resources according to an items relevance. However, the neural mechanisms supporting such a critical operation remain unknown. Here, we developed computational neuroimaging methods to decode and demix neural responses associated with multiple items in working memory with different priorities. In striate and extrastriate cortex, the gain of neural responses tracked the priority of memoranda. Higher-priority memoranda were decoded with smaller error and lower uncertainty. Moreover, these neural differences predicted behavioral differences in memory prioritization. Remarkably, trialwise variability in the magnitude of delay activity in frontal cortex predicted differences in decoded precision between low and high-priority items in visual cortex. These results suggest a model in which feedback signals broadcast from frontal cortex sculpt the gain of memory representations in visual cortex according to behavioral relevance, thus, identifying a neural mechanism for resource allocation.

neuroscience↗

bioRxiv2024

A split-GAL4 driver line resource for Drosophila CNS cell types

Techniques that enable precise manipulations of subsets of neurons in the fly central nervous system have greatly facilitated our understanding of the neural basis of behavior. Split-GAL4 driver lines allow specific targeting of cell types in Drosophila melanogaster and other species. We describe here a collection of 3060 lines targeting a range of cell types in the adult Drosophila central nervous system and 1373 lines characterized in third-instar larvae. These tools enable functional, transcriptomic, and proteomic studies based on precise anatomical targeting. NeuronBridge and other search tools relate light microscopy images of these split-GAL4 lines to connectomes reconstructed from electron microscopy images. The collections are the result of screening over 77,000 split hemidriver combinations. Previously published and new lines are included, all validated for driver expression and curated for optimal cell type specificity across diverse cell types. In addition to images and fly stocks for these well-characterized lines, we make available 300,000 new 3D images of other split-GAL4 lines.

neuroscience↗

bioRxiv2023

Mechanical transmission of Dengue Virus by Aedes aegypti may influence disease transmission dynamics during outbreaks

The escalating number of dengue virus (DENV) outbreaks and their worldwide spread pose a major threat to global public health. DENV transmission dynamics significantly influence outbreak duration and magnitude. Conventional DENV transmission requires an incubation period between mosquitoes biting infected humans and the mosquitoes becoming infectious. However, the possibility of immediate, mechanical transmission of DENV without viral replication in the mosquito has received little attention despite its potential importance. Here, we show that Aedes aegypti mosquitoes can mechanically transmit DENV to susceptible mice immediately after biting infected mice without the need for an incubation period. By incorporating parameters from our experiments into a newly developed mathematical model, we found a significant impact on DENV outbreak characteristics. Mechanical transmission may amplify existing disease transmission routes and influence outbreak dynamics. Our findings have implications for vector control strategies that target mosquito lifespan and suggest the possibility of similar mechanical transmission routes in other disease-carrying mosquitoes.

microbiology↗

bioRxiv2023

Engineered Antiviral Sensor Targets Infected Mosquitoes

Escalating vector disease burdens pose significant global health risks, so innovative tools for targeting mosquitoes are critical. We engineered an antiviral strategy termed REAPER (vRNA Expression Activates Poisonous Effector Ribonuclease) that leverages the programmable RNA-targeting capabilities of CRISPR Cas13 and its potent collateral activity. Akin to a stealthy Trojan Horse hiding in stealth awaiting the presence of its enemy, REAPER remains concealed within the mosquito until an infectious blood meal is up taken. Upon target viral RNA infection, REAPER activates, triggering programmed destruction of its target arbovirus such as chikungunya. Consequently, Cas13 mediated RNA targeting significantly reduces viral replication and its promiscuous collateral activity can even kill infected mosquitoes. This innovative REAPER technology adds to an arsenal of effective molecular genetic tools to combat mosquito virus transmission. One-Sentence SummaryEngineered Cas13-based antiviral sensor kills infected mosquitoes upon activation from arbovirus infection.

bioengineering↗

bioRxiv2022

Neural population dynamics of human working memory

Temporally evolving neural processes maintain working memory (WM) representations of information no longer available in the environment. Nonetheless, the dynamics of WM remain largely unexplored in the human cortex. With fMRI, we found evidence of both stable and dynamic WM representations in human cortex during a memory-guided saccade task. The stability of WM varied across brain regions with early visual cortex exhibiting the strongest dynamics. Leveraging population receptive field modeling, we visualized and made the neural dynamics interpretable. Early in the trial, neural responses in V1 were dominated by narrowly tuned activation at the location of the peripheral target. Over time, activity spread toward foveal locations and targets were represented by diffuse activation among voxels with receptive fields along a line between the fovea and the target. We suggest that the WM dynamics in early visual cortex reflects a transformation of sensory inputs into abstract task-related representations.

neuroscience↗

bioRxiv2022

Cell-free, methylated DNA in blood samples reveals tissue-specific, cellular damage from radiation treatment

Radiation therapy is an effective cancer treatment although damage to healthy tissues is common. Here we characterize the methylomes of healthy human and mouse tissues to establish sequencing-based, cell-type specific reference DNA methylation atlases. Identified cell-type specific DNA blocks were mostly hypomethylated and located within genes intrinsic to cellular identity. Cell-free DNA fragments released from dying cells into the circulation were captured from serum samples by hybridization to CpG-rich DNA panels. The origins of the circulating DNA fragments were inferred from mapping to the established DNA methylation atlases. Thoracic radiation-induced tissue damages in a mouse model were reflected by dose-dependent increases in lung endothelial, cardiomyocyte and hepatocyte methylated DNA in serum. The analysis of serum samples from breast cancer patients undergoing radiation treatment revealed distinct tissue-specific epithelial and endothelial responses to radiation across multiple organs. Strikingly, patients treated for right-sided breast cancers also showed increased hepatocyte and liver endothelial DNA in the circulation indicating the impact on liver tissues. Thus, changes in cell-free methylated DNA can uncover cell-type specific effects of radiation and provide a quantitative measure of the biologically effective radiation dose received by healthy tissues. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=174 SRC="FIGDIR/small/487966v3_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@129f229org.highwire.dtl.DTLVardef@d999bcorg.highwire.dtl.DTLVardef@1fc3543org.highwire.dtl.DTLVardef@10cebc2_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

Exosomal MFGE8 from high glucose induced endothelial cells is involved in calcification/senescence of vascular smooth muscle cells

Vascular calcification/aging is a crucial feature of diabetic macro vasculopathy, resulting in serious cardiovascular diseases. The calcification/senescence of vascular smooth muscle cells (VSMCs) induced by hyperglycemia can cause diabetic vascular calcification/aging. However, the mechanism of VSMCs calcification/senescence involved in diabetic vascular calcification/aging remains unknown. The purpose of this study was to determine how the high glucose (HG) information in circulating blood is transmitted from vascular endothelial cells (ECs) to VSMCs, which are not contacted with blood directly. Exosomes have attracted much attention for their vital roles in regulating cell-to-cell communication. In this study, we found that milk fat globule epidermal growth factor 8 (MFGE8) was enriched in high glucose induced human umbilical vein endothelial cell exosomes (HG-HUVEC-Exo) and regulate VSMCs calcification/senescence, characterized by up-regulated expressions of alkaline phosphatase (ALP) and Runt-related transcription factor 2 (Runx2), as well as the increased mineralized nodules and senescence-associated {beta}-galactosidase (SA-{beta}-gal) positive cells. Upstream mechanism studies showed that sirtuin1 (SIRT1) was involved in VSMCs calcification/senescence by affecting the expression of MFGE8. We also found that inflammatory response mediated by IL-1{beta}, IL-6, and IL-8 was closely associated with MFGE8 and played a key role in regulating HG-HUVEC-Exo-induced VSMCs calcification/senescence. These findings provide a new insight into the mechanism of exosomal MFGE8 as a potential preventive and therapeutic target for the intervention of diabetic vascular calcification/aging.

molecular biology↗

bioRxiv2021

Joint representation of working memory and uncertainty in human cortex

Neural representations of visual working memory (VWM) are noisy, and thus, decisions based on VWM are inevitably subject to uncertainty. However, the mechanisms by which the brain simultaneously represents the content and uncertainty of memory remain largely unknown. Here, inspired by the theory of probabilistic population codes, we test the hypothesis that the human brain represents an item maintained in VWM as a probability distribution over stimulus feature space, thereby capturing both its content and uncertainty. We used a neural generative model to decode probability distributions over memorized locations from fMRI activation patterns. We found that the mean of the probability distribution decoded from retinotopic cortical areas predicted memory reports on a trial-by-trial basis. Moreover, in several of the same mid-dorsal stream areas the spread of the distribution predicted subjective trial-by-trial uncertainty judgments. These results provide evidence that VWM content and uncertainty are jointly represented by probabilistic neural codes.

neuroscience↗

bioRxiv2020

Different computations underlie overt and covert spatial attention

Perception and action are tightly coupled: visual responses at the saccade target are enhanced right before saccade onset. This phenomenon, presaccadic attention, is a form of overt attention--deployment of visual attention with concurrent eye movements. Presaccadic attention is well-documented, but its underlying computational process remains unknown. This is in stark contrast with covert attention--deployment of visual attention without concurrent eye movements--for which the computational process is well characterized. Here, a series of psychophysical experiments reveal that presaccadic attention modulates visual performance only via response gain changes even when attention field size increases, violating the predictions of a normalization model of attention, which has been widely used to explain the computations underlying covert attention. Our empirical results and model comparisons reveal that the perceptual modulations by overt and covert spatial attention are mediated through different computations.

neuroscience↗

bioRxiv2019

Confidence reports in decision-making with multiple alternatives violate the Bayesian confidence hypothesis

Decision confidence reflects our ability to evaluate the quality of decisions and guides subsequent behaviors. Experiments on confidence reports have almost exclusively focused on two-alternative decision-making. In this realm, the leading theory is that confidence reflects the probability that a decision is correct (the posterior probability of the chosen option). There is, however, another possibility, namely that people are less confident if the best two options are closer to each other in posterior probability, regardless of how probable they are in absolute terms. This possibility has not previously been considered because in two-alternative decisions, it reduces to the leading theory. Here, we test this alternative theory in a three alternative visual categorization task. We found that confidence reports are best explained by the difference between the posterior probabilities of the best and the next-best options, rather than by the posterior probability of the chosen (best) option alone, or by the overall uncertainty (entropy) of the posterior distribution. Our results upend the leading notion of decision confidence and instead suggest that confidence reflects the observers subjective probability that they made the best possible decision.

neuroscience↗