Biology subjects

Hsu, M.

Publications and source records attributed to Hsu, M..

18 recordsLinked to original sources

bioRxiv2026

Cribriform Plate Microenvironment Assembles a Suppressive Myeloid Network during EAE-induced Neuroinflammation

During neuroinflammation, CD11c+CD11b+ myeloid cells accumulate at the cribriform plate, a key cerebrospinal fluid (CSF) and antigen outflow site in mice. At this site, podoplanin (PDPN)-expressing cells, including lymphatic vessels and meningeal layers, expand to create a distinct drainage microenvironment. In this study we sought to characterize myeloid cells which populate this region using a mouse model of neuroinflammation, experimental autoimmune encephalomyelitis (EAE). Utilizing a combination of immunohistochemistry, flow cytometry, and scRNAseq, we report that macrophages and dendritic cells (DCs) from this region display unique expressional signatures related to tolerance, cell death, and reduced inflammatory profile. Together this data supports that myeloid retention at the cribriform plate and olfactory bulb meninges promotes a local immunosuppressive environment.

immunology↗

bioRxiv2025

MNase stratification reveals heterogeneous 5hmC in naive B cells

DNA demethylation is essential for gene activation and is primarily mediated by the Ten-Eleven-Translocation (TET) dioxygenase family. TET initiates the demethylation by oxidizing 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), a chemically stable derivative that is not only an intermediate in demethylation but also an epigenetic mark. 5hmC is enriched at active gene bodies, promoters, and enhancers that exist at accessible chromatin. Yet, 75-90% of genomic DNA is physically packaged in nucleosomes, raising the question about where 5hmC resides relative to nucleosomes. To address this question, we used micrococcal nuclease (MNase) to biochemically stratify 5hmC according to nucleosome protection in naive mouse B cells. Using multiple approaches, we showed that [~]95% of 5hmC peaks are retained after MNase digest, suggesting that 5hmC is nucleosome-associated. Despite the majority of 5hmC being similar in nucleosomal DNA compared to total DNA, we identified minor subsets that were MNase-sensitive (accessible 5hmC, [~]3%) or further MNase-resistant (protected 5hmC, [~]1-2%). Integrative analyses revealed that the accessible 5hmC is preferentially located at promoters and enhancers, and the presence of promoter-proximal accessible 5hmC showed a stronger correlation with gene expression than total 5hmC. In contrast, protected 5hmC is enriched in chromatin states with mixed active and repressive features. These results shed new light on the relationship between 5hmC and accessible chromatin, suggesting 5hmC is predominantly associated with nucleosomes and revealing heterogeneous 5hmC subsets with potential distinct regulatory roles.

molecular biology↗

bioRxiv2025

T cell AIM2 Exacerbates Lung Inflammation in OVA-LPS and HDM-induced Asthma Models

Asthma is a complex airway inflammatory disease characterized by immune dysregulation, with diverse cellular contributors to inflammation that result in airway hyperresponsiveness (AHR) and excessive immune responses. The role of the inflammasome in asthma is conflicted. AIM2 is an innate immune receptor that activates the inflammasome through DNA binding. The clinical relevance of AIM2 in asthma is supported by analysis of blood or endobronchial biopsies from patients with severe asthma, showing increased AIM2 but not NLRP3 expression. We investigated the role of AIM2 in allergic asthma using ovalbumin (OVA)-LPS and house dust mite (HDM)- induced models. AIM2 expression was elevated in lung homogenates and bronchoalveolar lavage fluid (BALF) cells from allergen-induced groups compared to controls. In the OVA-LPS model, deletion of Aim2 led to reduced airway smooth muscle actin expression and DNA damage, contributing to decreased AHR and lung inflammation in whole body Aim2-/- mice. Surprisingly, cell-specific deletion in CD4+ T cells but not regulatory T cells or myeloid cells significantly affected AHR, indicating AIM2 in CD4+ T cells is a main driver of pathogenesis. Additionally, in HDM-induced asthma, Aim2-/- mice also exhibited reduced AHR. Cell-specific deletion reveals that AIM2 in CD4+ T cells promotes AHR and cytokine production, while AIM2 in myeloid cells modulates IgG1 levels and IL-13-producing CD4+ T cells, and the percentage of alveolar macrophages in BALF. These findings reveal that AIM2 differentially regulates HDM-induced allergic asthma through distinct exacerbating roles in T cells and myeloid cells, highlighting its potential as a therapeutic target. SignificanceAllergic asthma is a complex, heterogeneous disease characterized by airway inflammation and hyper-responsiveness. AIM2, an inflammasome activated by DNA, has emerged as a critical regulator of inflammatory diseases. In humans, AIM2 expression is elevated in severe asthma. In vivo studies highlight AIM2 as a key modulator of allergic asthma in both OVA-LPS and HDM- induced models. Surprisingly, its functional relevance in both models is mediated by its intrinsic role in T cells, while a modest role in myeloid cells is restricted to the HDM model. AIM2 promotes airway hyper-responsiveness and lung inflammation through enhancing type II cytokines, immune subpopulations and DNA damage response. These findings suggest AIM2 as a biomarker and therapeutic target for managing asthma, particularly in severe asthma subtypes.

immunology↗

bioRxiv2025

Amyloid-beta deposition and reduced drainage at the cribriform plate lymphatics in APP/PS1 mouse model of Alzheimer's Disease

Alzheimers disease (AD) is the most common cause of dementia, leading to substantial personal, economic, and medical costs to patients and society; it is characterized by the build-up of toxic amyloid-beta (A{beta}) and hyperphosphorylated tau. It is crucial to the health of the brain that these proteins are processed or drained effectively, but mounting research has shown that in AD pathology there is dysfunction in the ability of the brain to effectively clear pathological A{beta} and tau. In this report, we detail the involvement of one important brain drainage pathway and potential site of A{beta} clearance, the cribriform plate lymphatics, in 24-month old APP/PS1 mice. We show that cerebrospinal fluid (CSF) efflux is decreased across the cribriform plate area utilizing multiple methods. Moreover, we demonstrate that A{beta} aggregates at the cribriform plate - coating surface of olfactory bulbs (OB), olfactory nerve (ON) bundles, and cribriform plate lymphatic endothelial cells (cpLECs). At 24-months, APP/PS1 mice have increased CD45+ cell infiltration and decreased LYVE-1+ vessel area at the cribriform plate, suggesting local inflammation and lymphatic atrophy. Additionally, cpLECs have higher expression of caspase-3 suggesting the decreased LYVE-1 area is due to cellular toxicity resulting in apoptosis. This study demonstrates that the cribriform plate is an important area for further research elucidating its contribution to AD disease pathogenesis.

neuroscience↗

bioRxiv2025

Circuit dynamics of approach-avoidance conflict in humans

Debilitating anxiety is pervasive in the modern world. Choices to approach or avoid are common in everyday life and excessive avoidance is a cardinal feature of anxiety disorders. Here, we used intracranial EEG to define a distributed prefrontal-limbic circuit supporting approach and avoidance. Presurgical epilepsy patients (n=20) performed a continuous-choice, approach-avoidance conflict decision-making task inspired by the arcade game Pac-Man, where patients trade-off harvesting rewards against potential losses from attack by the ghost. As patients approached increasing rewards and threats, we found evidence of a limbic circuit mediated by increased theta power in the hippocampus, amygdala, orbitofrontal cortex (OFC) and anterior cingulate cortex (ACC), that drops rapidly during avoidance. Theta band connectivity within this circuit and with the lateral prefrontal cortex increases during approach and falls during avoidance, and amygdala and lateral frontal activity granger-caused the theta oscillations in both the OFC and ACC. Importantly, the degree of network connectivity predicted how long patients approach, with enhanced network synchronicity extending approach times. Finally, when threat is imminent, the system dynamically switches to a sustained increase in high-frequency activity (70-150Hz) in the middle frontal gyrus (MFG), tracking the degree of threat. The results provide evidence for a distributed prefrontal-limbic circuit, mediated by theta oscillations and high frequency activity, underlying approach-avoidance conflict in humans.

neuroscience↗

bioRxiv2024

Nothing but lies: improving the validity of neural predictors of deception

Deception is a universal human behavior. Yet longstanding skepticism about the validity of measures used to understand the biological mechanisms underlying deceptive behavior has relegated such studies to the scientific periphery. Here we address these fundamental questions by applying novel machine learning methods and functional neuroimaging to signaling games capturing motivated deception in human participants. First, we develop an approach to test for the presence of confounding processes and thereby validate past skepticism by showing that much of the predictive power of neural predictors trained on deception data comes from confounding processes. Second, we show that the presence of confounding signals need not be fatal, and we improve the validity of our neural predictor via a novel machine learning procedure that identifies and removes these confounding signals. Together, these findings point to a scientific approach for studying a neglected class of behavior, with important methodological and societal implications.

neuroscience↗

bioRxiv2023

Dual role of Vascular Endothelial Growth Factor-C (VEGF-C) in post-stroke recovery

Using a mouse model of ischemic stroke, this study characterizes stroke-induced lymphangiogenesis at the cribriform plate (CP). While blocking CP lymphangiogenesis with a VEGFR-3 inhibitor improves stroke outcome, administration of VEGF-C induced larger brain infarcts. AbstractCerebrospinal fluid (CSF), antigens, and antigen-presenting cells drain from the central nervous system (CNS) into lymphatic vessels near the cribriform plate and dural meningeal lymphatics. However, the pathological roles of these lymphatic vessels surrounding the CNS during stroke are not well understood. Using a mouse model of ischemic stroke, transient middle cerebral artery occlusion (tMCAO), we show that stroke induces lymphangiogenesis near the cribriform plate. Interestingly, lymphangiogenesis is restricted to lymphatic vessels at the cribriform plate and downstream cervical lymph nodes, without affecting the conserved network of lymphatic vessels in the dura. Cribriform plate lymphangiogenesis peaks at day 7 and regresses by day 14 following tMCAO and is regulated by VEGF-C/VEGFR-3. These newly developed lymphangiogenic vessels transport CSF and immune cells to the cervical lymph nodes. Inhibition of VEGF-C/VEGFR-3 signaling using a blocker of VEGFR-3 prevented lymphangiogenesis and led to improved stroke outcomes at earlier time points but had no effects at later time points following stroke. Administration of VEGF-C after tMCAO did not further increase post-stroke lymphangiogenesis, but instead induced larger brain infarcts. The differential roles for VEGFR-3 inhibition and VEGF-C in regulating stroke pathology call into question recent suggestions to use VEGF-C therapeutically for stroke.

immunology↗

bioRxiv2023

Dynamic expectations: Behavioral and electrophysiological evidence of sub-second updates in reward predictions

Expectations are often dynamic: any sports fan knows that expectations are rapidly updated as games unfold. Yet expectations have traditionally been studied as static. Here, using slot machines as a case study, we provide parallel behavioral and electrophysiological evidence of sub-second moment-to-moment changes in expectations. In Study 1, we show that the dynamics of the EEG signal before the slot machine stopped differed depending on the nature of the outcome, including not only whether the participant won or lost, but also how close they came to winning. In line with our predictions, Near Win Before outcomes (the slot machine stops one item before a match) were similar to Wins, but different than Near Win After (the machine stops one item after a match) and Full Miss (the machine stops two or three items from a match). In Study 2, we designed a novel behavioral paradigm to measure moment-to-moment changes in expectations via dynamic betting. We found that different outcomes also elicited unique expectation trajectories in the deceleration phase. Notably, these behavioral expectation trajectories paralleled Study 1s EEG activity in the last second prior to the machines stop. In Studies 3 (EEG) and 4 (behavior) we replicated these findings in the loss domain where a match entails a loss. Again, we found a significant correlation between behavioral and EEG results. These four studies provide the first evidence that dynamic sub-second updates in expectations can be behaviorally and electrophysiologically measured. Our findings open up new avenues for studying the ongoing dynamics of reward expectations and their role in healthy and unhealthy cognition.

neuroscience↗

bioRxiv2022

Multi-areal neural dynamics encode human decision making

Value-based decision-making involves multiple cortical and subcortical brain areas, but the distributed nature of neurophysiological activity underlying economic choices in the human brain remains largely unexplored. Here, we use intracranial recordings from neurosurgical patients to show that risky choices are reflected in high frequency activity distributed across multiple prefrontal and subcortical brain regions, whereas reward-related computations are less widely represented and more modular. State space modeling reveals sub-second neural dynamics underlying choices during deliberation and allows high-accuracy trial-by-trial decoding of subjects choices robustly across patients despite differences in anatomical coverage. These results shed light into the neural basis of choice across brain areas and open the door to new intracranial approaches for brain state decoding.

neuroscience↗

bioRxiv2022

To share or not to share? iEEG evidence for state-dependent inequity encoding in the human OFC

Social decision-making requires the integration of reward valuation and social cognition systems, both dependent on the orbitofrontal cortex (OFC). How these two OFC functions interact is largely unknown. We recorded intracranial activity from the OFC of ten patients making choices in the context of different types of inequity (disadvantageous vs. advantageous). We found that high-frequency activity (70-150 HZ) encoded the amount of self-reward, consistent with previous reports. We also observed novel evidence for encoding in human OFC of the social counterparts reward as well as the type of inequity being experienced. Additionally, we find social context modulates reward encoding: depending on inequity type, reward encoding was switched on and off rapidly within electrodes, across trials. These results provide direct evidence for explicit encoding of self- and other- rewards in the human OFC, and for rapid and reversible changes in encoding schemes driven by socially relevant contexts.

neuroscience↗

bioRxiv2021

MiSDEED: a synthetic multi-omics engine for microbiome power analysis and study design

SummaryMiSDEED is a command-line tool for generating synthetic longitudinal multi-omics data from simulated microbial environments. It generates relative-abundance timecourses under perturbations for an arbitrary number of samples and patients. All simulation parameters are exposed to the user to facilitate rapid power analysis and aid in study design. Users who want additional flexibility may also use MiSDEED as a Python package. Availability and implementationMiSDEED is written in Python and is freely available at https://github.com/pchlenski/misdeed. Contactpac@cs.columbia.edu

bioinformatics↗

bioRxiv2021

Neural representations of stereotype content predict social decisions

To guide social interaction, people often rely on expectations about the traits of other people based on markers of social group membership, i.e., stereotypes. Although the influence of stereotypes on social behavior is widespread, key questions remain about how traits inferred from social group membership are instantiated in the brain and incorporated into neural computations that guide social behavior. Here, we show that the human lateral orbitofrontal cortex (OFC) represents the content of stereotypes about members of different social groups in the service of social decision-making. During fMRI scanning, participants decided how to distribute resources across themselves and members of a variety of social groups in a modified Dictator Game. Behaviorally, we replicated our recent finding that perceptions of others traits, captured by a two-dimensional framework of stereotype content (warmth and competence), biased participants monetary allocation choices in a context-dependent manner: recipients warmth increased advantageous inequity aversion and their competence increased disadvantageous inequity aversion. Neurally, representational similarity analysis (RSA) revealed that perceptions of others traits in the two-dimensional space were represented in the temporoparietal junction and superior temporal sulcus, two regions associated with mentalizing, and in the lateral OFC, known to represent latent environmental features during goal-directed outcome inference outside the social domain. Critically, only the latter predicted individual choices, suggesting that the effect of stereotypes on behavior is mediated by inference-based, domain-general decision-making processes in the OFC.

neuroscience↗

bioRxiv2021

Dissociable oscillatory networks support gain and loss processing in human orbitofrontal cortex

Human neuroimaging and animal studies have linked neural activity in orbitofrontal cortex (OFC) to valuation of positive and negative outcomes. Additional evidence shows that neural oscillations, representing the coordinated activity of neuronal ensembles, support information processing in both animal and human prefrontal regions. However, the role of OFC neural oscillations in reward-processing in humans remains unknown, partly due to the difficulty of recording oscillatory neural activity from deep brain regions. Here, we examined the role of OFC neural oscillations (<30Hz) in reward processing by combining intracranial OFC recordings with a gambling task in which patients made economic decisions under uncertainty. Our results show that power in different oscillatory bands are associated with distinct components of reward evaluation. Specifically, we observed a double dissociation, with a selective theta band oscillation increase in response to monetary gains and a beta band increase in response to losses. These effects were interleaved across OFC in overlapping networks and were accompanied by increases in oscillatory coherence between OFC electrode sites in theta and beta band during gain and loss processing, respectively. These results provide evidence that gain and loss processing in human OFC are supported by distinct low-frequency oscillations in networks, and provide evidence that participating neuronal ensembles are organized functionally through oscillatory coherence, rather than local anatomical segregation.

neuroscience↗

bioRxiv2020

Structurally distinct duplex telomere repeat-binding proteins in Ustilago maydis execute specialized, non-overlapping functions in telomere recombination and telomere protection

Duplex telomere binding proteins exhibit considerable structural and functional diversity in different phyla. Herein we address the distinct properties and functions of two Myb-containing, duplex telomere repeat-binding factors in Ustilago maydis, a basidiomycete fungus that is evolutionarily distant from the standard budding and fission yeasts. The two telomere-binding proteins in U. maydis, named UmTrf1 and UmTrf2, have different domain organizations and belong to distinct protein families with different phylogenetic distributions. Despite these differences, they exhibit comparable affinities and similar sequence specificity for the canonical, 6-base-pair telomere repeats. Deletion of trf1 triggers preferential loss of long telomere tracts, suggesting a role for the encoded protein in promoting telomere replication. Trf1 loss also partially suppresses the ALT-like phenotypes of ku70-deficient mutants, suggesting a novel role for a telomere protein in stimulating ALT-related pathways. In keeping with these ideas, we found that purified Trf1 can modulate the helicase activity of Blm, a conserved telomere replication and recombination factor. In contrast, trf2 appears to be essential and transcriptional repression of this gene leads to severe growth defects and profound telomere aberrations that encompass telomere length heterogeneity, accumulation of extrachromosomal telomere repeats such as C-circles, and high levels of single-stranded telomere DNA. These observations support a critical role for UmTrf2 in telomere protection. Together, our findings point to a unique, unprecedented division of labor between the two major duplex telomere repeat-binding factors in Ustilago maydis. Comparative analysis of UmTrf1 homologs in different phyla reveals a high degree of functional diversity for this protein family, and provides a case study for how a sequence-specific DNA binding protein can acquire and lose functions at different chromosomal locations.

molecular biology↗

bioRxiv2019

Excessive deliberation in social anxiety

A goal of computational psychiatry is to ground symptoms in more fundamental computational mechanisms. Theory suggests that rumination and other symptoms in mood disorders reflect dysregulated mental simulation, a process that normally serves to evaluate candidate actions. If so, these covert symptoms should have observable consequences: excessively deliberative choices, specifically about options related to the content of rumination. In two large general population samples, we examined how symptoms of social anxiety disorder (SAD) predict choices in a socially framed reinforcement learning task, the Patent Race game. Using a computational learning model to assess learning strategy, we found that self-reported social anxiety was indeed associated with an increase in deliberative evaluation. The effect was specific to learning from a particular (\"upward counterfactual\") subset of feedback, broadly matching the biased content of rumination in SAD. It was also robust to controlling for other psychiatric symptoms. These results ground the symptoms of SAD, such as overthinking and paralysis in social interactions, in well characterized neuro-computational mechanisms and offer a rare example of enhanced function in disease

animal behavior and cognition↗

bioRxiv2018

Individual differences in dopamine are associated with reward discounting in clinical groups but not in healthy adults

Some people are more willing to make immediate, risky, or costly reward-focused choices than others, which has been hypothesized to be associated with individual differences in dopamine (DA) function. In two studies using PET imaging, one empirical (Study 1: N=144 males and females across 3 samples) and one meta-analytic (Study 2: N=307 across 12 samples), we sought to characterize associations between individual differences in DA and time, probability, and physical effort discounting in human adults. Study 1 demonstrated that individual differences in DA D2-like receptors were not associated with time or probability discounting of monetary rewards in healthy humans, and associations with physical effort discounting were inconsistent across adults of different ages. Meta-analytic results for temporal discounting corroborated our empirical finding for minimal effect of DA measures on discounting in healthy individuals, but suggested that associations between individual differences in DA and reward discounting depend on clinical features. Addictions were characterized by negative correlations between DA and discounting but other clinical conditions like Parkinsons Disease, obesity, and ADHD were characterized by positive correlations between DA and discounting. Together the results suggest that trait differences in discounting in healthy adults do not appear to be strongly associated with individual differences in D2-like receptors. The difference in meta-analytic correlation effects between healthy controls and individuals with psychopathology suggests that individual difference findings related to DA and reward discounting in clinical samples may not be reliably generalized to healthy controls, and vice-versa.\n\nSignificance StatementDecisions to forgo large rewards for smaller ones due to increasing time delays, uncertainty, or physical effort have been linked to differences in dopamine (DA) function, which is disrupted in some forms of psychopathology. It remains unclear whether alterations in DA function associated with psychopathology also extend to explaining associations between DA function and decision making in healthy individuals. We show that individual differences in dopamine D2 receptor availability are not consistently related to monetary discounting of time, probability, or physical effort in healthy individuals across a broad age range. By contrast, we suggest that psychopathology accounts for observed inconsistencies in the relationship between measures of dopamine function and reward discounting behavior.

neuroscience↗

bioRxiv2018

Common Neural Code for Reward and Information Value

Adaptive acquisition of information is critical for goal-directed behavior. Popular theories posit that information acquisition is driven by intrinsic motives (curiosity or exploration bonus) and mediated by valuation system. However, they are insufficient when agents need to evaluate instrumental benefit of new information in a forward-looking manner. We tested whether human brain computes value of information (VOI) on a scale common with more basic rewards to acquire information. In an fMRI task, subjects purchased information for choices on monetary lotteries. Behaviorally, subjective VOI was largely driven by instrumental benefit, as normatively predicted, but additionally affected by non-instrumental motive, particularly the utility of anticipation. Neurally, VOI was represented in striatum, ventromedial prefrontal cortex, and dorsolateral prefrontal cortex. Cross-categorical decoding revealed that these regions use a common scale for VOI and another type of value, expected utility of the lotteries. These provide new insight on neurocognitive mechanism of forward-looking, value-based information acquisition.

neuroscience↗

bioRxiv2018

Spatial gradient in activity within the insula reflects dissociable neural mechanisms underlying context-dependent advantageous and disadvantageous inequity aversion

Humans are capable of integrating social contextual information into decision-making processes to adjust their attitudes towards inequity. This context-dependency emerges both when individual is better off (i.e. advantageous inequity) and worse off (i.e. disadvantageous inequity) than others. It is not clear however, whether the context-dependent processing of advantageous and disadvantageous inequity rely on dissociable or shared neural mechanisms. Here, by combining an interpersonal interactive game that gave rise to interpersonal guilt and different versions of the dictator games that enabled us to characterize individual weights on aversion to advantageous and disadvantageous inequity, we investigated the neural mechanisms underlying the two forms of inequity aversion in the interpersonal guilt context. In each round, participants played a dot-estimation task with an anonymous co-player. The co-players received pain stimulation with 50% probability when anyone responded incorrectly. At the end of each round, participants completed a dictator game, which determined payoffs of him/herself and the co-player. Both computational model-based and model-free analyses demonstrated that when inflicting pain upon co-players (i.e., the guilt context), participants cared more about advantageous inequity and became less sensitive to disadvantageous inequity, compared with other social contexts. The contextual effects on two forms of inequity aversion are uncorrelated with each other at the behavioral level. Neuroimaging results revealed that the context-dependent representation of inequity aversion exhibited a spatial gradient in activity within the insula, with anterior parts predominantly involved in the aversion to advantageous inequity and posterior parts predominantly involved in the aversion to disadvantageous inequity. The dissociable mechanisms underlying the two forms of inequity aversion are further supported by the involvement of right dorsolateral prefrontal cortex and dorsomedial prefrontal cortex in advantageous inequity processing, and the involvement of right amygdala and dorsal anterior cingulate cortex in disadvantageous inequity processing. These results extended our understanding of decision-making processes involving inequity and the social functions of inequity aversion.

neuroscience↗