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Choi, H.

Publications and source records attributed to Choi, H..

At least 55 records · Page 3Linked to original sources

A unified derivative-like dopaminergic computation across valences

Dopamine activity in the brain affects decision-making and adaptive behaviors. A wealth of studies indicate that dopamine activity encodes discrepancy between actual and predicted reward, leading to the reward prediction error (RPE) hypothesis. Specifically, it has been claimed that mesolimbic dopamine activity conforms to temporal-difference reward prediction error (TD RPE), a teaching signal in machine learning algorithms. Recently, there is growing evidence suggesting that dopamine is also involved in learning during aversive situations. However, the fundamental computation of dopamine activity in aversive situations is still unknown. A plausible but untested hypothesis is that dopamine activity in aversive situations also encodes TD RPE. Here, we tested this hypothesis by using mice in virtual reality. Mice were trained to avoid electrical tail shocks by running out of a virtual shock zone. Using probe conditions with speed manipulation or teleportation, we revealed that the dopamine signal in the ventral striatum follows the temporal derivative form of a value function. Delivering a reward at the end of the track enabled us to observe the integration of aversion and reward in a derivative form. Moreover, the value functions unbiasedly estimated from the recorded signal is consistent with the initial hypothetical form, with a realistic reflection of a received shock distribution. Taken together, our results show that mesolimbic dopamine activity can operate as a unified teaching signal in natural situations with positive and negative valences.

neuroscience↗

Thermogenic adipocytes alleviate hepatic steatosis and insulin resistance via macrophage cytokine secretion in obese mice

The Nrip1 gene encodes the protein Rip140, which suppresses nuclear receptors that regulate energy metabolism. Here we show adipocyte-selective deficiency of Nrip1 (AdNrip1KO) in mice causes a striking expansion of alternatively activated, M2-like macrophages within subcutaneous inguinal adipose tissue (iWAT) in addition to the appearance of thermogenic adipocytes expressing uncoupling protein 1 (UCP1). AdNrip1KO mice are less cold sensitive but showed no differences in whole body energy expenditure or food intake compared to control mice at 22 {degrees}C. Strikingly, AdNrip1KO mice on HFD display markedly attenuated hepatic steatosis and insulin resistance compared to control mice on HFD. Secreted factors that might mediate this crosstalk from adipose tissue to liver were searched for by iWAT RNAseq. Unexpectedly, upregulation of genes associated with cytokines and cytokine receptor signaling were the most highly correlated with adipocyte-selective Nrip1 loss in obese mice. Furthermore, the top upregulated genes that encode secreted proteins in AdNrip1KO iWAT are most highly expressed in macrophages, not adipocytes. This list included the IL-1b antagonist IL-1rn, known to attenuate hepatic steatosis and insulin resistance. Indeed, the IL-1rn protein in AdNrip1KO mice was found to circulate at levels we previously reported strongly attenuates hepatic steatosis and glucose tolerance in obese mice. Taken together, these results suggest a paradigm for metabolic crosstalk from thermogenic adipose tissue to liver that is mediated by IL-1rn and potentially other factors secreted from M2-like macrophages within beige adipose tissues. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/667482v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@15fb086org.highwire.dtl.DTLVardef@13e6689org.highwire.dtl.DTLVardef@1bde77borg.highwire.dtl.DTLVardef@a83f2e_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIAdipocyte Nrip1 deficiency (AdNrip1KO) strongly promotes adipose browning C_LIO_LIMouse AdNrip1KO polarizes adipose tissue macrophages towards M2-like C_LIO_LIAdNrip1KO reduces the hepatic fat and insulin resistance of obese mice C_LIO_LIAdNrip1KO adipose tissue macrophages secrete IL-1rn, known to mitigate hepatic fat and insulin resistance C_LI

physiology↗

Identification of reactive CpGs and RNA expression in early COVID-19 through cis-eQTM analysis reflecting disease severity and recovery

Multi-omics analyses of severe COVID-19 cases are crucial in deciphering the complex interplay between genetic and epigenetic factors. Here, we present an analysis of Expression Quantitative Trait Methylation (eQTM) to investigate the complex interplay of methylation and gene expression pattern during the acute phase of severe COVID-19. We identified 16 differentially expressed genes and 30 nearby differentially methylated CpG sites. Six key genes--SRXN1, FURIN, IL18RAP, FOXO3, GCNT4, and FKBP5--were either up-regulated or down-regulated near hypomethylated CpG sites. These genes are associated with viral infiltration, immune activation, lung damage, and oxidative stress-related multi-organ failure, which are the hallmarks of severe COVID-19. Interestingly, during the recovery phase, methylation and gene expression levels returned to baseline, underscoring the rapid and reversible nature of these molecular changes. These findings provide insight into the dynamics of epigenetic and transcriptomic shifts according to the infectious stage, supporting potential prognostic and therapeutic approaches for severe COVID-19.

bioinformatics↗

Longitudinal study of liver disease progression in the PEX1-Gly844Asp mouse model of mild Zellweger Spectrum Disorder

IntroductionZellweger spectrum disorder (ZSD) is an autosomal recessive disorder caused by mutations in any of 13 PEX genes encoding proteins required for peroxisome assembly and function. Chronic liver disease is one of the major clinical manifestations in patients and impacts quality of life and survival. However, the pathophysiology of liver disease is ZSD remains largely unknown, and current interventions are limited. To further study the liver disease mechanism, we use the PEX1-Gly844Asp (G844D) mouse model for mild ZSD, which was previously shown to develop hepatomegaly and cholestasis, similar to ZSD patients. MethodsThe natural history of hepatopathy was broadly characterized in PEX1-G844D mice and littermate controls from 1 to 18 months of age using liver histology, electron microscopy, cultured hepatocytes and blood. Metabolite and mechanism analysis included liver functions, respiratory chain dynamics, lipidomics, peroxisome metabolites, gene and protein expression assays. ResultsPEX1-G844D mice featured liver disease progression from hepatomegaly (1 month) to cluster cell death (4 months), hepatosteatosis (6 months), inflammation (8 months), fibrosis, and hepatic cancer (12 and 15 months). Hepatocyte proliferation and reduced glycogen was observed across all ages. Measurement of peroxisomal functions showed defective peroxisomal import and secondary mitochondrial defects in cultured hepatocytes. In blood and liver, plasmalogens were decreased, and C26:0 lyso-phosphatidylcholine and C27 bile acid intermediates were elevated. In liver, we observed accumulation of triglycerides and cholesterol, and reduced membrane phospholipids and sphingolipids. In contrast, in serum we observed reduced triglycerides, cholesterol and membrane lipids. Gene expression profiles confirmed by immunoblotting supported reduced hepatic de novo lipogenesis, increased hepatic lipid uptake and oxidation, PPAR activation, and modulated glucose and glycogen metabolism. Liver X receptor agonist (T0901317) applied to cultured hepatocytes enhanced hepatic lipogenesis and lipid secretion, but aggravated steatosis. ConclusionTaken together, these results suggested the following mechanisms of hepatopathy progression. We propose that global peroxisome dysfunction (1) causes PPAR activation, leading to chronic hyperplasia and partially contributing to disrupted hepatic lipid homeostasis with hepatosteatosis, and (2) underlies chronic hypoglycemia, causing hypoinsulinemia and contributing to reduced hepatic lipogenesis and systemic lipid deficiency. Growth restriction in the mouse model and in ZSD patients could be attributable to systemic lipid deficiency. Our mechanistic delineation of the pathophysiology provides other additional novel potential therapeutic targets to halt liver disease in ZSD.

pathology↗

Smooth muscle LRRC8A knockout preserves vascular function in AngII hypertension

Angiotensin II (AngII) causes hypertension and vascular inflammation both directly and indirectly via cytokines. In vascular smooth muscle cells (VSMCs) AngII and TNF activate NADPH oxidase 1 (Nox1) to produce superoxide. TNF receptors associate with Nox1 and Leucine Rich Repeat Containing 8A (LRRC8A) anion channels to modulate inflammation, as well as contractility in a RhoA-dependent manner. VSMC-specific LRRC8A knockout (KO) mesenteric arteries are protected from TNF-induced injury and vasodilated better. We hypothesized that LRRC8A KO would preserve vascular function and decrease blood pressure (BP) in AngII-infused mice. Wild type (WT) and LRRC8A KO mice received AngII infusions for 14 days. Systolic BP was not different, but KO mice had more BP "dipping" during inactive periods and dipping was preserved after AngII. Contraction of KO mesenteric vessels to AngII itself was not altered, however after AngII exposure the function of KO aortic and mesenteric vessels was less impaired as reflected by less augmented contraction to norepinephrine and serotonin and preserved relaxation to acetylcholine and sodium nitroprusside. Western blotting revealed increased soluble guanylate cyclase alpha and reduced CPI-17 in hypertensive KO aortae. Consistent with the presence of lower Rho kinase activity in KO VSMCs, phosphorylation of Ezrin/Radixin/Moesin (ERM) and Cofilin was reduced. Aortic wall/lumen was not different between hypertensive WT and KO mice, but AngII caused less proliferation (lower PCNA), and less induction of antioxidant enzymes and senescence markers in KO vessels. Thus, while AngII-induced contraction does not require LRRC8A, these channels support the associated inflammatory response which modifies BP dipping.

physiology↗

Cell-type-specific encoding of prediction and reward in cortical microcircuits during novelty detection

Cortical circuits comprise diverse neuron types whose distinct activity patterns suggest specialized computational roles. Recent large-scale recordings reveal striking, cell-type-specific responses to novelty in cortex: excitatory neurons respond strongly to novel and unexpected stimuli, VIP interneurons respond more to novelty and omissions, while SST neurons are suppressed. What computational principles give rise to these dynamics? We introduce a normative model of a canonical cortical micro-circuit that jointly optimizes predictive coding, energy efficiency, and reinforcement learning under realistic connectivity constraints. By mapping algorithmic roles onto specific interneuron subtypes, the model reproduces absolute, contextual, and omission novelty effects observed experimentally. Critically, these emerge without hard-coded novelty detection and reveal a computational role for the VIP-SST disinhibitory motif in balancing representational capacity and metabolic cost. Mechanistic alternatives relying only on adaptation and Hebbian learning capture contextual but not absolute or omission effects. Our framework provides a unifying, falsifiable theory of how diverse cortical cell types implement coding principles underlying expectation and surprise.

neuroscience↗

Separable global and local beta burst dynamics in motor cortex of primates

Sensorimotor beta band oscillations are known to modulate during normal movement control and abnormal beta modulation is linked to pathological bradykinesia. However, the functional differences between beta localized to one brain area versus beta synchronized across brain areas remains unclear. We monitored beta bursts in non-human primates, both neurotypical and stroke- impaired, during the performance of complex motor tasks. Across both groups of animals, we identified two distinct beta burst types: global bursts that tend to be synchronized across cortical and subcortical areas, and local bursts that tend to be confined to cortex. These two types exhibited distinct neural dynamics, with global bursts linked to reduced firing variability and overall slowed movements. In contrast, local bursts often occurred during the execution of complex behaviors, particularly during prehension. We found evidence for changes in the distribution of global and local bursts during recovery after stroke. In impaired animals early after stroke, global bursts predominated and were associated with reduced speed and impaired grasping. Notably, recovery of grasping was associated with a reduction in global bursts and an increase in local bursts, suggesting that local bursts may play an important role during prehension. Our findings reveal distinct roles of global and local beta bursts and indicate that the normalization of global and local burst timing tracks recovery of dexterity.

neuroscience↗

Integrated Classification of Cortical Cells and Quantitative Projectomic Mapping Unveil Organizational Principles of Brain-Wide Connectomes at Single Cell Level

Molecularly defined cortical cell types have recently been linked to whole neuronal morphology (WNM), particularly those characterized by whole-brain-wide projections, such as intratelencephalic (IT), extratelencephalic (ET), and corticothalamic (CT) neurons. In contrast, classical morphological classifications (e.g., tufted TPC, small tufted SPC, and stellate SSC) are based primarily on local dendrosomatic and axonal structures, especially apical dendrites. This study bridges these perspectives by establishing a new neuronal taxonomy, analyzing the connectomes of defined cortical cell types, and comparing them with those obtained from bulk anterograde injections. Neurons were sparsely labeled via tamoxifen-inducible Cre lines with GFP reporters, and 1,419 WNM cells were comprehensively reconstructed with Vaa3D-TeraVR from [~]15 areas across six functional regions of molecularly labeled brains imaged with 2p-fMOST. These cells were newly classified by integrating current molecular-WNM and classical morphological perspectives, with sample size augmented by 1,455 publicly available WNM cells reconstructed from the Mouse-Light project and CEBSIT. This effort defined ten combined molecular-WNM-classical morphological cell types: L5ET_TPC, L6CT_NPC, L6b_HPC, and seven IT types--L2/3IT_TPC, L4IT_SSC, L4IT_UPC, L4IT_TPC, L5IT_SPC, L6IT_IPC, and L6IT_car3PC. Clustering, quantitative analyses and random Forest classifier objectively validated these types and revealed their distinct connectomes, along with convergent, topographic, and hierarchical organizations across their projection brain regions. At the single-cell level, multiple organizational principles governing cortico-cortical (C-C) and cortico-subcortical (C-subC) connectomes emerged with unprecedented detail, offering a precise GPS-like tool for in vivo recordings and robust datasets for neuronal network modeling. Comparisons with bulk anterograde injection data underscored the limitations of traditional methods in identifying projection targets. Overall, our approach provides significant insights into cortical circuitry and elucidates the complex interplay between neuronal molecular identity, whole morphology, and classical morphological classification.

neuroscience↗

Light-guided molecular patterning for programmable multiplexed single-molecule manipulation

Single-molecule force spectroscopy enables the detailed probing of molecular interactions, providing new insights into molecular mechanisms--yet studying biology "one molecule at a time" can lead to throughput challenges that limit applications. While multiplexed single-molecule assays can address these issues, suitable functionalization of surfaces is required, which remains a technical challenge--many commonly used approaches are constrained by random and sparse biomolecules arrangements, limiting programmability and throughput. An ideal anchoring method would enable (i) high surface densities to maximize throughput, (ii) precise control of spatial position and molecular identity for maximum control, (iii) covalent linking for high force application, and (iv) efficient patterning without the need for expensive facilities to maximize accessibility. To achieve these aims, we have developed a light-guided surface patterning method that can covalently organize oligonucleotides (oligos) without the need for lithographic equipment. Oligos with 3-Cyanovinylcarbazole (CNVK) nucleoside are crosslinked by UV patterns reflected through a digital micromirror device (DMD), with beads arranged accordingly. To demonstrate compatibility with established single-molecule methods, we performed single-molecule force spectroscopy experiments on patterned coverslips, using both magnetic tweezers and hydrodynamic-based systems. Our light-guided approach provides a scalable and accessible solution for biomolecular patterning that allows precise control over molecular identity and spatial positioning, enabling high-throughput measurements in single-molecule research.

biophysics↗

Cortex-wide voltage imaging in a sensory cued reaching task reveals fast subnetwork dynamics

Oscillatory activities and network dynamics are fundamental to sensorimotor processing, motor control, and cognitive functions. Capturing the fast cortical dynamics underlying sensorimotor behaviors demands temporal resolution beyond conventional imaging methods. We employed pan-cortical JEDI-1P voltage imaging of layer 2/3 activity in a skilled reaching task to reveal previously inaccessible rapid networks dynamics. Our approach uncovered distinct spectral signatures including reward-related gamma oscillations in M2, global low-frequency suppression during movement execution, and 8 Hz large-amplitude oscillations in sensorimotor cortex during task disengagement. Using independent component analysis, we were able to separate multiplexed functional networks with fast temporal features shared among sensorimotor regions and slower dynamics such as a global preparatory ramp. These distributed activity patterns successfully predicted both sensorimotor parameters and trial outcomes. Our study bridges critical gaps in understanding rapid temporal organization of cortical networks during complex behaviors, revealing how fast neural dynamics coordinate to produce motor actions across distributed cortical regions.

neuroscience↗

Estimating Brain Similarity Networks with Diffusion MRI

Structural similarity has emerged as a promising tool in mapping the network organization of an individual, living human brain. Here, we propose diffusion similarity networks (DSNs), which employ rotationally invariant spherical harmonic features derived from diffusion magnetic resonance imaging (dMRI), to map gray matter structural organization. Compared to prior approaches, DSNs showed clearer laminar, cytoarchitectural, and micro-architectural organization; greater sensitivity to age, cognition, and sex; higher heritability in a large dataset of healthy young adults; and straightforward extension to non-cortical regions. We show DSNs are correlated with functional, structural, and gene expression connectomes and their gradients align with the sensory-fugal and sensorimotor-association axes of the cerebral cortex, including neuronal oscillatory dynamics, metabolism, immunity, and dopaminergic and glutaminergic receptor densities. DSNs can be easily integrated into conventional dMRI analysis, adding information complementary to structural white matter connectivity, and could prove useful in investigating a wide array of neurological and psychiatric conditions.

neuroscience↗

Inhibitory cell type heterogeneity in a spatially structured mean-field model of V1

Inhibitory interneurons in the cortex are classified into cell types differing in their morphology, electrophysiology, and connectivity. Although it is known that parvalbumin (PV), somatostatin (SST), and vasoactive intestinal polypeptide-expressing neurons (VIP), the major inhibitory neuron subtypes in the cortex, have distinct modulatory effects on excitatory neurons, how heterogeneous spatial connectivity properties relate to network computations is not well understood. Here, we study the implications of heterogeneous inhibitory neurons on the dynamics and computations of spatially-structured neural networks. We develop a mean-field model of the system in order to systematically examine excitation-inhibition balance, dynamical stability, and cell-type specific gain modulations. The model incorporates three inhibitory cell types and excitatory neurons with distinct connectivity probabilities and recent evidence of long-range spatial projections of SST neurons. Position-dependent firing rate predictions are validated against simulations, and balanced solutions under Gaussian assumptions are derived from scaling arguments. Stability analysis shows that while long-range inhibitory projections in E-I circuits with a homogeneous inhibitory population result in instability, the heterogeneous network maintains stability with long-range SST projections. This suggests that a mixture of short and long-range inhibitions may be key to providing diverse computations while maintaining stability. We further find that conductance-based synaptic transmissions are necessary to reproduce experimentally observed cell-type-specific gain modulations of inhibition by PV and SST neurons. These gain modulations are distance-dependent, and a linear response analysis suggested that shifts in the excitation-inhibition balance of the network underlie these effects. Our theoretical approach offers insight into the computational function of cell-type-specific and distance-dependent network structure.

neuroscience↗

Omics-based insights into human liver reveal GTPase-driven mechanisms of MASLD progression in obesity

Metabolic dysfunction-associated steatotic liver disease (MASLD) is often asymptomatic early on but can progress to irreversible conditions like cirrhosis. Due to limited access to human liver biopsies, systematic and integrative molecular resources remain scarce. In this study, we performed transcriptomic analyses on liver and metabolomic analyses on liver and plasma samples from morbidly obese individuals without liver pathology or at early-stage MASLD. While, the plasma metabolomic profile did not fully mirror liver histological features, dual-omics integration of liver samples revealed significantly remodeled lipid and amino acid metabolism pathways. Integrative network analysis uncoupled metabolic remodeling and gene expression as independent features of hepatic steatosis and fibrosis progression, respectively. Notably, GTPases and their regulators emerged as a novel class of genes linked to early liver fibrosis. This study offers a detailed molecular landscape of early MASLD in obesity and highlights potential targets of obesity-linked liver fibrosis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/632747v3_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@1188eborg.highwire.dtl.DTLVardef@1340070org.highwire.dtl.DTLVardef@108d560org.highwire.dtl.DTLVardef@f0adda_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

Constructing Biologically Constrained RNNs via Dale's Backprop and Topologically-Informed Pruning

AO_SCPLOWBSTRACTC_SCPLOWRecurrent neural networks (RNNs) have emerged as a prominent tool for modeling cortical function, and yet their conventional architecture is lacking in physiological and anatomical fidelity. In particular, these models often fail to incorporate two crucial biological constraints: i) Dales law, i.e., sign constraints that preserve the "type" of projections from individual neurons, and ii) Structured connectivity motifs, i.e., highly sparse yet defined connections amongst various neuronal populations. Both constraints are known to impair learning performance in artificial neural networks, especially when trained to perform complicated tasks; but as modern experimental methodologies allow us to record from diverse neuronal populations spanning multiple brain regions, using RNN models to study neuronal interactions without incorporating these fundamental biological properties raises questions regarding the validity of the insights gleaned from them. To address these concerns, our work develops methods that let us train RNNs which respect Dales law whilst simultaneously maintaining a specific sparse connectivity pattern across the entire network. We provide mathematical grounding and guarantees for our approaches incorporating both types of constraints, and show empirically that our models match the performance of RNNs trained without any constraints. Finally, we demonstrate the utility of our methods for inferring multi-regional interactions by training RNN models of the cortical network to reconstruct 2-photon calcium imaging data during visual behaviour in mice, whilst enforcing data-driven, cell-type specific connectivity constraints between various neuronal populations spread across multiple cortical layers and brain areas. In doing so, we find that the interactions inferred by our model corroborate experimental findings in agreement with the theory of predictive coding, thus validating the applicability of our methods.

neuroscience↗

Modeling tumor dynamics and predicting response to chemo-, targeted-, and immune-therapies in a murine model of pancreatic cancer

We seek to establish a parsimonious mathematical framework for understanding the interaction and dynamics of the response of pancreatic cancer to the NGC triple chemotherapy regimen (mNab-paclitaxel, gemcitabine, and cisplatin), stromal-targeting drugs (calcipotriol and losartan), and an immune checkpoint inhibitor (anti-PD-L1). We developed a set of ordinary differential equations describing changes in tumor size (growth and regression) under the influence of five cocktails of treatments. Model calibration relies on three tumor volume measurements obtained over a 14-day period in a genetically engineered pancreatic cancer model (KrasLSLG12D-Trp53LSLR172H-Pdx1-Cre). Our model reproduces tumor growth in the control and treatment scenarios with an average concordance correlation coefficient (CCC) of 0.99{+/-}0.01. We conduct leave-one-out predictions (average CCC=0.74{+/-}0.06), mouse-specific predictions (average CCC=0.75{+/-}0.02), and hybrid, group-informed, mouse-specific predictions (average CCC=0.85{+/-}0.04). The developed mathematical model demonstrates high accuracy in fitting the experimental tumor data and a robust ability to predict tumor response to treatment. This approach has important implications for optimizing combination NGC treatment strategies.

bioinformatics↗

Effect of Stroma-directed Drugs in Combination with Chemotherapy Against Pancreatic Cancer- a Preclinical Study

Cytotoxic chemotherapy plays an important role for extending the survival of patients with pancreatic ductal adenocarcinoma (PDAC). To enhance the efficacy of chemotherapy for eradicating the cancer cells, we have compared the standard care chemotherapy (combination of nab-paclitaxel, gemcitabine and cisplatin, NGC) versus NGC plus stroma-directed agents (calcipotriol and losartan, respectively) in a genetically engineered mouse model of PDAC. Over a 2-week study period, MRI was conducted to measure the tumor size and to test the sensitivity of imaging markers derived from diffusion-weighted imaging (DWI), dynamic contrast enhanced MRI (DCE) and magnetization transfer ratio (MTR) for assessing the tumor cellularity and stromal changes. Detailed immunohistochemistry and preliminary single cell RNA sequencing (scRNAseq) study were applied to tumor tissues collected upon euthanasia on day-14. Our major findings are: 1. Compared the untreated controls, NGC chemotherapy induced significant tumor growth inhibition and stromal changes including pronounced reduction of fibroblast associated protein (FAP) level accompanied by increased matrix collagen content, significantly reduced microvascular permeability revealed by DCE corroborated with reduced microvascular density. 2. Losartan+NGC significantly enhanced inhibition of tumor growth beyond NGC and increased lymphocytes infiltration in the tumor which may contribute to enhanced cancer cells eradication. 3. NGC treatment enriched the fraction of mesenchymal (M) subtype while reducing the epithelial (E) subtype of cancer cells compared to the controls, and this trend was reversed by calcipotriol+NGC. In conclusion, our study captured changes in cancer cell and tumor microenvironment in response to chemo stromal therapy versus chemotherapy alone with mechanistic insights.

cancer biology↗

Intestinal Dysbiosis Alters Acute Seizure Burden and Antiseizure Medicine Activity in the Theiler's Virus Model of Encephalitis

ObjectiveBrain infection with Theilers virus (TMEV) in C57BL/6J mice produces an etiologically relevant model of acquired seizures. Dietary changes can modify acute seizure presentation following TMEV brain infection and influence intestinal microbiome diversity and composition. Intestinal dysbiosis may thus similarly affect seizure burden and antiseizure medicine (ASM) activity in this model, independent of pharmacokinetic effects. We thus sought to define the influence of antibiotic (ABX)-induced gut dysbiosis on acute seizure presentation, anticonvulsant activity of carbamazepine (CBZ), and CBZ pharmacokinetics with TMEV infection. MethodsMale C57BL/6J mice (4-5 weeks) received oral (p.o.) ABX or saline (SAL) once daily beginning on arrival through Day 7 post-TMEV infection (p.i.). Mice were infected with TMEV or PBS on Day 0. Mice received intraperitoneal (i.p.; 20 mg/kg) CBZ or vehicle (VEH) twice daily Days 3-7 p.i. and were assessed for handling-induced seizures 30 min after treatment. Plasma was collected on Day 7 p.i. at 15 and 60 min post-CBZ administration for bioanalysis. ResultsTMEV infection induced acute seizures, but ABX-induced gut dysbiosis altered seizure presentation. There were 75% SAL-VEH, 35% SAL-CBZ, 35% ABX-VEH, and 72% ABX- CBZ mice with seizures during the 7-day monitoring period. There was a significant pretreatment x ASM interaction (p=0.0001), with differences in seizure burden in SAL- versus ABX-pretreated mice (p=0.004). CBZ significantly increased latency to seizure presentation; an effect absent in ABX-CBZ mice. Plasma CBZ concentrations did not differ between SAL and ABX pretreatment groups, suggesting that ABX did not influence CBZ pharmacokinetics. SignificanceABX-induced gut dysbiosis markedly altered acute disease trajectory with TMEV- induced encephalitis, reflecting a novel contribution of the gut microbiome to seizure presentation. ABX-induced gut dysbiosis also significantly changed acute seizure control by CBZ, but did not influence plasma CBZ concentrations. The gut-brain axis is thus an under- recognized contributor to TMEV infection-induced seizures, ASM activity, and disease burden. Key PointsO_LITheilers virus infection in mice models encephalitis that exhibits differential disease trajectory with gut microbiome modulation. C_LIO_LIExperimentally evoked gut dysbiosis, i.e. a disrupted gut microbiome, dramatically shifts the anticonvulsant activity of carbamazepine. C_LIO_LIThere is no concomitant shift in circulating carbamazepine concentrations in TMEV- infected mice with and without a dysbiotic microbiome. C_LIO_LIThe gut microbiome is an under-recognized driver of seizure risk and antiseizure medicine activity in the Theilers virus mouse model. C_LI

neuroscience↗

Quantitative MRI Measurements Capture Pancreatic Cancer and Stroma Reactions to New KRAS Inhibitor

PurposeIn pancreatic ductal adenocarcinoma (PDAC), KRAS mutations drive both cancer cell growth and formation of a dense stroma. Small molecule KRAS inhibitors (KRASi) represent a promising new treatment hence clinical tools that can assess early response, detect resistance and/or predict prolonged survival are desirable to understand clinical biology of KRASi. We hypothesized that diffusion-weighted MRI (DWI) can detect cell death while dynamic contrast enhanced MRI (DCE) and magnetization transfer ratio (MTR) imaging are sensitive to tumor microenvironment changes, and these metrics shed insights into tumor size change induced by KRASi treatment. Experimental DesignMultiple preclinical PDAC models including a genetically engineered mouse model (KPC) received MRTX1133, a KRASi specific for KRASG12D mutation. Quantitative imaging markers were corroborated with immunohistochemistry (IHC) analyses. ResultsSignificant increase of tumor apparent diffusion coefficient (a DWI metric) was detected as early as 48h and persisted to Day7 after initiation of KRASi treatment and was strongly correlated with cell death and reduced cellularity, resulting in greatly prolonged median survival in treated mice. Capillary perfusion/permeability (a DCE metric) exhibited an inverse relationship with microvascular density. Distinct responses of KRASG12C versus KRASG12D tumors to MRTX1133 were captured by the MRI metrics corroborated with IHC. When tumors developed resistance to MRTX1133, the imaging marker values exhibited a reversal from those of responding tumors. ConclusionsMultiparametric MRI provides early biological insights of cancer and stromal response to KRASi treatment and sets the stage for testing the utility of these clinically ready MRI methods in patients receiving KRASi therapy. Translational relevanceEmerging small molecule KRAS inhibitors (KRASi) represent a new class of therapy for PDAC. Clinical tools that can provide early biological insights of KRASi therapy are desirable. In PDAC models, we examined a clinically ready imaging protocol that combines MRI-based tumor size, diffusion-weighted MRI (DWI), dynamic contrast enhanced MRI (DCE), and magnetization transfer ratio (MTR) for detection of early response as well as acquired resistance to MRTX1133, a KRASi being evaluated in clinical trials. Our data show that DWI and DCE metrics provided key insights of significant cell death and tumor microenvironment changes underlying tumor size regression as early as 48 hours after KRASi treatment initiation. These MRI metrics also captured resistance to KRASi developed over prolonged treatment. This study has high translational relevance by employing clinically applied MRI methods, an investigational new drug and a genetically engineered mouse model that recapitulates salient features of human PDAC.

cancer biology↗