Biology subjects

Choi, K.

Publications and source records attributed to Choi, K..

At least 19 recordsLinked to original sources

bioRxiv2026

Acute social defeat induces cannabinoid type 1 receptor-dependent synaptic depression in the anterior ventral subiculum to anterior hypothalamic nucleus pathway to drive social avoidance in male mice

BACKGROUND: Social avoidance is a protective response that limits exposure to harmful social stimuli. Although avoidance is a characteristic stress phenotype, its circuit-level regulation remains unclear. The ventral subiculum (vSUB), a major hippocampal output, projects to the anterior hypothalamic nucleus (AHN), a key region for stress responses. METHODS: Male mice underwent acute social defeat stress (ASDS) or subthreshold social defeat stress. We combined social interaction, open field, and elevated plus maze testing with optogenetic-assisted slice recording, pharmacology, pathway-specific chemogenetics and optogenetics, retrograde and anterograde transsynaptic tracing, and in situ hybridization. RESULTS: ASDS induced presynaptic depression at anterior vSUB (avSUB) [->] AHN synapses through a glucocorticoid- and cannabinoid type 1 receptor (CB1R)-dependent mechanism, while posterior vSUB (pvSUB) [->] AHN synapses were unaffected. Infusing a CB1R antagonist into the AHN before ASDS attenuated both the synaptic depression and the social avoidance. Chemogenetic activation of the avSUB [->] AHN pathway during ASDS attenuated social avoidance, whereas its inhibition induced avoidance under subthreshold stress. Optogenetic activation of the avSUB [->] AHN pathway produced an immediate increase in social approach. Anterograde tracing revealed that anterior and posterior vSUB neurons project to largely separate AHN populations. The pvSUB [->] AHN pathway modulates anxiety-like behavior without altering social approach. CONCLUSIONS: These findings reveal specialized roles for vSUB subregions in social and emotional responses, and identify presynaptic gating of the avSUB [->] AHN synapse as a control point for stress-induced social withdrawal.

neuroscience↗

bioRxiv2026

Striatal interneuron microcircuits gate reinforcement to stabilize adaptive choice

The dorsomedial striatum guides learning and adaptive decision-making through excitatory synaptic control of its spiny projection neuron outputs. However, the contributions of local inhibitory microcircuitry remain poorly understood. Here, we identify an interneuron circuit in the dorsomedial striatum that links outcome processing to adaptive action selection. During probabilistic push-pull reversal learning, interneurons represented immediate outcomes: somatostatin interneurons were recruited on unrewarded trials and unexpected rewarded trials, whereas tyrosine hydroxylase interneurons were suppressed on unrewarded trials and recruited on rewarded trials. In vivo recruitment of tyrosine hydroxylase interneurons suppressed somatostatin interneuron activity and increased activity in both direct- and indirect-pathway striatal projection neurons, revealing a polysynaptic disinhibitory microcircuit. Transient inhibition of somatostatin interneurons in this pull-tuned region produced a sustained increase in aberrant pull choices and occupancy of a suboptimal pull-preferring behavioral state, whereas inhibition of tyrosine hydroxylase interneurons produced a sustained impairment of pull reinforcement. Longer-term policy changes following somatostatin interneuron inhibition coincided with postsynaptic potentiation of excitatory synapses onto striatal projection neurons, suggesting a potential substrate for the persistence of altered behavioral policies. Together, these findings identify a disinhibitory striatal circuit motif gating reinforcement which transforms individual trial outcomes into temporally broader policy.

neuroscience↗

bioRxiv2026

Reprogramming VHL with molecular glues enables selective degradation of caspase-2

Molecular glue degraders (MGDs) reprogram E3 ligases to eliminate neosubstrates, yet their application has largely been confined to CRBN. Here, we identify caspase-2 as a new neosubstrate for von Hippel-Lindau (VHL), expanding the scope of VHL-based MGDs. Guided by a focused VHL ligand library design, we employed TurboID-based proximity labeling to discover stereoisomeric compounds (dCASP2-1 and dCASP2-2) that selectively recruit caspase-2 to VHL and promote its ubiquitin-proteasome system-dependent degradation. Further structure-activity relationship (SAR) studies yielded dCASP2-3 and dCASP2-4, which enhanced degradation potency (by 622-fold relative to dCASP2-1) and abolished enantioselectivity. Mechanistic mapping localized the degrader-induced interface to a two-helix region of the caspase-2 CARD domain, with residues H33, P34, and D100 essential for VHL engagement. Degron-guided computational modeling of the VHL/MGD/caspase-2 ternary complex provided structural insight into neosubstrate recognition. Together, we report the development of VHL molecular glues that selectively and potently degrade caspase-2, offering chemical probes to interrogate its functions in apoptosis and stress responses, while broadening the substrate landscape of VHL-based MGDs.

biochemistry↗

bioRxiv2026

Functional segregation of body-brain signals in the area postrema

Nausea arises from activation of specialized neurons in the area postrema (AP)1-8. The AP also mediates much of the satiety produced by GLP1R agonists9-12, suggesting a broader role in non-aversive physiology, yet the functions of AP cell types are not well understood. Here, we have used optical recordings in behaving mice to systematically define the natural regulation of an array of AP neurons, including the cell types that are principal targets of widely-used weight loss drugs. We discover that neurons expressing GFRAL, the receptor for the sickness-related hormone GDF15, are unexpectedly activated when mice consume food rich in fat. This fat-specific GFRAL neuron activation is required for fat satiation but does not involve GDF15 or canonical gut-brain pathways. Instead, "anti-nausea" neurons expressing GIPR, which directly inhibit GFRAL neurons, are selectively activated by sugar, enabling macronutrient-specific gating of GFRAL responses. In addition, we show that CALCR neurons link intestinal hyperosmolality to the suppression of feeding, whereas PRLHR neurons respond to changes in blood volume and pressure. These findings reveal a broad role for AP cell types in sensing and responding to physiologic signals unrelated to nausea. They also reveal that GFRAL and GIPR neurons, which are key targets of the weight-loss drug tirzepatide, have a natural function in sensing ingestion of fat and sugar, respectively.

neuroscience↗

bioRxiv2026

Holotomography reveals biophysical remodeling of mouse oocytes during post-ovulatory aging

Routine assessment of oocyte state in reproductive biology and clinical embryology still relies largely on two-dimensional transmitted-light morphology, leaving the underlying three-dimensional intracellular organization largely unmeasured. Here, we use holotomography to reconstruct volumetric refractive index (RI) distributions in unlabeled live mouse oocytes and combine this imaging with sparse-annotation, AI-assisted compartment segmentation and multidimensional feature extraction across geometry, RI statistics, dry-mass density, and intracellular texture. Applied to an in vitro model of post-ovulatory aging, holotomography-derived biophysical profiles separated fresh and aged oocytes more strongly than two-dimensional brightfield-derived features, and feature-family ablation indicated that non-morphological descriptors contributed substantially to this separation. At the population level, aged oocytes showed coordinated ooplasmic remodeling, including reduced volume, increased RI heterogeneity, and increased dry-mass density while total dry mass was broadly conserved. These findings demonstrate a label-free quantitative framework for detecting post-ovulatory aging-associated biophysical remodeling in intact mammalian oocytes. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=167 SRC="FIGDIR/small/733271v1_ufig1.gif" ALT="Figure 1"> View larger version (89K): org.highwire.dtl.DTLVardef@c7257aorg.highwire.dtl.DTLVardef@6d92f0org.highwire.dtl.DTLVardef@1c9f7eborg.highwire.dtl.DTLVardef@b36637_HPS_FORMAT_FIGEXP M_FIG C_FIG

Developmental Biology↗

bioRxiv2026

Investigating the coupled effects of stiffness and stretch on the trabecular meshwork cells using a hydrogel-integrated microfluidic system

Glaucoma is characterized by progressive stiffening of the trabecular meshwork (TM), which elevates intraocular pressure and contributes to tissue dysfunction. Although substrate stiffness and mechanical stimulation both regulate TM homeostasis, their combined effects remain poorly understood. Here, a hydrogel-integrated microfluidic platform is presented that enables simultaneous control of substrate stiffness via tunable gelatin methacryloyl (GelMA) hydrogels and equi-biaxial quasi-static stretch via hydraulic actuation. Finite element analysis validates the applied strain field, and optimized crosslinking ensures structural stability. Primary normal TM (nTM) and glaucomatous TM (gTM) cells cultured under coupled conditions exhibit selective mechanotransduction dysregulation rather than global mechanosensory impairment. While nTM cells dynamically regulate -smooth muscle actin (-SMA), myocilin (MYOC), matrix metalloproteinase-2 (MMP2), and collagen type I (COL1), gTM cells display constitutively elevated -SMA, loss of mechanical regulation of MMP2, and impaired stretch-mediated COL1 suppression, while retaining stiffness-dependent focal adhesion kinase and MYOC sensitivity. Key differences between normal and glaucomatous cells emerge only under combined stiff and stretched conditions, underscoring the importance of coupled mechanical cues in revealing disease-relevant phenotypes. These findings implicate tissue stiffening in selective pathway dysregulation and highlight mechanotransduction-targeted therapeutic strategies.

bioengineering↗

bioRxiv2026

Thalamocortical network dynamics in focal epilepsy: SEEG investigation

Thalamic neuromodulation is clinically effective in drug{-}resistant epilepsy, suggesting critical contributions of the thalamus to the epileptogenic process. However, the underlying electrophysiologic mechanisms remain poorly characterized. Converging evidence implicates the thalamus in shaping large{-}scale functional interactions across the cortex. We hypothesized that ictal changes in thalamic activity track cortical network dynamics associated with seizure propagation. We analyzed stereo{-}electroencephalography recordings from 16 patients with focal epilepsy (255 seizures) with simultaneous sampling of the thalamus (anterior nucleus, N=14; pulvinar, N=11) and cortex. Cortical regions of interest included the seizure onset zone (SOZ), surrounding cortices (near{-}SOZ), and control regions from the contralateral hemisphere. We characterized seizure dynamics across spatial scales, from local activity within each region to network{-}level, inter{-}regional interactions. Local activity was decomposed into its periodic (oscillatory) and aperiodic components. Network interactions were characterized by directed functional connectivity computed with a multivariate method. Seizures were associated with increased broadband power (a proxy for neuronal population firing rates) and low{-}frequency rhythmic activity across the thalamocortical network relative to interictal baseline levels. In contrast, consistent changes in aperiodic slope (a putative marker of excitation{-}inhibition balance) were specific to the thalamus, which showed an early and sustained steepening (i.e., more negative slope). While local rhythms were heterogeneous across the canonical frequency bands, inter{-}regional interactions predominantly involved the beta band (13{-}30 Hz). Shortly after onset, both forward outflow from SOZ to near{-}SOZ and feedback inflow in the reverse direction were increased. These bidirectional effects were expressed via both a direct cortico{-}cortical pathway and an indirect transthalamic route, operating in parallel. These dynamics were further stratified based on seizure subtypes, leveraging the fact that there was minimal propagation of ictal activity to the near{-}SOZ in subclinical seizures. The ictal drop in thalamic aperiodic slope was primarily observed in clinical seizures. At the network level, whereas SOZ[->]near{-}SOZ outflow was present across seizure types, reverse feedback was particularly enhanced in clinical seizures. Multivariable regression showed that the degree of thalamic slope steepening uniquely tracked seizure{-}to{-}seizure fluctuations in the strength of near{-} SOZ[->]SOZ feedback, and further predicted seizure durations. Together these findings highlight thalamic aperiodic slope as an index of cortical network dynamics linked to seizure propagation, with potential clinical utility for further development of physiology{-}informed precision neuromodulation.

neuroscience↗

bioRxiv2025

High-resolution cryo-EM structures of small protein-ligand complexes near the theoretical size limit

Cryo-electron microscopy (cryo-EM) is widely used to determine macromolecular structures at atomic resolution. The theoretical size lower limit of particles for cryo-EM analysis is 38 kDa, limited by factors such as contrast and particle alignment accuracy. To date, no cryo-EM structures have been reported for proteins near this size limit. This study presents cryo-EM structures of two protein-ligand complexes around 40 kDa. The structure of maltose-binding protein (43 kDa) was determined at 2.32 [A] resolution, clearly revealing the bound maltose and water molecules. Additionally, the kinase domain of human PLK1 (37 kDa), slightly below the theoretical limit, was determined at 3.04 [A] resolution, allowing the identification of the bound ligand, onvansertib. These findings demonstrate that cryo-EM can be effectively employed for structure determination and structure-based drug screening of small proteins or domains.

biophysics↗

bioRxiv2025

MYD88 mutations in clonal hematopoiesis promote inflammation and hematopoietic stem cell expansion

Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by expansion of mutant hematopoietic stem and progenitor cells (HSPCs) and an increased risk of chronic diseases and cancers. While mutations in DNMT3A, TET2, and ASXL1 are common in CHIP, the contribution of less frequent gene mutations is not well understood. Here, we report MYD88 mutations, including lymphoma-associated and novel variants in blood cells of the general population and newly diagnosed solid cancer patients. MYD88 CHIP mutations in HSPCs activate NF-{kappa}B, indicating a gain-of-function activity. Modeling MYD88 CHIP in mice, Myd88L252P (equivalent of human L265P) expression resulted in a competitive fitness advantage of HSPCs. Myd88L252P HSPCs exhibit a myeloid cell bias and inflammation, leading to hematologic disease. Single-cell RNA sequencing indicated that Myd88L252P expands distinct hematopoietic and immune cell clusters and activates immune-related pathways in HSPCs. An IRAK1/4 inhibitor suppressed MYD88-dependent NF-{kappa}B activation and reversed Myd88L252P cell expansion. Overall, MYD88 mutations contribute to CHIP by inducing innate immune pathways in HSPCs and inflammatory disease.

cancer biology↗

bioRxiv2025

Kidney cystogenesis in embryonic- and adult-onset ADPKD is suppressed from lack of adenylyl cyclase targeting to cilia

Multiple cellular pathways are dysregulated in autosomal dominant polycystic kidney disease (ADPKD), but mechanisms initiating cyst formation are unknown. ADPKD is caused by mutations in Pkd1/Pkd2 genes that encode for polycystins that localize to primary cilia. The primary cilium is a miniscule subcellular compartment for generating signaling outputs that profoundly affect cellular function. Severe cystogenesis from polycystin loss is mostly cilia dependent. However, the polycystin-repressed ciliary signals that promote cyst growth are unknown and have been challenging to uncouple from downstream cystogenic pathways. Here we aimed at differentiating ciliary adenylyl cyclase signaling from total cellular changes in second messenger cAMP implicated in cystogenesis. We studied an Ankyrin repeat and MYND domain protein, ANKMY2 that we previously implicated in maturation and ciliary localization of adenylyl cyclases in fibroblasts. We studied kidney-specific conditional knockout mouse models of Ankmy2/Pkd1 and ciliary localization of adenylyl cyclases in kidney epithelial cells. We found suppression of early postnatal renal cystogenesis and prolonged survival in an embryonic onset Pkd1 deletion model from ANKMY2 loss. Phosphorylated CREB formation, from elevated cellular cAMP levels, remained unaffected. Cyst load in male mice in an adult inducible conditional Pkd1 deletion model was suppressed from ANKMY2 loss. Mechanistically, ANKMY2 determined ciliary trafficking of adenylyl cyclases in kidney epithelial cells without disrupting cilia. Further, ANKMY2 loss prevented ciliary length increase in ADPKD mouse models irrespective of cyst load or sex. Cilia length increase was seen preceding cystogenesis. Our results suggest that targeting of adenylyl cyclases to renal epithelial cilia promotes PC1/2-inhibited cilia-dependent cyst activation distinct from cyst progression involving cellular cAMP.

cell biology↗

bioRxiv2025

Prevalent cross-cell type QTL trans-regulatory genetic effects impacting innate lymphoid cells in the small intestine

Tissue function in homeostasis and disease arise from coordinated interactions between different cell types and can vary between individuals in a population, in part due to the impact of genetic variants. In barrier tissues such as the gut, innate lymphoid cells (ILCs) play critical roles in maintaining tissue homeostasis and immunity, but the genetic basis and associated regulatory circuitry affecting tissue ILCs remain largely unknown. Here, we systematically mapped the regulatory functions of genetic variants across 273,370 gut ILCs profiled by single cell RNA-seq from 274 diversity outbred (DO) mice. Computational analysis identified quantitative trait loci (QTL) impacting ILCs at three levels: cell subtype-specific mRNA expression (local and distal), cell subset proportions, and ILC gene expression programs (in trans), of which we experimentally validated a pivotal role for the transcription factor Rbpj in regulating ILC3s. All three classes of ILC QTL display polygenic inheritance signatures and broadly overlap with QTL affecting peripheral cytokine levels that we measured in another 261 DO mice. Strikingly, nearly half of trans-QTL affecting ILC traits did not overlap (within a 50-kb window) genes expressed in ILCs, and such loci were enriched for genes expressed by non-ILCs especially enteric neurons and intestinal glia. This suggests that such loci may act instead across cell type boundaries and allowed us to recover causal trans-cell type regulatory circuits in the tissue, including loci encoding multiple neuron-expressed peptides, epithelial-cell expressed Sox9, and phagocyte-expressed Ccl17. Finally, human orthologs of genes in QTL impacting gene expression and cell proportions are enriched for autoimmune disease risk heritability, suggesting their relevance to human disease. Our findings highlight how the impact of genetic variants may propagate to maintain tissue homeostasis and show a path to understand causality in tissue biology using quantitative genetics.

genetics↗

bioRxiv2025

Temporally and Functionally Distinct Contributions to Value Based Choice Along the Anterior-Posterior Dorsomedial Striatal Axis

While the dorsoventral and mediolateral organization of striatum has resolved clear functional distinctions, far less is known about how the anterior-posterior striatal axis contributes to behavioral control. We explore this within the dorsomedial striatum (DMS), a key region for value-based choice, by comparing population neuronal activity and function within anterior (A-DMS) and posterior (P-DMS) subregions while mice operantly seek reward. Neural recordings show that P-DMS encoded action values and strategy information prior to choice selection while A-DMS activity represented recently selected choices and their anticipated values via a dynamic population reorganization immediately following action selection. Optogenetic perturbations were consistent with these temporally distinct coding properties as unilateral manipulation of the P-DMS prior to choice biased choice contralaterally in a value-dependent manner and unilateral inhibition of the A-DMS following choice impaired future value-based action selection. Using anterograde tracing, we found that the A-DMS and P-DMS projected to a common region within the ventromedial substantia nigra pars reticulata (vmSNr), which contained value-related signals combining aspects of upstream DMS processing. Together, our results support a model for temporally distributed influence on value-based choice across the anterior-posterior axis of the DMS.

neuroscience↗

bioRxiv2024

Effect of flicker-induced retinal stimulation of mice revealed by full-field electroretinography

PurposeTo investigate the effects of brief flickering light stimulation (FLS) on retinal electrophysiology and its blood flow in normal C57BL6J mice. MethodsRetinal blood flow (RBF) and full-field electroretinography (ffERG) were measured before and after a 60-second long FLS (12 Hz, 0.1 cd{middle dot}s/m2) in a cohort of 8-12 weeks old C57BL6J mice (n=10) under anaesthetic and light-adapted conditions. A separate set of age-matched mice (n=9) underwent RBF and ffERG measurements before and after steady light stimulation (SLS) at 1 cd/m2 under similar conditions. The changes in RBF (arterial and venous flow) and ffERG responses (amplitudes and implicit times of a- and b-wave) were analyzed. ResultsFLS significantly increased both arterial (p=0.003) and venous (p=0.018) blood flow as well as b-wave amplitudes (p=0.017) compared to SLS, which did not have any significant changes in both RBF and ERG. However, no significant differences were found in other ffERG responses (amplitude and implicit time of a-wave and b-wave implicit time) between the two groups after light stimulation. An increase in b-wave amplitude was positively associated with increase in both arterial (r=0.655, p=0.040) and venous blood flow (r=0.638, p=0.047) in the FLS group. ConclusionsTransient FLS induced a significant increase in both RBF and electro-retinal activity, but such increase was not observed after SLS. Our results suggest the role of FLS, which exerts metabolic stress on the retina, in triggering retinal neurovascular coupling.

neuroscience↗

bioRxiv2024

Exploring Organ-Specific Extracellular Vesicles in Metabolic Improvements Following Bariatric Surgery in Adolescents with Obesity

Aims/hypothesisVertical sleeve gastrectomy (VSG) leads to significant metabolic improvements, though the underlying molecular mechanisms are not yet fully understood. Emerging evidence suggests that small extracellular vesicles (sEVs) contribute to metabolic improvements post-VSG; however, it is still unclear which organ-specific sEV correlate with various metabolic parameters and how they exert these effects. The study aimed to establish the role of organ-specific sEVs in the metabolic improvements associated with VSG. MethodsDemographic, anthropometric, and blood samples were collected pre-VSG and 3- and 6-month post-VSG in adolescents with obesity. Blood samples were utilized to measure metabolic parameters and to isolate sEVs. sEV RNAs were analyzed via small RNA sequencing then bioinformatics analyses. ResultsA significant reduction in mRNA cargo from liver-specific genes was observed post- VSG, whereas adipose tissue- or skeletal muscle-specific genes showed no such reduction. Liver-derived RNA correlated with BMI, leptin, and resistin, while adipose-derived RNA correlated with leptin. Analysis of delta values (post-minus pre-surgery) revealed that adipose-derived RNA cargo correlated with markers of liver damage and HOMA-IR, whereas liver-derived RNA cargo correlated with BCAAs. ConclusionsVSG modulates the EV system in the liver and adipose tissue. Liver-derived sEVs appear to regulate adipose metabolism, while adipose-derived sEVs are associated with liver function, suggesting a dynamic crosstalk between these tissues through sEVs that shapes systemic metabolic outcomes. Research in ContextO_ST_ABSWhat is already known about this subject?C_ST_ABS- Vertical sleeve gastrectomy (VSG) is the most performed bariatric surgery, leading to significant metabolic improvements. - Small extracellular vesicles (sEVs) and their RNA cargo play a crucial role in metabolic regulation. - Levels of branched-chain amino acids (BCAAs), which are known metabolic regulators, decrease following bariatric surgery. What is the key question?- How do sEVs, BCAA and other metabolic molecules interact to drive the significant metabolic improvements observed after VSG? What are the new findings?- The levels of liver-specific RNA cargo in sEVs decrease after VSG and are correlated with BMI and leptin levels at 6 months post-surgery, suggesting a potential role for liver-specific RNA cargo in the metabolic benefits associated with VSG. - Changes in BCAA levels from baseline to 6 months post-surgery correlate with changes in liver-specific RNA cargo in sEVs, indicating liver-specific RNA cargo in sEVs may influence metabolic parameters through BCAA modulation. - Changes in the level of adipose-specific RNA cargo in sEVs from baseline to 6 month post-surgery correlate with changes HOMA-IR and ALT levels. How might this impact on clinical practice in the foreseeable future?The study identifies liver- and adipose-derived sEV RNA cargo as potential targets for non-invasive therapies that could replicate the metabolic benefits of VSG. While further investigation is needed, these findings suggest a tentative alternative for adolescents facing obesity who may be ineligible or reluctant to undergo bariatric surgery.

cell biology↗

bioRxiv2024

COmapper: High-resolution mapping of meiotic crossovers by long-read sequencing in Arabidopsis

O_LIMeiotic crossovers rearrange existing genetic variation between homologous chromosomes, profoundly affecting genomic diversity. Crossovers are typically constrained to 1-3 events per chromosome pair, and their distribution is shaped by chromatin accessibility and DNA polymorphisms. Genome-wide crossover maps can be generated in plants by high-throughput short-read sequencing or linked-read sequencing. C_LIO_LIHere, we use long-read nanopore sequencing technology to develop a crossover mapping pipeline, COmapper, for high-resolution mapping of genome-wide crossovers from pooled DNA of F1 hybrid pollen and F2 recombinant seedlings derived from a cross between Arabidopsis thaliana accessions Col and Ler. We validate the high accuracy of COmapper by applying nanopore long-read sequencing to pooled DNA of Arabidopsis F2 individuals with crossovers mapped by short-read sequencing. C_LIO_LIUsing the COmapper, we constructed high-resolution genomic maps of crossovers using F1 hybrid pollen and F2 seedlings in wild type and crossover-elevated recq4a recq4b mutant, showing results comparable to short-read sequencing. Crossovers were enriched at gene-proximal promoters in wild type and increased but reshaped by high polymorphism density in recq4a recq4b. C_LIO_LIWe propose that COmapper will be widely applicable for exploring the effects of genetic, epigenetic and environmental changes on the crossover patterns across diverse plant species. C_LI

plant biology↗

bioRxiv2024

Bifurcation enhances temporal information encoding in the olfactory periphery

Living systems continually respond to signals from the surrounding environment. Survival requires that their responses adapt quickly and robustly to the changes in the environment. One particularly challenging example is olfactory navigation in turbulent plumes, where animals experience highly intermittent odor signals while odor concentration varies over many length- and timescales. Here, we show theoretically that Drosophila olfactory receptor neurons (ORNs) can exploit proximity to a bifurcation point of their firing dynamics to reliably extract information about the timing and intensity of fluctuations in the odor signal, which have been shown to be critical for odor-guided navigation. Close to the bifurcation, the system is intrinsically invariant to signal variance, and information about the timing, duration, and intensity of odor fluctuations is transferred efficiently. Importantly, we find that proximity to the bifurcation is maintained by mean adaptation alone and therefore does not require any additional feedback mechanism or fine-tuning. Using a biophysical model with calcium-based feedback, we demonstrate that this mechanism can explain the measured adaptation characteristics of Drosophila ORNs.

neuroscience↗

bioRxiv2024

Tryptanthrin Analogs Substoichiometrically Inhibit Seeded and Unseeded Tau4RD Aggregation

Microtubule-associated protein tau is an intrinsically disordered protein (IDP) that forms characteristic fibrillar aggregates in several diseases, the most well-known of which is Alzheimers disease (AD). Despite keen interest in disrupting or inhibiting tau aggregation to treat AD and related dementias, there are currently no FDA-approved tau-targeting drugs. This is due, in part, to the fact that tau and other IDPs do not exhibit a single well-defined conformation but instead populate a fluctuating conformational ensemble that precludes finding a stable "druggable" pocket. Despite this challenge, we previously reported the discovery of two novel families of tau ligands, including a class of aggregation inhibitors, identified through a protocol that combines molecular dynamics, structural analysis, and machine learning. Here we extend our exploration of tau druggability with the identification of tryptanthrin and its analogs as potent, substoichiometric aggregation inhibitors, with the best compounds showing potencies in the low nanomolar range even at a [~]100-fold molar excess of tau4RD. Moreover, conservative changes in small molecule structure can have large impacts on inhibitory potency, demonstrating that similar structure-activity relationship (SAR) principles as used for traditional drug development also apply to tau and potentially to other IDPs.

biochemistry↗

bioRxiv2024

Histone variant H2BE enhances chromatin accessibility in neurons to promote synaptic gene expression and long-term memory

Regulation of histone proteins affects gene expression through multiple mechanisms including exchange with histone variants. However, widely expressed variants of H2B remain elusive. Recent findings link histone variants to neurological disorders, yet few are well studied in the brain. We applied new tools including novel antibodies, biochemical assays, and sequencing approaches to reveal broad expression of the H2B variant H2BE, and defined its role in regulating chromatin structure, neuronal transcription, and mouse behavior. We find that H2BE is enriched at promoters and a single unique amino acid allows it to dramatically enhance chromatin accessibility. Lastly, we show that H2BE is critical for synaptic gene expression and long-term memory. Together, these data reveal a novel mechanism linking histone variants to chromatin regulation, neuronal function, and memory. This work further identifies the first widely expressed H2B variant and uncovers a single histone amino acid with profound effects on genomic structure.

genetics↗