Biology subjects

Guo, Z.

Publications and source records attributed to Guo, Z..

At least 55 records · Page 3Linked to original sources

bioRxiv2026

Delta PSA: A New Metric for Conformational Dynamics Underlying Macrocyclic Peptide Permeability

Development of oral cyclic drugs often suffers from low oral bioavailability resulting from limited passive permeability making accurate prediction a central challenge in drug development. Existing approaches generally fall into two categories: deep learning-based models and accelerated molecular dynamics (aMD) simulations. While deep learning models enable rapid, high-throughput predictions, they often suffer from dependence on training data, and sensitivity to dataset biases. On the other hand, aMD provide mechanistic interpretability by explicitly modeling peptide translocation across lipid bilayers, however, suffer from huge computational cost. Here, we present a conventional MD-based framework for predicting macrocyclic peptide permeability, designed to facilitate interpretation. Importantly, we show that Delta PSA ({Delta}PSA) directly quantifies a peptides chameleon propensity, providing a mechanistically meaningful measure. Furthermore, we identify two key structural indicators--the sidechain PSA ratio and the radius of gyration--as refined metrics for assessing conformational behavior. When applied to a benchmark dataset of macrocyclic peptides, our framework achieves an MSE of 0.22, surpassing the 0.25 reported for Multi_CycGT and demonstrating its superior performance. Our work also provides a large dataset of MD trajectories for macrocyclic peptides in both polar and nonpolar environments. This dataset offers access to a broader conformational space for cyclic peptide studies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=97 SRC="FIGDIR/small/697862v2_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@18fc9e4org.highwire.dtl.DTLVardef@10fbc70org.highwire.dtl.DTLVardef@1c763aorg.highwire.dtl.DTLVardef@95d9e4_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2026

Empagliflozin alleviates doxorubicin-induced cardiotoxicity by suppressing oxidative stress via modulation of the JNK/Nrf2 signaling pathway

Doxorubicin (DOX) treatment increases the risk of myocardial dysfunction and heart failure, in which oxidative stress plays a central role. Empagliflozin (EMPA) has been shown to benefit heart failure patients, yet its underlying mechanism remains unclear. In this study, we showed that EMPA treatment improved cardiac function, ameliorated structural remodeling, and increased survival in DOX-treated mice. Furthermore, EMPA reduced DOX-induced reactive oxygen species (ROS) overproduction and myocardial injury. Through functional analysis overlapping DIC- and EMPA-regulated genes, we identified the involvement of JNK signaling in addition to redox pathways. Subsequent investigations demonstrated that EMPA restored redox homeostasis by inhibiting JNK activation, reactivating NRF2 and its downstream antioxidant proteins HO-1, NQO1, GPX4, and SOD2 both in vivo and in vitro. These protective effects were abolished by the Nrf2 inhibitor ML385 or the JNK activator anisomycin. Collectively, our findings indicate that EMPA protects against DOX-induced cardiotoxicity by modulating the JNK/Nrf2 signaling and attenuating oxidative stress. This study provides a rationale for further investigation of EMPA as a potential therapeutic strategy for chemotherapy-associated cardiac injury. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/697595v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@16743d4org.highwire.dtl.DTLVardef@96495borg.highwire.dtl.DTLVardef@aa343dorg.highwire.dtl.DTLVardef@4ba18c_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2026

Phenotype-Guided In Silico Molecular Generation Using Large Language Models

Complex diseases often emerge from coordinated, system-level cellular state changes that are difficult to address with target centric drug discovery. Phenotypic drug discovery offers a principled alternative but remains constrained by the cost and scalability of pathologically relevant assays. Here we present GEMGen, a large language model-based framework that performs in silico phenotypic drug discovery by generating small molecules directly from transcriptomic representations of cellular states. GEMGen encodes desired phenotypic transitions as text-based representations of up- and down-regulated gene sets, enabling transferable modeling across experimental platforms and data modalities. Trained on large scale chemical perturbation data, GEMGen robustly identifies phenotype-oriented compounds and mechanistically related but structurally distinct candidates across multiple benchmarks. Applied to signatures induced by genetic perturbations, GEMGen produces small molecules that phenocopy gene knockdown effects and identifies chemically novel inhibitors, including previously unreported KEAP1 inhibitors that activate NRF2 signaling. Extending this approach to a disease relevant model of fibrosis, GEMGen generates compounds that reverse profibrotic transcriptional programs and cellular phenotypes. These results establish a scalable framework for translating transcriptomic phenotypes into candidate therapeutic molecules, enabling systems-level exploration of vast chemical space and offering a complementary in silico counterpart to physical phenotypic drug screens.

cell biology↗

bioRxiv2025

Pulmonary mRNA-LNP Vaccines for Rapid and Durable Protection Against Bacterial Infection

Pulmonary bacterial infections remain a major clinical challenge. Although vaccination reduces infection rates and mortality, the vulnerable post-vaccination immunity gap can still result in infection and vaccine failure. In addition, effective vaccines are unavailable for many clinically important bacterial pathogens. Here, we report a pulmonary mRNA-lipid nanoparticle (mRNA-LNP) vaccine incorporating a novel ionizable lipid engineered for localized high-level expression, which elicits both rapid and durable protections against bacterial lung infections, effectively bridging this critical window of vulnerability. Intratracheal delivery of mRNA-LNP rapidly primes lung neutrophils and macrophages into a transcriptionally pre-activated state, enhancing their phagocytic activity and enabling rapid, antigen-independent bacterial clearance during the early post-vaccination period (approximately 1-7 days). Subsequently, vaccination induces potent antigen-specific adaptive responses, conferring sustained protection against both laboratory and clinical drug-resistant Pseudomonas aeruginosa strains. Single-cell transcriptomics and immune profiling reveal coordinated activation of innate and adaptive immune programs. This dual-phase immune response exemplifies a paradigm-shifting vaccine design that integrates innate and adaptive immunity to confer both immediate and long-term protection. Our findings establish a mechanistic basis for rapid antibacterial defense and highlight pulmonary mRNA-LNP vaccination as a promising strategy for combating respiratory infections.

bioengineering↗

bioRxiv2025

TaoChongBao: A Large-Scale Caenorhabditis elegans Mutagenesis and Missense Variant Database Bridging Worm and Human Genomes

We generated and sequenced 12,069 viable Caenorhabditis elegans strains produced by ethyl methanesulfonate mutagenesis, identifying 20,315,536 variants, including 541,102 unique missense mutations across 20,914 genes. To organize and visualize this resource, we developed TaoChongBao, an open-access database and strain repository that integrates C. elegans mutation data with AlphaMissense-predicted pathogenicity scores and ClinVar clinical annotations. TaoChongBao enables users to explore worm missense variants, identify conserved residues corresponding to human pathogenic sites, and access viable strains for experimental validation. Compared with the previous Million Mutation Project in C. elegans, TaoChongBao expands mutation coverage over twenty-fold and emphasizes amino acid-altering variants. This resource provides a scalable platform for functional residuomics, variant interpretation, and comparative analyses between C. elegans and human genomes.

bioinformatics↗

bioRxiv2025

The Human Hippocampus Is Involved in Auditory Short-Term Memory Trace Formation

The human hippocampus has been claimed to play an important role in long-term memory, or episodic memory, but its contribution to short-term memory remains debated. Here, we demonstrate human hippocampal involvement in auditory short-term memory (ASTM) trace formation. We used a classic oddball paradigm and intracranial recordings across various human brain areas. High frequency activities evoked by deviant stimuli in subjects indicate the generation of ASTM trace. Analysis of auditory response latencies across the hippocampus, insula, and temporal, parietal, and frontal lobes revealed the early processing of ASTM trace at a pre-attention stage. Granger causality analysis further showed that ASTM trace processing engages hierarchical cortical areas and clarified their interactions. Bottom-up signals flow from the insula and auditory temporal regions to the frontal lobe early on, followed by top-down information from the frontal lobe to the hippocampus, inferior temporal lobe, and insula at a later pre-attentive stage. Critically, Bayesian model selection of dynamic causal modeling revealed that deviant stimuli selectively enhanced the effectiveness of top-down connections to the hippocampus, thereby facilitating ASTM trace formation. These results provide compelling evidence that the human hippocampus contributes to auditory short-term memory at a pre-attention stage and suggests a challenge to entrenched beliefs in the classification of memory systems.

neuroscience↗

bioRxiv2025

Conserved Gαq-PLCβ-PKC signaling mediates trametinib resistance in BRAFV600E melanoma

Oncogenic BRAFV600E mutations drive constitutive MAPK signaling across various cancers; however, resistance to MEK inhibitors such as trametinib undermines clinical benefits, and the mechanisms sustaining MAPK activity under treatment remain unclear. We developed a lin-45(V627E) Caenorhabditis elegans model to mimic oncogenic BRAF signaling and found that these animals tolerate ultra-high doses of trametinib. This survival is driven by an adaptive resistance bypass, mediated by Gq-PLC{beta}-PKC signaling, which sustains MAPK activity despite MEK inhibition. Transcriptomic analyses of patient tumors and resistant melanoma cells reveal upregulation of the Gq subunits and GPCR PAR2 upon acquisition of resistance. Functional inhibition of PAR2 or downstream Gq signaling suppresses ERK reactivation, selectively impairs the viability of resistant cells. Furthermore, combined inhibition of MEK and Gq-PLC{beta}-PKC signaling synergistically suppresses tumor growth and restores trametinib sensitivity in xenograft models. These findings uncover adaptive GPCR-Gq-driven signaling rewiring as an evolutionarily conserved and therapeutically actionable vulnerability in MAPK-driven cancers.

cancer biology↗

bioRxiv2025

An AI-driven approach for nanobody affinity maturation

B7-H3 (CD276), an immunoregulatory checkpoint molecule overexpressed in numerous cancers, is a promising therapeutic target. Nanobodies possess unique advantages for targeting B7-H3, such as small size, high stability, and the ability to bind cryptic epitopes. However, the rational affinity maturation of these nanobodies is challenging, especially in the absence of detailed structural data on antigen-antibody interactions. Here, we present a computational strategy that leverages artificial intelligence (AI) and molecular modeling, including homology modeling, molecular docking, and free-energy calculations--to systematically predict affinity-enhancing mutations for humanized anti-B7-H3 nanobodies. This AI-driven framework provides a powerful and cost-effective pipeline for accelerating the development of high-affinity nanobody therapeutics prior to experimental validation.

immunology↗

bioRxiv2025

APOE4-Aβ synergy drives brain network dysfunction and neuronal lysosomal-ER proteostasis dysregulation in preclinical Alzheimer's disease

Amyloid-{beta} (A{beta}) and APOE4 represent two of the strongest pathological and genetic risk factors for Alzheimers disease (AD), but how these co-pathogens interact during preclinical stages remains undefined. We addressed this question by developing a humanized knock-in model expressing physiological, endogenously regulated human A{beta} and APOE4. Aged AppNLF:APOE4 mice displayed incipient amyloidosis with subtle memory-related changes, consistent with preclinical AD. We found largely distinct, non-overlapping APOE4- and A{beta}-driven functional synaptic, sleep, and behavioral alterations. However, at the transcriptomic level, APOE4xA{beta} had a pronounced detrimental interaction in neuronal populations, whereas glial populations were primarily affected by either genotype. We found APOE4xA{beta} molecular interactions in neuronal populations, including excitatory and inhibitory cells, converged on a core lysosomal-ER proteostasis axis. We propose that APOE4xA{beta} interaction produces an early neuronal pathogenic signature, involving the lysosomal-ER proteostasis axis, preceding functional decline and driving disease progression. APOE4xA{beta}-KI models provide a physiologically relevant platform to study early pathogenesis. HighlightsO_LIEarly synergistic APOE4xA{beta} interaction emerges predominantly at the transcriptomic level in neurons, but not in glial cells. C_LIO_LIAPOE4 and A{beta} drive largely non-overlapping physiological changes in preclinical stages of disease, but converge at the level of network hyperexcitability. C_LIO_LIAPOE4xA{beta} neuronal synergy converges on a conserved lysosomal-ER proteostasis axis. C_LIO_LIHumanized APOE4xA{beta} KI mice provide a physiologically relevant model to dissect early AD pathogenesis in preclinical stages C_LI

neuroscience↗

bioRxiv2025

MetaboliteChat: A Unified Multimodal Large Language Model for Interactive Metabolite Analysis and Functional Insights

Accurately characterizing the mechanisms and properties of metabolite molecules is essential for advancing metabolomics and systems biology. Yet most existing approaches are narrow, task-specific models that do not transfer across tasks and cannot express the richer, multimodal biological context of a metabolite in natural language. To address these challenges, we introduce MetaboliteChat, a multimodal ChatGPT-like large language model (LLM) that provides a unified and interactive framework for metabolite analysis. MetaboliteChat integrates molecular-graph and image reasoning with natural language understanding to generate comprehensive, free-form predictions about metabolite mechanisms and properties. The MetaboliteChat architecture consists of a graph neural network (GNN), a convolutional neural network (CNN), a large language model (LLM), and adapters, all trained end to end. This unified, multimodal design enables interactive reasoning over unseen metabolites, allowing the model to integrate structural and contextual cues and support discovery and translational insights across diverse biological systems.

bioinformatics↗

bioRxiv2025

A simplified MiMe for producing clonal gametes to enable synthetic apomixis in allotetraploid Brassica napus

Synthetic apomixis has been established in Arabidopsis and rice by combining MiMe that produces clonal unreduced gametes with the factors inducing parthenogenesis or haploids. The MiMe requires the simultaneous inactivation of three genes, which imposes challenges for its application in polyploids harbouring multiple copies for each gene. Here, we demonstrate that mutating two genes in the allotetraploid oil crop Brassica napus effectively converts meiosis into mitosis-like division, producing over 95% viable clonal gametes and thus establishing a simplified MiMe system in polyploids.

plant biology↗

bioRxiv2025

A newly identified Duck orbivirus as the etiological agent of egg-production decline in Chinese breeder ducks

The genus Orbivirus comprises double-stranded RNA viruses, many of which are transmitted by arthropods and cause febrile, hemorrhagic, or reproductive diseases in animals. In recent years, unexplained outbreaks characterized by marked egg-production decline have occurred in breeder duck flocks in China. To identify the causative agent, samples were collected from affected farms in multiple regions across China between 2022 and 2025. Representative samples were analyzed by high-throughput sequencing, followed by phylogenetic analysis, transmission electron microscopy, host cell infection assays, and animal challenge experiments. A previously unreported Orbivirus, designated Duck orbivirus (DORV), was identified. Epidemiological investigation indicated that outbreaks mainly affected breeder ducks during the peak laying period (21-55 weeks of age), with higher incidence in summer and autumn. The DORV genome contains ten double-stranded RNA segments encoding seven structural and five nonstructural proteins. Phylogenetic analysis showed that DORV is closely related to Parrys Lagoon virus (PLV) and Corriparta virus (CORV). Electron microscopy revealed icosahedral particles 30-40 nm in diameter. DORV replicated efficiently in DEF, DEL and C6/36 cells but not in MDCK and LMH cells, suggesting a restricted host range with potential arthropod-borne features. Infection of breeder ducks with DORV-SD01 reduced egg production by 30-40% and caused lesions in the ovary, liver, and spleen. This study describes a novel duck-origin Orbivirus linked to egg-production decline, offering new etiological insights and extending the host spectrum of Orbivirus. The results provide a foundation for future surveillance and prevention of emerging waterfowl diseases.

microbiology↗

bioRxiv2025

FlexRibbon: Joint Sequence and Structure Pretraining for Protein Modeling

AO_SCPLOWBSTRACTC_SCPLOWProtein foundation models have advanced rapidly, with most approaches falling into two dominant paradigms. Sequence-based language models (e.g., ESM-2) capture sequence semantics at scale, and a number of recent works incorporate structural signals into sequence encoders. MSA-based predictors (e.g., AlphaFold 2/3) achieve accurate folding by exploiting evolutionary couplings, but their reliance on homologous sequences makes them less reliable in highly mutated or alignment-sparse regimes. We present FlexRibbon{ddagger}, a pretrained protein model that jointly learns from amino acid sequences and three-dimensional structures. Our pretraining strategy combines masked language modeling with diffusion-based denoising, enabling bidirectional sequence-structure learning without requiring MSAs. Trained on both experimentally resolved structures and AlphaFold 2 predictions, FlexRibbon captures global folds as well as flexible conformations critical for biological function. Evaluated across diverse tasks spanning interface design, intermolecular interaction prediction, and protein function prediction, FlexRibbon establishes new state-of-the-art performance on 12 different tasks, with particularly strong gains in mutation-rich settings where MSA-based methods often struggle.

molecular biology↗

bioRxiv2025

JMJD1B-mediated FEN1 demethylation allows timely switching of Okazaki fragment maturation core enzymes to avoid mutagenic flap ligation by PARP1-LIG3

Efficient and faithful Okazaki fragment maturation (OFM) depends on the PCNA-coordinated actions of core enzymes Pol{delta}, FEN1, and LIG1. We demonstrate that Pol{delta}, FEN1, and LIG1 sequentially but not simultaneously bind to PCNA in mammalian cells. The association of FEN1 with PCNA, which lies at the center of this orderly program, is mediated by FEN1 R192 methylation, which is also crucial for preventing premature loading of LIG1. Conversely, FEN1 demethylation by the recently identified arginine demethylase JMJD1B promotes FEN1 dissociation from PCNA and LIG1 recruitment. Disruption of the sequential PCNA binding program in R192Q or Jmjd1b-/- cells results in unprocessed 5 flaps that prevent OFM and induction of PARP1-dependent recruitment of LIG3, which has flap ligation activity to join incompletely processed OFs. This alternative OFM process supports cell survival but causes duplications and other DNA mutations. Our findings define fundamental and alternative DNA replication processes underlying mutagenesis and cell survival. HighlightsO_LIThe core enzymes involved in Okazaki fragment maturation (OFM), DNA polymerase {delta} (Pol{delta}), flap endonuclease 1 (FEN1), and ligase 1 (LIG1), sequentially bind to the scaffold protein PCNA for their concerted actions C_LIO_LIFEN1 R192 methylation enables FEN1 binding to PCNA; JMJD1B-mediated FEN1 arginine demethylation provokes FEN1 exit from PCNA and LIG1 recruitment C_LIO_LIFEN1 R192Q mutation and JMJD1B deficiency oppositely alter dynamic PCNA interactions with FEN1 and LIG1 and result in distinct OFM DNA intermediate structures C_LIO_LIActivation of PARP1 at replication forks due to disruption of the sequential PCNA binding program induces LIG3-mediated alternative mutagenic 5 flap ligation for survival. C_LI

cell biology↗

bioRxiv2025

Unveiling the unique interaction mechanism of herpes simplex virus 2 glycoprotein C with C3b

AbstractThe complement cascade is part of the first line of defence against viral infections, and many viruses have evolved to block it. For example, glycoprotein C (gC) from Herpes Simplex Virus 1 and 2 (gC1 and gC2) facilitates infection by modulating the complement cascade through an interaction with C3b. gC is also involved in attachment and other viral processes. However, our understanding of the molecular mechanisms of gC have been limited due to the absence of a structure. AlphaFold predicts that gC contains a disordered N-terminus and three immunoglobulin-like domains. Here, we generated various gC2 constructs and demonstrated that gC2 domains 1 and 2 are necessary and sufficient to interact with C3b and block the alternative pathway. A gC2 construct lacking the N-terminus in complex with C3b was characterised by cryo-EM at 3.6 [A], providing the first structure for gC2, and revealing that the interaction is predominantly driven by gC2 domain 2 and the MG8 domain of C3b. This structure was confirmed by cross-linking mass spectrometry and by using C3b-blocking antibodies that recognised gC2 linear epitopes at the interface with C3b. Overall, the gC-C3b interaction is different from other C3b-interacting partners, providing a novel mechanism to regulate the complement cascade.

molecular biology↗

bioRxiv2025

A comprehensive functional landscape of α-tubulin TUBA1A variants illuminates microtubule biology and refines clinical classification

Missense variant interpretation in highly conserved, paralog-rich gene families remains a critical bottleneck for precision medicine. Here, we developed an integrated experimental-computational platform to systematically assess the functional impact of all possible missense mutations in the -tubulin TUBA1A. Combining high-throughput comprehensive mutagenesis, high-content imaging, convolutional neural network- driven phenotyping, and machine learning-guided prediction, we quantified microtubule assembly phenotypes for every coding variant. This approach outperforms conservation-based predictors and enables functional reinterpretation of disease-associated variants. Structural mapping of the TUBA1A mutational landscape reveals distinct domains critical for GTP binding, chaperone-assisted folding or protofilament interaction, illuminating diverse mechanisms of tubulin-related diseases. Integration with ACMG-AMP guidelines demonstrates this mutational landscape improves clinical variant classification in redundant gene families. This framework is broadly applicable to other structurally conserved proteins, linking variant effect prediction to mechanistic insight and clinical translation.

genetics↗

bioRxiv2025

Vascular and Lymphatic Dysregulation via Non-EndoMT Col2a1 Signaling in Bisphosphonate-Related Osteonecrosis of the Jaw

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is one of the most severe complications of antiresorptive therapy. Although impaired angiogenesis is commonly observed in BRONJ, the underlying vascular mechanisms remain poorly understood, impeding the development of effective treatments. In this study, we integrated whole-organ tissue-clearing imaging, single-cell transcriptomics, and proteomics to construct a multimodal atlas of the mandibular microenvironment in both mouse and human BRONJ. Our findings revealed gross vascular and lymphatic rarefaction in BRONJ, along with 4 endothelial subtypes uniformly exhibiting aberrant upregulation of Col2a1. Moreover, fibroblasts and macrophages emerged as key endothelial interactors, collectively underscoring dysregulation of the endothelium-matrix-immune axis. Unlike homeostatic Dmp1/Tfap2a fibroblasts and Stab1 macrophages, BRONJ lesions featured pathological Lrrc15/Chad fibroblasts and Il6 macrophages, which promote ectopic chondrogenesis and inflammation. Mechanistically, BRONJ activated the COL2A1-CD44 axis (EC-to-fibroblast/macrophage signaling) and COL2A1-SDC4 axis (EC-to-fibroblast signaling), whereas lineage tracing excluded endothelial-to-mesenchymal transition (EndoMT), implicating extracellular matrix remodeling as the driver of dysfunction. Cross-species validation in human mandibles further confirmed vascular-lymphatic dysregulation, inflammatory activation, and aberrant chondrogenesis. Overall, this study establishes vascular and lymphatic dysfunction as a central pathological hallmark of BRONJ, driving matrix remodeling dysregulation and immune-inflammatory imbalance, and identifies the COL2A1-CD44/SDC4 axis as a potential therapeutic target for BRONJ.

cell biology↗

bioRxiv2025

A neural circuit for female-specific defensive homeostasis in risk assessment

HighlightsSC CB1R+ neurons encode visual survival threats and initiate risk assessment in both sexes CB1R+ SC-LHb GABAergic circuit maintains defensive homeostasis in risk assessment in females eCBs gate this circuit by disinhibiting presynaptic GABA release exclusively in females Disruption of this mechanism female-specifically impairs risk assessment and stress coping In BriefLiu et al. identify a female-specific subcortical circuit in which eCB signaling, via CB1R on GABAergic terminals in the SC, suppresses transmission to the LHb to maintain precise defensive homeostasis in risk assessment. These findings uncover the circuit and neuronal mechanisms that contribute to the sexually dimorphic maintenance of defensive homeostasis. Risk assessment in defensive behavior is an adaptive mechanism shaped by natural selection, enabling individuals to evaluate potential threats and thereby maintain defensive homeostasis. However, it remains unknown whether specific neural circuits maintain their behavioral homeostasis in a sex-specific manner. To address this, we investigated its neural basis by hierarchical behavior analysis framework with neural circuit dissection. In mice of both sexes, visual survival threats activated cannabinoid 1 receptor (CB1R)-expressing neurons in the superior colliculus (SC) to initiate consistent risk assessment. Deletion of CB1R in SC GABAergic neurons female-specifically impairs risk assessment by disinhibiting GABA release in SC-lateral habenula (LHb) projections, resulting in shortened risk assessment. This disruption furthermore increases the occurrence of abnormal spontaneous behavior following chronic stress exclusively in females. We identified a female-specific SC-LHb GABAergic circuit gated by CB1R maintains defensive homeostasis in risk assessment. Our findings reveal how a conserved neuromodulatory system sex-specifically gates a subcortical circuit to orchestrate distinct survival strategies.

neuroscience↗