Biology subjects

Li, Y.

Publications and source records attributed to Li, Y..

At least 73 records · Page 4Linked to original sources

bioRxiv2026

Beyond RMSD: Deterministic Dlow Matching for Ultrafast and Physically Validated Transition-State Generation

Transition state (TS) generation is typically evaluated by geometric similarity, yet low root-mean-square deviation (RMSD) does not establish first-order saddle-point character or reaction-path connectivity. Here we introduce Kairos-GFM, a deterministic equivariant flow-matching model that combines a two-dimensional reaction graph with the Kabsch-aligned mean of three-dimensional reactant and product geometries. Using 881 Transition1x reactions whose reference TSs passed strict saddle-point and bidirectional intrinsic reaction coordinate validation, Kairos-GFM generates one candidate in 0.0118 s with a median RMSD of 0.14 [A]. A hierarchical physical-validation framework--spanning reaction-center geometry, raw single-point energy, DFT saddle-point optimization, harmonic frequency analysis, and IRC endpoint matching reveals that low RMSD and saddle-point convergence do not guarantee the intended reaction channel. Kairos-GFM recovers the target channel in 75.94% of reactions, outperforming diffusion-based baselines but remaining below transport-based methods. These results position Kairos-GFM as a rapid initial-geometry generator for quantum-chemical refinement and provide a transferable validation standard that distinguishes geometric similarity from physical fidelity.

biochemistry↗

bioRxiv2026

Motor learning refines premotor cortical constraint during skilled forelimb behavior

Motor learning transforms variable actions into reliable skilled behavior, but how premotor cortex supports this transformation remains unclear. We longitudinally recorded bilateral local field potentials and single-unit activity from the rat rostral forelimb area while animals acquired a single-pellet retrieval task. Here, we show that improved skill was accompanied by reduced, rather than increased, task-related premotor recruitment. Despite this attenuation, firing remained dominated by suppression around pellet retrieval, and stronger pre-retrieval suppression was associated with greater odds of successful performance. Population neural state analysis further showed that successful actions were most strongly coupled to sustained pre-retrieval engagement early in learning, whereas later success occurred with less population-level engagement. These findings reveal premotor cortical constraint as a population-level process that is progressively refined as motor learning transforms variable actions into reliable skilled behavior.

neuroscience↗

bioRxiv2026

Environmental modulation of social isolation-induced sleep loss in Drosophila

Chronic social isolation induces persistent behavioral and physiological changes across species. In humans, prolonged social isolation is associated with insomnia and increased risks of cognitive decline, cardiovascular disease, compromised immunity, and premature mortality. Yet whether these consequences are modified by the environment in which social isolation is experienced remains unclear. In particular, can access to social sensory information from conspecifics alleviate the effects of isolation and can various ambient environmental settings modify them? A related question arises during behavioral measurement because behavioral assays themselves impose a new environmental context. Whether these assays simply capture the enduring effects of prior social experience or further modify those effects remains unknown. Using social isolation-induced sleep loss in Drosophila as a model, we systematically examined how the social, spatial, and photoperiodic environments during isolation and behavioral monitoring influence the isolation phenotype. Providing isolated flies with visual, olfactory, or tactile social cues from conspecifics living behind a divider, either individually or in combination, was insufficient to alleviate sleep loss. Spatial confinement exacerbated isolation-induced sleep loss, while winter-like photoperiod in spatially confined Drosophila Activity Monitor assays revealed the clearest progressive decline in sleep during sleep monitoring. Together, these findings demonstrate that social isolation-induced sleep loss is both enduring and dynamic: it persists despite exposure to social cues yet remains sensitive to the environmental context in which isolation is experienced and behavior is measured. More broadly, our study establishes a tractable framework for investigating the environmental modulation of chronic social isolation.

neuroscience↗

bioRxiv2026

Novel protein networks in motile cilia from human epithelial cells revealed by cryo-ET and proteomics analysis of cilia from PCD patients

In our past study on human cilia from primary ciliary dyskinesia (PCD) patients using cryo-electron tomography and mass spectrometry, defects in the DNAH5 gene were proven to cause the loss of the entire outer dynein arm along with other proteins. This phenomenon was not observed in the unicellular green alga Chlamydomonas. In this study, we examined the loss of ciliary components caused by defects in various genes, based on proteomic and structural analyses of motile cilia from multiple PCD patients. The absence of single outer arm dynein genes causes a loss or significant decrease in other inner and outer arm dyneins. Interestingly, some patients with outer dynein defects show decreased intraflagellar transport (IFT) proteins, suggesting an influence of cargo components or assembly on transport. These phenomena were not observed in Chlamydomonas, suggesting a more complex mechanism of ciliogenesis in humans despite the high similarity in the final 3D architecture of the 9+2 axoneme. Defects in certain central pair proteins unexpectedly reduced components on the doublets as well. Our results demonstrate protein-protein interactions during stages of human motile ciliogenesis that are more complex than those in unicellular organisms.

cell biology↗

bioRxiv2026

Senescence-associated KRAS upregulation in peripheral T cells links to premature coronary artery disease

Aims: Premature coronary artery disease (PCAD) lacks specific molecular drivers, and the role of immunosenescence is unclear. We investigated whether aging-related gene dysregulation in T cells contributes to PCAD. Methods: We combined bulk transcriptomics of PBMCs from 12 PCAD patients and 21 controls, single-cell RNA sequencing of PBMCs and human atherosclerotic plaques, weighted gene co-expression network analysis, gene perturbation network analysis, and molecular docking. Results: KRAS was identified as a hub gene intersecting PCAD-associated genes and aging-related genes. Single-cell analysis showed KRAS upregulation predominantly in effector CD8+ T cells, which exhibited the highest senescence scores that were further elevated in disease. Network perturbation of KRAS strongly impacted the cell killing pathway. KRAS-high effector CD8+ T cells were detected in coronary and carotid plaques, displaying enhanced cytotoxicity, exhaustion, and senescence features. Additionally, a candidate small molecule was computationally predicted to bind inactive KRAS. Conclusions: Elevated KRAS expression in senescent, cytotoxic CD8+ T cells is associated with PCAD, bridging immunosenescence and premature atherosclerosis. This finding provides a novel biomarker candidate and potential therapeutic entry point, awaiting further functional validation.

bioinformatics↗

bioRxiv2026

Agentic transcranial functional ultrasound imaging: @fUS

Functional ultrasound (fUS) imaging provides deep, wide-field access to brain function, but instrument cost and complex acquisition and analysis workflows restrict its wider adoption. Here we introduce @fUS, an agentic transcranial imaging platform with an open architecture that integrates purpose-built hardware with executable experimental skills and persistent structured memory. The system combines 128-channel, 16-bit acquisition at 125 MHz with GPU-based processing and enables functional imaging through the intact scalp and skull of mice, with approximately 100-m spatial resolution and 10-Hz temporal sampling, providing a basis for longitudinal studies without cranial-window surgery. Its agent connects scientific objectives to experimental design, direct instrument control and data analysis, retaining context across interactions and supporting inspectable workflows through text and hands-free voice control. Neuroscience trainees with limited engineering experience independently configured the system within 30 min. Agent-assisted exploration of whisker-stimulation datasets revealed low-frequency vascular changes beyond conventional response mapping, supported by complementary two-photon measurements of single-vessel diameter. By combining transcranial imaging with accessible instrument control and analysis, @fUS provides a foundation for wider adoption and larger, more diverse neuroscience datasets. More broadly, it offers a framework for scientific instruments in which measurement, computation and experimental reasoning are developed as parts of the same system.

bioengineering↗

bioRxiv2026

Cell Type-Specific Structural and Functional Signatures of APOE4, Age and Sex in the Mouse Anterior Olfactory Nucleus

As the strongest genetic risk factor for late-onset Alzheimer's disease (AD), the human APOE {varepsilon}4 allele alters neuronal physiology before overt pathology. However, how aging and sex modify these effects in the anterior olfactory nucleus (AON), an early AD-affected brain region, remains unclear. Here, we performed whole-cell recordings and post hoc morphological reconstructions of pyramidal cells (PCs) and interneurons (INs) in acute AON slices from adult and aged humanized APOE3 (E3) and APOE4 (E4) knock-in mice of both sexes with identification of context-dependent remodeling across structural, intrinsic, and synaptic domains. In PCs, morphology was broadly susceptible to APOE genotype x age x sex and their interactions. Functionally, aged E4 PCs exhibited a more depolarized resting membrane potential than aged E3 PCs. Additionally, afterhyperpolarization amplitude displayed a marked age x genotype interaction, reversing the direction of the E4 - E3 difference from adulthood to aging. Excitatory synaptic event frequency showed a complex genotype and age and sex interaction, whereas inhibitory synaptic event amplitude was elevated in E4 mice. In contrast, INs displayed far more restricted alterations. Morphological changes were limited to dendritic length, which was modulated by age and sex specifically in E4 mice. Physiologically, genotype effects were confined to action potential amplitude, while aging primarily altered membrane properties and excitatory synaptic inputs. Together, these findings demonstrate that APOE genotype cell-specifically shapes AON neuronal properties through interactions with age and sex, suggesting that APOE4 establishes altered cellular states that influence how this circuit responds to subsequent disease-related stress.

neuroscience↗

bioRxiv2026

Restoring Aquaporin-4 alleviates molecular and motor phenotypes in zQ175 mouse model of Huntington disease

Huntington&'s disease (HD) is characterized by progressive accumulation of mutant huntingtin (mHTT), neurodegeneration and motor dysfunction. Increasing evidence implicates impaired glymphatic function and loss of perivascular aquaporin 4 (AQP4) polarization in HD, suggesting that defective brain waste clearance may contribute to disease pathogenesis. Whether restoration of AQP4&-mediated glymphatic transport can ameliorate HD pathology remains unknown. We tested whether genetic restoration of AQP4 improves glymphatic function and HD&-associated phenotypes in heterozygous zQ175 knock-in mice. At 2 months of age, premanifest zQ175 mice received a single retro-orbital injection of BBB-penetrant AAV9&-PHP.eB encoding the AQP4 (M1 isoform). Glymphatic transport was assessed by intracisternal injection of fluorescent BSA 647 and quantification of parenchymal influx and drainage to the deep cervical lymph nodes. Perivascular AQP4 localization, mHTT aggregation, gliosis, DARPP32 immunoreactivity, CSF neurofilament light chain (NfL) and total Tau, structural brain volumes by 11.7T MRI, and motor behavior were assessed longitudinally through 12 months of age. AAV9&-PHP.eB&-AQP4 produced widespread brain expression and restored perivascular AQP4 localization in the striatum and cortex of zQ175 mice. AQP4 overexpression significantly increased glymphatic tracer influx into brain parenchyma and BSA-647 drainage to the deep cervical lymph nodes. At 12 months, AQP4 restoration reduced CSF NfL and total Tau concentrations, mHTT aggregate number and mean aggregate size, and striatal Iba1 positive microglia and GFAP-positive astrocytes (P < 0.05). AQP4 overexpression also preserved striatal DARPP32 immunoreactivity and significantly attenuated striatal atrophy measured by MRI. Female zQ175 mice showed improved balance-beam performance and locomotor activity, while effects on motor performance in males did not reach statistical significance. AQP4 overexpression attenuated body-weight loss in both sexes. No detectable structural, behavioral or body-weight abnormalities were observed following sustained AQP4 overexpression in wild-type mice. In summary, restoration of AQP4 enhances glymphatic transport and is associated with reduced proteopathic, neuroinflammatory and neurodegenerative phenotypes in zQ175 HD mice. These findings provide proof-of-concept that impaired glymphatic function is a modifiable component of HD pathology and support AQP4&-mediated restoration of brain waste clearance pathways as a potential disease-modifying therapeutic strategy.

neuroscience↗

bioRxiv2026

CardioChrom Reconstructs the Human Cardiac Virtual Epigenome from Single-Nucleus Transcriptomes

Background: Matched epigenomic profiling remains scarce in human heart failure, limiting regulatory interpretation of single-nucleus ribonucleic acid (RNA) sequencing data. We developed CardioChrom, a cardiac-specialized framework that reconstructs chromatin accessibility, histone H3 lysine 27 acetylation (H3K27ac), and histone H3 lysine 27 trimethylation (H3K27me3) from single-nucleus RNA profiles. Methods: CardioChrom was developed using same-nucleus human heart datasets jointly measuring RNA with chromatin accessibility by assay for transposase-accessible chromatin (ATAC), H3K27ac, or H3K27me3, with donor-separated development and leave-one-cell-type-out testing. Frozen models were evaluated in 10-donor and 23-sample external human heart cohorts. Histone reconstruction was benchmarked against measured profiles and a Transformer. The models were then applied without refitting to an RNA-only cohort of 43 donors with heart failure with preserved ejection fraction (HFpEF). Results: Across unseen cardiac cell types, CardioChrom increased area under the precision-recall curve by 0.0109 relative to within-cell-type RNA shuffling in 11 of 12 cell types and increased area under the receiver operating characteristic curve by 0.0179 in all 12. CardioChrom exceeded controls in both external cohorts and matched or exceeded the Transformer across 6 prespecified histone metrics. In HFpEF, 3,581 donor-level pathway-layer associations met global false discovery rate, sex-adjustment, and leave-one-donor-out robustness criteria. Endothelial cells showed prominent reconstructed histone-associated changes involving coagulation, inflammation, hypoxia, and profibrotic signaling. Von Willebrand factor expression and its reconstructed regulatory states were consistently reduced, and all 6 linked candidate cis-regulatory elements were classified as repressed. Motif-supported TF-cCRE-gene hypotheses were generated in endothelial cells and fibroblasts. Conclusions: CardioChrom extends RNA-only human heart failure cohorts toward cell-type-resolved virtual epigenomic and regulatory analysis while distinguishing predictions from direct measurements.

bioinformatics↗

bioRxiv2026

An accumbal cholinergic ISR-HCN2 axis sustains maladaptive cue motivation

Environmental cues associated with rewarding outcomes can exert persistent control over behavior long after the reward is absent, yet the cellular adaptations that stabilize such maladaptive motivation remain unclear. Here we identify nucleus accumbens cholinergic interneurons (CINs) as causal regulators of persistent cue-driven seeking. Self-administration of addictive drugs or high-fat reward, but not sucrose, selectively increased CIN pacemaker firing. Cocaine-paired cues evoked rapid acetylcholine release in the nucleus accumbens core, and bidirectional manipulation of CINs suppressed or enhanced cue-induced cocaine seeking. Mechanistically, cocaine experience engaged the integrated stress response (ISR) in CINs, increased HCN2 expression and Ih, and stabilized a hyperexcitable state. CIN-specific ISR suppression or HCN2 knockdown reduced cocaine seeking, whereas HCN2 overexpression enhanced it. Local HCN blockade and systemic treatment with the clinically approved HCN blocker ivabradine reduced cue-driven seeking across addictive-drug and high-fat-reward paradigms while sparing sucrose seeking. These findings identify an ISR-HCN2-dependent cholinergic mechanism that stabilizes maladaptive cue-driven motivation and nominate HCN-dependent excitability as a tractable target for therapeutic intervention.

neuroscience↗

bioRxiv2026

Cell-Lens: Advancing LLM Reasoning at Single-Cell Resolution

Recent work applies large language models (LLMs) to single-cell data, but the cell usually reaches the model as a short ranked list of genes. This list drops much of what defines a cell, so the model reasons from a partial view. Yet the information is not lost in the measurement, only in the text. Here, we introduce Cell-Lens, a training-free structured representation of the measured cell. It writes the cell as typed blocks, from paired measurements to marker-supported programs. On CellVerse, SOAR, CellPuzzles, and SC-Arena, across five model families, Cell-Lens improves performance by up to 27.1 points. It also narrows the model gap and reduces API-reported reasoning-token usage. The largest gains occur when a defining RNA marker falls out of the ranked list. In these cases, the paired protein data still capture the corresponding signal. Shuffling the added blocks removes the gain. The gain persists after selected label-associated proteins are removed. These controls link the improvement to cell-matched biological content. We also build and release CellSpectrum, a broader benchmark spanning eight sources and seven tasks with paired modalities. The gains hold there across tasks, tissues, and modalities. These results show that a better cell representation can improve single-cell reasoning without retraining the model. Code and CellSpectrum are publicly available at https://github.com/LiZaiyuan0619/Cell-Lens.

bioinformatics↗

bioRxiv2026

A general method to develop excitation ratiometric neuropeptide sensors with enhanced sensitivity for in vivo applications

Neuropeptides regulate a wide range of physiological processes throughout the nervous and endocrine systems, yet their spatiotemporal dynamics in vivo remain poorly understood. While recently developed intensiometric sensors can detect neuropeptides, their use in vivo is often confounded by artifacts induced by hemodynamic changes, pH fluctuations, and motion. Here, we present a general strategy for engineering dual-excitation ratiometric (Ex-ratiometric) neuropeptide sensors by tuning the excited-state proton transfer properties of the fluorescent reporter. Dual excitation at 405 nm and 488 nm produces a ratiometric signal that intrinsically corrects fluorescence fluctuations unrelated to ligand binding. Using an AlphaFold3-guided in silico design approach combined with experimental validation, we developed a suite of Ex-ratiometric sensors. As a representative example, Ex-NTS2.0 enables robust detection of neurotensin (NTS) in vivo while remaining largely resistant to hemodynamics, pH, and motion-induced artifacts. Overall, these findings establish a scalable and mechanistically grounded platform for developing new Ex-ratiometric tools and provide a broadly applicable strategy for sensitive detection of neuropeptide dynamics in living systems.

neuroscience↗

bioRxiv2026

Loss of TCA cycle turning promotes stem cell function

The citric acid cycle (TCA cycle) is the common terminal pathway for the oxidation of all nutrients. Citrate oxidation to oxaloacetate produces CO2, and citrate synthase (CS) uses nutrient-derived acetyl groups to regenerate citrate and fuel cycle turning. However, the essentiality of cycle fueling and turning in vivo remains unclear. Here we use hematopoiesis, the most proliferative system in the body, as a model to show that, contrary to common assumptions, TCA cycle turning is dispensable for respiration, survival, and proliferation of stem and progenitor cells in vivo, and its loss promotes stem cell function. Hematopoietic-specific Cs deletion in adult mice blocked citrate cycling without reducing the frequency of hematopoietic stem (HSC) and progenitor cells. HSCs and progenitor cells adapted to TCA cycle loss by markedly increasing nutrient consumption and biosynthesis. Disruption of cycle turning increased HSC regeneration, myeloid progenitor proliferation, and myelopoiesis in vivo. HSCs without a turning TCA cycle outcompeted wild-type HSCs within the same environment. The effect of CS deletion on HSC function was not phenocopied by genetic ablation of cytosolic citrate use and was rescued by ablation of glutamine use in biosynthesis. Therefore, TCA cycle turning restrains nutrient uptake, biosynthesis, cell proliferation, and stem cell function. These results suggest an explanation for the reduction in cycle activity observed in many normal proliferating cells and cancer cells.

biochemistry↗

bioRxiv2026

Cancer-associated nucleolar morphological changes coincide with altered subcompartment organization and accelerated nascent rRNA trafficking in breast cancer cells

Nucleolar alterations are characteristic features of cancer cells; however, how changes in the overall morphology relate to internal subcompartment organization and ribosomal RNA (rRNA) dynamics remains unclear. In this study, the nucleolar organization of non-transformed MCF-10A mammary epithelial cells and MDA-MB-231 breast cancer cells was quantitatively compared. MDA-MB-231 cells exhibited differences in nucleolar morphology, accompanied by altered spatial organization of the dense fibrillar component and granular component, and accelerated intranucleolar trafficking of nascent rRNA. Pharmacological perturbation with SU056 shifted multiple structural and dynamic parameters toward an MCF-10A-like profile. Conversely, transient physicochemical perturbation with 1,6-hexanediol induced several MDA-MB-231-like nucleolar features in MCF-10A cells, which returned to their untreated profile after washout. These findings support the view that cancer-associated nucleolar alterations are an integrated reorganization across morphological, spatial, and dynamic dimensions. The observed reversibility further indicates that cancer-associated nucleolar organization can be remodeled in response to perturbations. By linking the morphology, subcompartment organization, and nascent rRNA dynamics within a common framework, this study provides a basis for exploring the establishment, maintenance, and remodeling of distinct nucleolar profiles in cancer.

cancer biology↗

bioRxiv2026

Harmine Plus Exendin-4 Enhances Remission of Recent-Onset Type 1 Diabetes Following Anti-CD3 Therapy

Type 1 diabetes (T1D) results from autoimmune destruction of pancreatic {beta}-cells. While anti-CD3 therapy can delay disease progression and preserve residual {beta}-cell function, disease reversal will likely require both immune modulation and {beta}-cell regeneration. We found that the combination of harmine and exendin-4 (H+E) reduced inflammation-induced human {beta}-cell apoptosis, suppressed cytokine signaling and immunogenicity pathways, and improved {beta}-cell function. Although H+E alone did not reverse diabetes in NOD mice, low-dose anti-CD3 followed by H+E normalized blood glucose, increased insulin levels, improved glucose tolerance, expanded {beta}-cell mass, and enhanced diabetes remission. These effects were associated with reduced pro-inflammatory T-cell responses, increased regulatory T cells, and greater expression of exhaustion-related T-cell markers, without broad lymphocyte depletion. Similar immunomodulatory effects were observed in activated human PBMCs. Transcriptomic analyses identified the lncRNA SNHG6 as a key mediator of H+E action; SNHG6 protected {beta}-cells from cytokine-induced stress, apoptosis, and immunogenicity. Together, these findings demonstrate that H+E promotes {beta}-cell recovery and resilience while reducing {beta}-cell immunogenicity, enabling remission of recent-onset T1D when combined with anti-CD3 therapy. SNHG6 emerges as a novel regulator of {beta}-cell protection during inflammation.

cell biology↗

bioRxiv2026

ACAN regulates VSMC mitochondrial homeostasis through the YAP1/TAZ pathway and contributes to the onset and progression of aortic dissection

Objective: Aortic dissection (AD) is a serious, life-threatening cardiovascular crisis. While vascular proteoglycans normally buffer hemodynamic stress, their aberrant accumulation in the AD aorta predisposes to rupture. Aggrecan (ACAN) is among the most frequently elevated proteoglycans in this setting, yet its pathogenic relationship to AD remains undefined. This study aimed to investigate the role of ACAN in AD and identify potential therapeutic targets. Approach and Results: We employed human tissues, animal models, and cell cultures. Western blotting and immunohistochemistry (IHC) were performed on aortic samples from AD patients and controls to assess contractile markers, MMPs, ACAN, and SOX9. In vivo, AD was induced in mice using {beta}-aminoisobutyric acid (BAPN) and Ang II, with AAV-mediated ACAN knockdown in VSMCs. Histological staining confirmed model validity and enabled assessment of AD incidence, mortality, and protein expression changes. In vitro, human aortic vascular smooth muscle cells (HAVSMCs) were stimulated with Ang II, and SOX9 and ACAN were silenced via siRNA to evaluate the functional impact of ACAN downregulation. In human AD aortas, elevated ACAN and its upstream transcription factor SOX9 drove VSMC phenotypic switching and ECM degradation. In mice, ACAN knockdown corrected AD-induced medial structural disruption, elastin fragmentation, and collagen deposition, markedly reducing incidence and mortality while curbing excessive mitochondrial fission and rescuing functional integrity. ACAN silencing attenuated Ang II-induced mitochondrial damage in HAVSMCs via the RNA-seq-identified YAP1/TAZ pathway, and Verteporfin restored homeostasis. Conclusion: ACAN is aberrantly expressed in AD and murine aortas. ACAN downregulation delays disease progression by preserving mitochondrial homeostasis and function via the YAP1/TAZ pathway.

pharmacology and toxicology↗

bioRxiv2026

Zero-shot evaluations expose structured generalization limits in predictive models of the brain

Artificial neural networks (ANNs) can predict neural responses to natural images with remarkable accuracy, making them promising models of human vision. However, prediction scores alone reveal little about what computations these models have captured or how well they generalize beyond the images on which they are trained. Here, we introduce a principled zero-shot model evaluation framework in which ANN-based encoding models are frozen before being tested on not just held out images but entirely new datasets. Our strongest tests repurpose decades of cognitive neuroscience experiments as diagnostic benchmarks for identifying which computations current models capture and where they fail. To implement this framework we built encoding models of human category-selective regions (FFA, PPA, and EBA) using several pretrained ANNs and evaluated these fixed models across 7 independent fMRI datasets and 31 cognitive experiments from 10 published studies. This framework revealed three broad patterns. First, zero-shot evaluations exposed systematic limits to model predictivity that were largely hidden by standard within-dataset cross-validation. These limits were structured varying across brain regions and model classes and depending strongly on the similarity between the images used to build and test the models. Second, current models reproduced some, but not all, classical findings from cognitive neuroscience, providing a diagnosis of the computations that current models have yet to capture. Finally, models that performed well on prediction tests also tended to succeed at reproducing cognitive neuroscience findings, suggesting that prediction and explanation are closely linked. Unlike prediction scores however, cognitive tests help diagnose where and why models fail. Together, the zero-shot evaluation framework provides a scalable and unified approach for evaluating brain models across prediction and cognitive neuroscience tests, which can help us better understand what current models capture and what still remains to be explained.

neuroscience↗

bioRxiv2026

A bipolar disorder-associated ultra-rare AKAP11 protein-truncating variant attenuates stimulus-dependent PKA activation and induces anxiety- and depression-related behaviors in mice

Rare genetic variants associated with psychiatric disorders are thought to have larger individual effect sizes and direct biological roles, offering a unique opportunity for understanding causal relationships between genetic architecture and disease phenotypes. A recent whole-exome sequencing meta-analysis identified an increased burden of ultra-rare protein-truncating variants (PTVs) in AKAP11 in patients with bipolar disorder and schizophrenia. AKAP11 encodes an A-kinase anchoring protein that mediates the association of protein kinase A (PKA) and its substrates. How ultra-rare AKAP11 variants contribute to psychiatric disorder pathogenesis remains unknown. Here, using CRISPR-Cas9 genome editing, we introduced into the mouse Akap11 locus an ultra-rare PTV identified in a human patient with bipolar disorder. This ultra-rare PTV reduced Akap11 mRNA and protein levels without producing stable novel mRNA isoforms, leading to Akap11 haploinsufficiency. Male heterozygous mice exhibited behavioral abnormalities consistent with anxiety- and depression-like phenotypes. Transcriptomic and proteomic profiling of the neocortex revealed molecular changes involving synaptic organization, synaptic signaling, and neurite morphogenesis. Notably, the heterozygous mutant showed selective elevation in type I, but not type II, PKA regulatory subunits, as well as PKA catalytic subunits, in the neocortex. Functionally, these changes were accompanied by reduced phosphorylation of PKA substrates, attenuated stimulus-dependent PKA activity in cortical excitatory neurons, and impaired nascent dendritic development in cortical neurons. Together, our study presents a clinically relevant and genetically precise mouse model that provides mechanistic insight into how ultra-rare PTVs may contribute to psychiatric disorder pathogenesis, and a platform for testing rational therapeutics.

neuroscience↗