Biology subjects

Wang, F.

Publications and source records attributed to Wang, F..

At least 55 records · Page 3Linked to original sources

bioRxiv2026

Robust lesion network mapping reveals genuine symptom-specific networks

Lesion network mapping (LNM) and its derivatives successfully integrate anatomically distributed brain loci into common symptom-associated functional networks, however, their statistical validity and specificity have recently become topics of debate. Here, we introduce a null model-based robust LNM (rLNM) framework to perform sensitivity and symptom-specificity testing. Across multiple lesion-based (10 conditions, 333 lesions) and task-based (4 conditions, 706 experiments) datasets, rLNM reveals biologically meaningful and symptom-specific networks while effectively controlling for false positives.

neuroscience↗

bioRxiv2026

CatIF-RL: Activity-Oriented Enzyme Sequence Design by Steered Inverse Protein Folding

Protein inverse folding models are designed to generate amino acid sequences compatible with a given backbone structure, but they are not explicitly optimized for specific biological functions. Here, we present CatIF-RL, a framework that steers a graph-based denoising diffusion inverse folding model toward designing enzyme variants with enhanced catalytic activity. CatIF-RL first adapts the inverse folding model to enzyme structural data, then introduces activity-oriented preference signals using predicted catalytic constant (kcat) as the optimization objective, enabling specialization through generative dataset curation and group-relative policy optimization (GRPO). This process iteratively shifts the sequence distribution toward higher predicted kcat while constraining sequence divergence to sequences that remain compatible with the input structure. On the independent benchmark, CatIF-RL achieves an approximately four-fold increase in predicted kcat relative to native enzymes, substantially outperforming representative inverse folding methods, while maintaining sequence recovery (0.55) and structural fidelity, and supporting motif-preserving partial sequence design. CatIF-RL establishes a practical framework for activity-oriented enzyme design and provides a generalizable strategy for steering structure-conditioned protein generation toward functional optimization.

bioinformatics↗

bioRxiv2026

Enhanced Radio-sensitization of Glioblastoma Using a Dendrimer-Based Metformin Nano-formulation through Direct Tumor Suppression and Indirect Immune Modulation

Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor in adults, with median survival remaining approximately 12-15 months despite aggressive multimodal therapy. Therapeutic resistance and tumor recurrence are driven in part by limited drug penetration across the blood-brain barrier (BBB) and the persistence of brain cancer stem cells (BCSCs), highlighting the need for brain-penetrant therapeutic platforms capable of achieving sustained intratumoral delivery. Here, we developed a dendrimer-based nanotherapeutic by conjugating metformin to a fourth-generation hydroxyl-terminated polyamidoamine dendrimer (P4-MET) to enhance intracranial bioavailability and therapeutic efficacy in GBM. P4-MET exhibited favorable pharmacokinetic properties, including prolonged retention within the tumor microenvironment, and demonstrated enhanced cytotoxicity against GBM cell lines relative to free metformin (f-MET). Mechanistical studies with transcriptomic profiling by RNA sequencing revealed distinct treatment-associated molecular signatures, identifying BOLA2B as the most significantly differentially expressed gene between treatment groups. Specifically, BOLA2B expression was markedly elevated in f-MET-treated cells but not so following P4-MET treatment. Given the established association of BOLA2B with mTORC1 signaling and GPX4-mediated ferroptosis resistance, these findings suggest that P4-MET may, at least in part, enhance therapeutic efficacy by modulating ferroptosis-associated pathways. In orthotopic GBM models, combination treatment with P4-MET and radiotherapy (RT) significantly prolonged overall survival and increased tumor cell death compared with either monotherapy alone, consistent with a synergistic radiosensitizing effect. Importantly, P4-MET demonstrated minimal systemic toxicity, supporting its favorable therapeutic index and translational potential. Collectively, these findings establish P4-MET as a brain-penetrant nanomedicine platform that improves metformin delivery, modulates ferroptosis-related signaling networks, and potentiates radiotherapeutic response in GBM. This study highlights the potential of dendrimer-enabled metabolic nanotherapies to overcome therapeutic resistance in malignant brain tumors.

cancer biology↗

bioRxiv2026

The nuclear structural protein NuMA is required for efficient DNA replication by ensuring association of core replication factors to replication forks

DNA replication is a strictly regulated process during cell proliferation to ensure faithful duplication of the genome. Its firing and elongation can be arrested or temporally inhibited in response to a variety of internal and external causes. Inside cells numerous factors including cell cycle checkpoints, protein kinases, and others are involved in the control of this process to maintain genome integrity. Here, we describe that NuMA, a nuclear scaffolding protein, plays an important role in regulating DNA replication. We show that NuMA is present at active replication forks, and its deficiency impairs cell viability, reduces the replication fork speed and increases origin firing, leading to increased level of {gamma}H2AX and the activation of the ATM-CHK2 DNA damage response pathway. Mechanistically, our results show that NuMA depletion reduced the association of multiple key replisome proteins to replication forks, suggesting that NuMA is essential for efficient replisome proteins binding to ongoing forks. Our study uncovers a novel function of NuMA in maintaining genome stability, providing new insights into the important role of nuclear structural proteins in safeguarding DNA replication.

molecular biology↗

bioRxiv2026

BRIDGE: A Multi-organ Histo-ST Foundation Model Enables Virtual Spatial Transcriptomics for Enhanced Few-shot Cancer Diagnosis

Recent studies have explored generating virtual spatial transcriptomics (ST) profiles from histological images, offering a promising alternative to laboratory-measured molecular profiling. However, existing approaches predominantly rely on single-organ models and require sub-stantial organ-specific training data, restricting their accuracy under challenging few-shot conditions in clincical practice, where less than 10 slides are available for specific organs or techniques. Here, we present BRIDGE, a multi-organ foundation model pre-trained on over 600,000 paired histology-ST profiles across 13 human organs and three sequencing techniques. By robustly aligning morphological features and genomic information within a shared multi-organ latent space, BRIDGE can leverage common biological knowledge across distinct tissues to enable accurate and generalizable pan-cancer molecular profiling. Without additional organ-specific fine-tuning, BRIDGE accurately predicts the spatial expression of 80 biomarker genes, achieving an average Pearson correlation coefficient (PCC) of 0.474--a 30% improvement over existing state-of-the-art models under three clinically challenging few-shot scenarios. With generated virtual ST, BRIDGE outperforms current state-of-the-art pathology foundation models in predicting cancer survival, achieving an average concordance index (C-index) of 0.724 across six TCGA cohorts. Notably, BRIDGE maintains exceptional performance even in zero-shot scenarios involving three cancer types not seen during its training, achieving an average C-index of 0.717, thereby demonstrating its strong generalization capability that transcends organ- and subtype-specific boundaries. Moreover, BRIDGE-generated virtual spatial transcriptomes match the prognostic accuracy of bulk RNA-seq, highlighting their potential as a spatially informative alternative to laboratory sequencing. In general, BRIDGE represents a data-efficient tool in virtual ST that facilitates biomedical discoveries in clinical few-shot contexts and advances diagnosis of understudied cancers without sufficient samples.

genomics↗

bioRxiv2026

Multimodal profiling reveals the centromedian nucleus of thalamus as a dynamic hub orchestrating staged consciousness recovery

Consciousness recovery from general anesthesia represents a fundamental brain state transition. The absence of objective, continuous metrics to monitor the shift from unconsciousness to full awareness has left its dynamic, multidimensional nature unresolved, fracturing consciousness theoretical framework and posing clinical risks due to unreliable assessment of emergence. To address this, we developed a multiscale framework integrating AI-driven behavioral analysis, continuous neuro-physiology recording, and whole-brain functional imaging. This decodes recovery into three hierarchical stages, reflex restitution, level restoration, and content re-establishment, each with unique multimodal signatures. We identified heart rate stabilization as a potential noninvasive biomarker for the restoration of consciousness level. Crucially, the centromedian nucleus of thalamus acts as a dynamic hub, actively orchestrating staged whole-brain reconfiguration via stage-dependent network routing. These findings resolve the temporal orchestration of consciousness recovery, ground disparate theories within a unified mechanistic sequence, and open transformative paths for real-time monitoring and neuromodulation in anesthesiology. HighlightsA multimodal framework decodes consciousness recovery into three hierarchical stages Recovery stages span from reflex restitution, to level restoration, and finally to content re-establishment Heart rate stabilization serves as a noninvasive biomarker for consciousness level restoration The CM paces this staged reconfiguration as a dynamic network hub In BriefZhang et al. develop a multiscale framework that delineates consciousness recovery from anesthesia as a three-stage process, identifies heart rate stabilization as a biomarker for the restoration of consciousness level, and reveals the CM as a dynamic hub orchestrating this progression. These findings clarify the temporal orchestration of consciousness recovery, pave the way for real-time monitoring and neuromodulation in anesthesiology and other fields.

neuroscience↗

bioRxiv2026

Sphk1-S1P signaling drives blood-brain barrier breakdown after intracerebral hemorrhage via HIF-1α-dependent upregulation of Bsg-MMP-9

Blood-brain barrier (BBB) breakdown is a critical pathological event driving secondary brain injury and poor outcomes following intracerebral hemorrhage (ICH). However, the mechanisms governing acute BBB breakdown after ICH remain incompletely understood. Here we demonstrate that the Sphk1-S1P-S1PR3 signaling plays a pivotal role in this process. Sphk1 expression was significantly upregulated in the perihematomal endothelial cells of both ICH patients and mice, with levels positively correlating with BBB dysfunction severity and poor clinical outcomes. Using endothelial-specific genetic gain- and loss-of-function approaches, we found that Sphk1 knockdown attenuated BBB leakage, reduced hematoma volume and brain edema, preserved tight junction integrity, and improved neurological function at 1-day post-ICH, whereas Sphk1 overexpression exacerbated these pathological features. Mechanistically, transcriptomic profiling of perihematomal endothelial cells revealed that prior to its established role in Nlrp3-mediated pyroptosis, Sphk1 promotes early BBB breakdown by regulating the Bsg-MMP-9 axis. Endothelial-specific Bsg deletion completely abrogated the deleterious effects of Sphk1, confirming Bsg as an indispensable intermediary through which Sphk1 signals to MMP-9. ATAC-seq and dual-luciferase assays further demonstrated that Sphk1-generated S1P signals through S1PR3 to activate HIF-1, which directly binds the Bsg promoter to drive its transcription, ultimately promoting MMP-9-mediated tight junction degradation. These findings delineate a complete hierarchical signaling cascade from metabolic enzyme to transcriptional regulation and subsequent barrier injury, establishing the Sphk1-Bsg-MMP-9 axis as a promising therapeutic target for ICH. One sentence summaryThis work identifies an early and pivotal mechanism of blood-brain barrier breakdown after intracerebral hemorrhage, demonstrating that Sphk1-generated S1P signals through S1PR3 to activate HIF-1, which directly transactivates Bsg expression, leading to MMP-9-mediated tight junction degradation, thereby establishing a novel hierarchical axis with therapeutic potential.

cell biology↗

bioRxiv2026

Blindness reveals that Heschl's gyrus folding is not altered by auditory experience

Heschls gyrus (HG), which contains the primary auditory cortex, shows marked individual variability in its folding pattern, ranging from a single gyrus to partial or complete duplication. Greater HG duplication has been reported in expert musicians, often interpreted as evidence that auditory experience can shape cortical morphology. However, these structural differences might alternatively indicate a bias for musical careers in individuals whose anatomical predispositions facilitate expertise. Here, we examined HG morphology in blind individuals--a population with extensive auditory experience but without selection based on auditory ability. T1-weighted MRI data from 100 human participants (48 females, 42 males, 10 unknown) across blind and sighted groups were analyzed. HG was manually defined in each hemisphere, and folding was measured using both categorical morphology classification and continuous surface-based metrics. Across all analyses, blindness did not increase HG folding. These results suggest that the morphology of HG is largely predetermined. Significance statementIncreased anatomical folding in the auditory cortex has been reported in professional musicians. Is this structural variability due to experience-dependent plasticity, or is it that individuals with increased anatomical folding are more likely to become musicians? We examined Heschls gyrus (HG), which contains the primary auditory cortex, in blind individuals who rely heavily on auditory input. Despite extensive auditory experience, blindness did not alter HG folding. This finding suggests that the morphology of HG is not strongly influenced by auditory experience.

neuroscience↗

bioRxiv2026

Extracellular Vesicles Enable CircRNA Delivery via in situ Biogenesis and Sorting

Extracellular vesicles (EVs) are promising vehicles for nucleic acid delivery, yet efficient delivery of circular RNA (circRNA) remains challenging due to inefficient loading and limited intracellular expression. Here, we establish an EV-based platform that enables efficient circRNA delivery via in situ biogenesis and sorting. By optimizing intracellular circularization and translation through vector design, we markedly enhance circRNA expression. By combining this with Snu13-mediated EV sorting and enhanced vesicle biogenesis, we achieve efficient packaging of circRNA without compromising vesicle integrity. This integrated strategy enables robust and sustained protein expression following EV-based circRNA delivery. By leveraging this platform, we demonstrate a dendritic cell-targeting circRNA vaccine that elicits strong antigen-specific CD8+ T cell responses and antitumor efficacy. We further show that systemic delivery of BNP-encoding circRNA attenuates doxorubicin-induced myocardial fibrosis. Together, this work establishes a generalizable platform for circRNA therapeutics by overcoming key barriers in circRNA expression and EV-mediated delivery. TeaserEngineered EVs enable efficient circRNA delivery for sustained protein expression and therapy.

bioengineering↗

bioRxiv2026

A telomere-to-telomere (T2T) pig genome assembly reveals Y chromosome diversity and structural variations of Wuzhishan pigs

BackgroudWuzhishan (WZS) pigs are native to Hainan Province of China, and serve as both important agricultural resources and biomedical models. Although the published WZS pig genome (T2T-pig1.0) even achieving telomere-to telomere (T2T) completeness, substantial genetic diversity still exists within the same pig breed, another WZS pig genome named WZS-T2T was assembled in this study. ResultsMultiple sequencing data were used to assemble genome, and finally yielded a [~]2.68 Gb telomere-to-telomere genome, with N50 length [~]142.87 Mb, and annotated protein coding genes of 23,100. Compared to T2T-pig1.0, QV and BUSCO value was higher, and the Y chromosome (ChrY) length was longer in WZS-T2T than that of T2T-pig1.0. ChrY of two WZS pigs shared 11 genes, including sex differentiation-related genes of SHOX, PRKX, and DDX3X, and SRY; however, energy metabolism gene SLC25A4 and the macrophage-related receptor gene CSF2RA of ChrY were specific to WZS-T2T. An inversion SV on chromosome 10 with length [~]33.86 Mb was identified between two WZS pigs, and three proofs were proposed for proving the accuracy sequence orientation of WZS-T2T.The genetic diversity was consistent with LD decay speed in population different analysis. WZS pigs exhibited higher genetic diversity than other four pig populations (Tunchang pigs, Yuxi black pigs, Large White pig, and Duroc pigs) examined in this study, and presented slower LD decay compared to other four breeds. ConclusionsTherefore, WZS-T2T provided a higher-quality assembly, and potential advantages of both agricultural production and biomedical targets for WZS pigs.

genomics↗

bioRxiv2026

Surveying the target tractability of cytokines with small molecules

Cytokines are key mediators of inflammation and are prominently involved in immune-mediated disorders, playing key roles in the pathogenesis of diseases such as rheumatoid arthritis, asthma, cancer, and systemic lupus erythematosus. Currently, cytokines are a challenging class of protein targets for traditional small-molecule drug discovery efforts. Biologic-based inhibitors have achieved clinical success, but the current suite of biologics therapies is limited, lack oral bioavailability, and have numerous side effects and compliance challenges. The development of small-molecule therapeutics is an attractive alternative that could further expand our therapeutic modulation of these targets. Here, we profiled a panel of 32 disease-relevant human cytokines to identify small-molecule ligands and inhibitors to survey their tractability for small-molecule modulation. Using a binding-first, small-molecule microarray-based approach we probed the binding preferences of each cytokine against a collection of 65,000 drug and lead-like compounds. We have identified 864 key chemical chemotypes that define structural motifs that bias for binding to specific cytokines. We further validated these chemotypes in a thermal denaturation sensitivity assay, resulting in 296 validated cytokine binders. We then prioritized three cytokines and established that novel, first-in-class inhibitors can be identified from these binders with potency ranging from single-digit to double-digit micromolar in reporter cellular assays. Boltz-2 predictions further delineated the binding landscape, underscoring how these inhibitors engage cytokine surfaces with defined structural complementarity. For the first time, our studies show that cytokines are indeed broadly amenable to small-molecule binding and inhibition with key insights into the chemical structures that can enable the inhibition of specific cytokines.

immunology↗

bioRxiv2026

Droplet-compatible single-cell DNA methylation sequencing with PreTIC

Single-cell DNA methylation sequencing has remained technically specialized due to challenges of interfacing conversion chemistry with droplet microfluidics. We introduce pre-tagmentation in situ conversion (PreTIC), which enables whole-methylome profiling on a commercial droplet platform using off-the-shelf reagents. With PreTIC, we produce over 13,000 single-cell methylomes from fixed frozen cells in two days and resolve cell-specific epigenetic variation in human peripheral blood mononuclear cells.

genomics↗

bioRxiv2026

An EEG-fMRI Jointly Constrained Digital Twin Brain and Its Application in Alzheime's Disease

Current digital twin brain (DTB) models are typically optimized using single-modality functional neuroimaging data, which restricts their ability to simulate brain dynamics across multiple spatiotemporal scales. Here, we bridged this gap by developing a two-stage DTB (TS-DTB) modeling framework jointly constrained by functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) data. Validation in both the healthy young and Alzheimers disease (AD) cohorts demonstrated that the TS-DTB model simultaneously captures subject-specific features of multi-scale brain dynamics. In particular, the TS-DTB models of AD patients successfully recapitulated spectral-temporal signatures of cognitive decline, mechanistically linking these deficits to excitation-inhibition (E-I) imbalances. By simulating responses to repetitive transcranial magnetic stimulation (rTMS), we further revealed that cognitive recovery in AD patients can be driven by E-I rebalancing via synaptic reconfiguration and background suppression. Overall, these findings underscore the potential of the TS-DTB to advance the mechanistic understanding of the brain and inform personalized digital therapeutics.

neuroscience↗

bioRxiv2026

AT2-intrinsic Z-AAT expression drives conserved inflammatory and proteotoxic stress responses and predisposes to emphysema

Individuals homozygous for the SERPINA1 "Z" mutation with alpha-1 antitrypsin deficiency (AATD) are highly susceptible to emphysema. This predisposition has classically been attributed to a relative deficiency of circulating alpha-1 antitrypsin (AAT) reaching the lungs and associated protease-antiprotease imbalance. Accumulating evidence suggests that the presence of misfolded Z-AAT protein either in the circulation, the lung interstitium, or within resident lung cells could contribute to emphysema pathogenesis. We have shown that type 2 alveolar epithelial cells (AT2s), progenitor cells of the lung alveolus, heterogeneously retain Z-AAT and exhibit a transcriptional disease signature in AATD patient samples. However, a lack of model systems that faithfully recapitulate AT2 biology and associated Z-AAT expression has limited our ability to study this phenomenon. Here, we apply syngeneic induced pluripotent stem cell-derived AT2s (iAT2s) and a novel mouse model featuring AT2-specific inducible human SERPINA1 expression to interrogate the cell-instrinsic consequences of Z-AAT expression, validating findings in an independent dataset of human COPD lung tissue comparing ZZ to MM SERPINA1 genotypes. We find further evidence of Z-AAT retention within AT2s and identify shared AT2 transcriptomic disease signatures conserved across model systems, characterized by innate immune and inflammatory signaling, NF-{kappa}B activation, and endoplasmic reticulum stress. Mice with AT2-specific Z-AAT expression additionally demonstrate increased susceptibility to elastase-induced emphysema, providing functional evidence for AT2-intrinsic contributions to AATD-associated lung disease. Within iAT2s, a subpopulation of Z-AAT expressing cells exhibits activation of the PERK-eIF2 signaling axis and markers of an alveolar basal intermediate (ABI) state, emerging cell-autonomously in the absence of mesenchymal co-culture.Together, these data provide evidence that Z-AAT expression in AT2s induces heterogenous cell-intrinsic stress responses including proteotoxic stress, inflammatory signaling, and aberrant cell fate adoption, and is sufficient to result in predisposition to injury, supporting a potential contribution of AT2-intrinsic Z-AAT toxicity to human AATD-associated emphysema pathogenesis.

cell biology↗

bioRxiv2026

sPRR signaling in macrophages via the AT1R/Yap/Taz axis to induce renal fibrosis

BackgroundWithin the kidney, (pro) renin receptor (PRR) is abundantly expressed in the collecting duct (CD) and modulate physiological and pathophysiological processes. We have recently reported that activation of CD PRR mediates obstructive renal fibrosis in a mouse model of unilateral ureteral obstruction (UUO). The current study addresses the underlying mechanisms by examining the profibrotic pathway mediated by soluble PRR (sPRR)-dependent alternative macrophage activation. MethodsWe performed UUO or sham surgery on mice with CD-specific deletion of PRR (CD PRR KO) and floxed controls. After 7 days, we assessed fibrosis-related parameters, inflammatory cytokines, M1/M2 macrophage markers, other gene expression markers of kidney injury, and the concentration of plasma sPRR. We also administered vehicle or site-1 protease (S1P) inhibitor PF-429242 (PF) to C57BL/6 mice with UUO to determine the role of sPRR. Experiments were performed in vitro to examine the mechanism of sPRR-His-mediated macrophage M2 polarization and activation of potential target genes in bone-marrow-derived macrophages (BMDMs). ResultsCompared with the floxed control, CD PRR KO decreased macrophage accumulation, M2 polarization, and Yap/Taz expression while improving renal fibrosis and suppressing plasma sPRR levels following UUO. In BMDMs, sPRR-His treatment promoted macrophage M2 polarization, fibrosis, and Yap/Taz expression, which was dependent on angiotensin type 1 receptor (AT1R). ConclusionCD PRR-derived sPRR acts via ATR to promote macrophage M2 polarization and stimulates the AT1R/Yap/Taz axis, which leads to renal fibrosis during UUO.

pathology↗

bioRxiv2026

A theory of subicular function and generalized vector coding

Located in the hippocampal formation, the subiculum exhibits numerous, seemingly unrelated neural codes, without a common account of neuronal selectivity. We propose Disco, a theory that can explain activity in the subiculum and related neural codes in other areas. Given the continuous flow of experience, subicular activity can be understood as signalling discontinuities in that flow, coded in a vector-base. Geometric discontinuities drive responses to walls, drops, objects, holes, corners and curved surfaces. The generality of Disco enables predictions for 3D environments, natural scenes, and mixed-modality coding. Non-spatial discontinuities in behavioral state yield axis-coding, and tracking population activity signals event boundaries as temporal discontinuities. The ability to generate this diverse set of neural activity suggests that discontinuity coding is a key principle underlying subicular activity.

neuroscience↗

bioRxiv2026

Human Lymph Node Cellular Senescence Atlas Reveals Age-Dependent Alteration in Germinal Center B Cell Function and Niches

Immunosenescence, the age-associated decline in immune function, is a key feature of human aging. In human lymphoid organs, however, the specific immune cell populations that acquire senescence-associated phenotypes during aging and how they influence the surrounding tissue microenvironment remain poorly understood. A spatially resolved map of these senescence-associated immune states in human lymphoid tissues could help clarify their relationship with aging and their potential contributions to the progressive decline of immune function. Here, we integrated single-cell and spatial multi-omics to systematically characterize age-related senescence in human lymph nodes (LNs). Single-cell transcriptomics of lymphoid tissues from donors aged 18 to 100 years old identified 34 immune and stromal cell types and revealed age-associated upregulation of senescence signatures in specific populations. Spatial proteomic profiling of 99 LN sections from 51 donors (18-86 years) using high-plex immunofluorescence ([~]20 million cells) mapped senescence markers (p16, p21, HMGB1, -H2AX) at single-cell resolution, revealing diverse senescent-like cell types ("senotypes") and a stepwise shift from extrafollicular to germinal center (GC) localization with age. Notably, we observed focal clonal-like senescence in GC B cells in older donor LNs. Spatial transcriptomics, epigenomics, and metabolic imaging of selected samples further elucidate the multi-omics signatures and underlying mechanisms of functional impairment, metabolic remodeling, and distinct regulatory programs in senescent-like GC B cells. This study presents a comprehensive spatial atlas of senescence-associated immune states in human lymph nodes, revealing cell-type-specific and spatial heterogeneity that may contribute to immunosenescence and the decline of immune function during aging.

immunology↗

bioRxiv2026

Paternal behavior is controlled by preoptic Trpc5 neurons

Male parenting behavior is highly conserved and activated only after offspring are born. Here we show that the behavioral switch from infanticide in virgin male mice to caregiving in wild-type sires is associated with enhanced expression and activation of Transient receptor potential channel 5 (Trpc5) in estrogen receptor (Esr1)-expressing neurons in the hypothalamic medial preoptic area (MPOA). While selective deletion of Trpc5 from Esr1MPOA neurons diminishes paternal behavior in sires, overexpression of Trpc5 in these neurons converts the otherwise infanticidal virgin males to exhibit care to pups. Mechanistically, Trpc5-dependent changes in neuronal excitability underlie fatherhood-associated Esr1MPOA neuron plasticity. Notably, Trpc5 overexpression also enhances escape behavior and elicits exploratory diving behavior, suggesting that these neurons control a broader adaptive parenting response in males. These findings establish a Trpc5-dependent MPOA neural signal as a critical regulator of paternal behavior.

neuroscience↗