Biology subjects

Zhang, N.

Publications and source records attributed to Zhang, N..

At least 109 records · Page 6Linked to original sources

bioRxiv2025

Idebenone Enhances the Early Microglial Response to Traumatic Brain Injury and Mitigates Acute Gene Expression Changes to Ephrin-A and Dopamine Signaling Pathways

Traumatic Brain Injury (TBI) leads to persistent pro-inflammatory microglial activation implicated in neurodegeneration. Idebenone, a coenzyme Q10 analogue that interacts with both mitochondria and the tyrosine kinase adaptor SHC1, inhibits aspects of microglial activation in vitro. We used the NanoString Neuropathology panel to test the hypothesis that idebenone post-treatment mitigates TBI pathology-associated acute gene expression changes by moderating the pro-inflammatory microglial response to injury. Controlled cortical impact to adult male mice increased the microglial activation signature in peri-lesional cortex at 24 hours post-TBI. Unexpectedly, several microglial signature genes upregulated by TBI were further increased by post-injury idebenone administration. However, idebenone significantly attenuated TBI-mediated perturbations to gene expression associated with behavior, particularly in the gene ontology:biological process (GO:BP) pathways "ephrin receptor signaling" and "dopamine metabolic process." Gene co-expression analysis correlated levels of microglial complement component 1q (C1q) and the neurotrophin receptor gene Ntrk1 to large (>3-fold) TBI-induced decreases in dopamine receptor genes Drd1 and Drd2 that were mitigated by idebenone treatment. Bioinformatics analysis identified SUZ12 as a candidate transcriptional regulator of idebenone-modified gene expression changes. Overall, results suggest that idebenone enhances TBI-induced microglial proliferation within the first 24 hours of TBI and identify Ephrin-A and dopamine signaling as novel idebenone targets.

neuroscience↗

bioRxiv2025

MAPT Splicing Modulators as a Therapeutic Strategy for Tauopathies

Tauopathies are neurodegenerative diseases characterized by the abnormal accumulation of microtubule-associated protein tau (MAPT) in the brain. These disorders, like frontotemporal dementia (FTD-Tau), currently lack effective therapies and can occur sporadically or be inherited when associated with MAPT gene mutations. The MAPT gene region encompassing exon 10 and adjacent introns is a hotspot for pathogenic variants, including splicing mutations that enhance exon 10 inclusion and increase 4R tau expression, and gain-of-function mutations that generate aggregation-prone mutant 4R tau protein. For these 4R-specific tauopathies, a targeted mRNA splicing approach that promotes exon 10 exclusion may offer therapeutic benefit. In this study, we discovered novel splicing modulator compounds (SMCs) that promote MAPT exon 10 exclusion, and demonstrated their efficacy in FTD patient-derived neuronal models carrying the tau-P301L gain-of-function mutation or the tau-S305N splicing mutation. Treatment with SMC reduced 4R tau expression and decreased the accumulation of hyperphosphorylated tau (pTau), oligomeric and insoluble tau, thereby rescuing tau-associated neuronal toxicity. Importantly, our lead SMC corrected the 3R/4R splice ratio in vivo and significantly reduced pTau in the brain of a gene- replacement (GR) mouse model expressing the human tau-N279K splicing mutation. These findings support the therapeutic potential of this class of small molecules and establish MAPT pre- mRNA splicing modulation as a promising strategy for the treatment of 4R tauopathies. One Sentence SummaryDiscovery of SMCs that correct MAPT splicing, reduce 4R tau, and rescue pathology in patient- derived neuronal and in vivo models of 4R tauopathies.

neuroscience↗

bioRxiv2025

A novel enterococcus phage endolysin Lys22 with a wide host range against mixed biofilm of Enterococcus faecalis, Staphylococcus aureus and Acinetobacter baumannii

The global surge in multidrug-resistant (MDR) bacterial pathogens has created an urgent imperative for innovative antimicrobial strategies. Enterococcus faecalis, Staphylococcus aureus, and Acinetobacter baumannii demonstrate remarkable antibiotic resistance and dominate hospital-acquired infections. These bacteria often form biofilms, a complex community structure that shields them from immune system phagocytosis, resists antibiotic penetration, and enhances their survival in harsh environments. In clinical cases, these bacteria often form mixed biofilms and lead to treatment failures. Phages and their derivatives have emerged as promising candidates in the fight against drug-resistant bacteria. Lys22, an endolysin derived from an enterococcus phage, has been cloned and demonstrated to possess a broad host range, effectively targeting E. faecalis, various Staphylococcus species, and A. baumannii. When applied to the biofilms formed by these bacteria, Lys22 was found to significantly inhibit both simple and complex biofilms in vitro. Virulent genes, including agrA, sarA, and icaA in S. aureus; asa1, cylA, and hyl in E. faecalis; and OmpA and lpsB in A. baumannii were also downregulated by Lys22. Notably, Lys22 also exhibited a robust protective effect against dual or triple infections involving E. faecalis, S. aureus, and A. baumannii in a zebrafish eggs model, highlighting its potential as a therapeutic agent in combatting multi-bacterial infections.

microbiology↗

bioRxiv2025

Deciphering the Pathogenic Landscape of Amyloid Light-Chain Cardiomyopathy

Amyloid light-chain cardiomyopathy (ALCA) is an infiltrative disorder marked by misfolded immunoglobulin light-chain deposition in the myocardium, ultimately leading to cardiac dysfunction. Despite its clinical severity, the underlying mechanisms remain poorly understood. Here, we integrated multi-omics analyses of human cardiac samples to construct a comprehensive cellular and spatial atlas of the ALCA heart. We observed a marked expansion of PTX3+ fibroblasts (FB), which undergo a distinct phenotypic transition into pro-fibrotic POSTN+ FB regulated by EGR1.Concurrently, SPP1+ macrophages (Mac) emerged as major drivers of fibrosis, interacting robustly with PTX3+ FB via APP-CD74, GAS6-MERTK, and TGF-{beta}1-TGF-{beta}1/2 pathways. Endothelial cell (EC) profiling revealed substantial vascular remodeling characterized by the emergence of specialized capillary-like immune endothelial cells expressing chemokines CXCL1, CXCL3, and CCL2, alongside depletion of functional capillary EC. Immunologically, elevated cytotoxic CD8+ T cells and reduced NK cells contributed to an imbalanced inflammatory milieu, with NF{kappa}B2 orchestrating both fibrotic and immune pathways across multiple cell types. These findings highlight the pivotal role of fibroblast-immune crosstalk, particularly the SPP1+ Mac-PTX3+ FB axis, in driving ALCA pathogenesis. Targeting these pathological cellular interactions may offer a promising therapeutic avenue to mitigate fibrosis, restore immune homeostasis, and improve cardiac function in ALCA.

bioinformatics↗

bioRxiv2025

The membrane skeleton density of red blood cells in MYH9-related disease patients is decreased

MYH9-related disease (MYH9-RD) is a rare autosomal dominant disorder caused by mutations in MYH9 gene, which encodes the heavy chain of nonmuscle myosin IIA. Nearly all MYH9-RD patients present with macrothrombocytopenia, characterized by decreased platelet count and increased platelet size. In this study, we collected blood samples from three MYH9-RD patients (R702S, D1424N, and R1464C) and unexpectedly found that the actin levels in the red blood cells (RBCs) from all three MYH9-RD patients are substantially lower than the healthy controls. We further revealed that the levels of two RBC membrane skeleton proteins, -spectrin and tropomodulin, are also reduced in MYH9-RD RBCs. We showed that the membrane skeleton of MYH9-RD RBCs was more porous and that MYH9-RD RBCs produced more severe deformation under hyperosmotic pressure compared to healthy controls. We conclude that MYH9-RD mutations reduce the RBC membrane skeleton density and impair its mechanical properties, and propose that defects in the membrane skeleton network in RBCs may be a common symptom in MYH9-RD. Key pointsThe levels of membrane skeleton proteins and the density of membrane skeleton network in RBCs of MYH9-RD patients are reduced. MYH9-RD RBCs produce greater deformation under hypertonic conditions compared to healthy controls.

pathology↗

bioRxiv2024

Long-read sequencing reveals extensive size variation and suggests evolutionary patterns of expansion in bivalve mitogenomes

Bilaterian mitochondrial genomes are generally of conserved size and gene content, typically ranging from 14 to 20 kb and coding 37 genes. However, the major exception to this rule has been found in many bivalve species which allow the presence of long unassigned region (regions that are functionally unassigned). It is still unclear whether there are universal patterns to expansions across bivalves. Additionally, the prevalence of highly repetitive sequences within complex mitogenomes has prevented its complete assembly and led to its systematic omission from mitogenomic analyses. Here, leveraging the growing genomic resources in Mollusca, we devised a mitogenome assembly pipeline using long-read sequencing to characterize mitogenome features in 178 mollusk species. Comparing our assemblies with reference mitogenomes based on Sanger/short-read sequencing, we identified missing sequences, repeats and novel gene duplications and found that bivalves exhibit an exceptional diversity in mitogenome size compared to other mollusks. Subsequently, we investigated the factors potentially influencing mitogenome size, the potential functional elements and the patterns of expansion regions. Furthermore, we discussed that the possible selective pressure on mitogenome size and hypothesized that the variability of bivalve mitogenomes may be linked to innate immunity. Our findings underscore the significance of long-read sequencing in elucidating complex mitogenomes and provide new insights into the evolution of bivalve mitogenomes.

genomics↗

bioRxiv2024

Oral supplementation with Nicotinamide Riboside treatment protects RGCs in DBA/2J mouse model

PurposeThe aim of this study was to test whether oral administration of nicotinamide riboside (NR), the nicotinamide adenine dinucleotide (NAD+) precursors, protect retina ganglion cells (RGCs) from neurodegeneration in DBA/2J (D2) mice, which is a widely used mouse model of age-related inherited glaucoma. MethodOral NR or NAM administration (NR low dose: 1150mg/kg; NR high dose: 4200mg/kg; NAM low dose group: 500mg/kg; NAM high dose: 2000mg/kg of body weight per day) essentially started when D2 mice were 4 or 9 months old and continued up to 12 months old. Control cohort identically received food/water without NAM or NR. Intraocular pressure (IOP) was measured every month until experiment completion. Pattern electroretinography (PERG) was recorded. Retinas were harvested for whole mount immunofluorescence staining with RGCs marker Brn3a and imaged by fluorescent confocal microscopy. Optic nerves were harvested for axon staining and quantification. Retinal NAD+ levels were enzymatically assayed. ResultsNR oral supplementary treatment started at 4 months old robustly increased retinal NAD+ levels in D2 mice (NRHigh vs. vehicle: 273.7{+/-}23.59% vs. 108.70{+/-}12.10%, p<0.001). In aged vehicle group (12 months old), there was significantly diminution of the P1 and N2 components of PERG response compare with naive group (naive vs. vehicle: P1: 7.82{+/-} 0.70uV vs 1.63{+/-} 0.17uV, p<0.0001; N2: -13.29{+/-} 0.83uV vs. -3.22{+/-} 0.27uV, p<0.0001; Kruskal-Wallis test with Dunn s multiple comparison test). NR treatment preserved aged D2 visual function when mice were 9 and 12 months old. In addition, long-term NR high dose treatment significantly protected against total RGCs loss and optic nerve atrophy (RGC: NRHigh vs. vehicle: 1412{+/-}62.00vs 475.2{+/-}94.68 cells/field, p<0.00001; axon numbers: NRHigh vs. vehicle: 23990{+/-}1159 vs 8573{+/-}1160, n=41-53, p<0.0001). Furthermore, long-term NR supplementation prevent iris depigmentation and delayed IOP elevation. ConclusionNR oral supplementary treatment significantly preserved RGC and axon numbers, potentially preserves retinal function via elevated retinal NAD+ level in aged D2 mice. Interestingly, NR treatment also prevented iris atrophy, delayed IOP elevation associated with this glaucoma model. NR oral supplementation thus treated several aspects of murine pigment dispersion glaucoma. Given parallels between this model and glaucoma in human, out data indicate that NR is worth exploring as a therapeutic candidate in treatment of glaucoma.

neuroscience↗

bioRxiv2024

Combined inhibition of S100A4 and TIGIT suppresses late-stage breast cancer metastasis to the lung by activating T and NK cells

Cancer metastasis is responsible for approximately 90% of cancer-related deaths, but very few treatment options exist currently. While the role of S100A4 in promoting metastasis has been known for decades, this knowledge has not been translated in the clinic. Here, we report that a novel monoclonal antibody against the human S100A4 protein (S1004-11) effectively suppresses breast cancer metastasis in two different mouse models. Importantly, a novel combination of ant-TIGIT and S100A4-11 can suppress lung metastases even in late-stage disease after the lung premetastatic niche (PMN) has already been established similar to a stage when many breast cancer patients are diagnosed. Mechanistically, S1004-11 mAb treatment block the formation of PMN by suppressing neutrophil infiltration and activating natural killer (NK) and T cells in the lung. Single-cell RNA-sequencing and cell:cell communication analyses indicate that TIGIT signaling suppresses NK cells, which is reversed in S100A4-11 treated PMN. In summary, this study provides compelling evidence for a novel mechanism of S100A4 function in PMN formation and the feasibility of using S100A4-11 monoclonal antibody to suppress metastases at different stages of breast cancer progression.

cancer biology↗

bioRxiv2024

Multi-purpose controllable protein generation via prompted language models

Deep learning is increasingly powerful for designing proteins that meet structural and functional requirements. However, most existing methods follow a conventional pipeline: first defining a backbone structure and then generating sequences consistent with it. This approach, which encodes all design goals indirectly through structures, restricts flexibility and struggles to address multiple, complex design objectives simultaneously. We present PROPEND, a multi-purpose protein sequence design method based on the "pre-train and prompt" framework. We show PROPENDs broad utility and accuracy both in silico and in vitro by directly controlling multiple properties through the prompt of backbones, blueprints, functional tags, and their combinations. For the five sequences tested with in vitro experiments, PROPEND achieved a maximum functional recovery of 105.2%, significantly outperforming the classical design pipelines 50.8%.

synthetic biology↗

bioRxiv2024

Integration of Imaging-based and Sequencing-based Spatial Omics Mapping on the Same Tissue Section via DBiTplus

Spatially mapping the transcriptome and proteome in the same tissue section can significantly advance our understanding of heterogeneous cellular processes and connect cell type to function. Here, we present Deterministic Barcoding in Tissue sequencing plus (DBiTplus), an integrative multi-modality spatial omics approach that combines sequencing-based spatial transcriptomics and image-based spatial protein profiling on the same tissue section to enable both single-cell resolution cell typing and genome-scale interrogation of biological pathways. DBiTplus begins with in situ reverse transcription for cDNA synthesis, microfluidic delivery of DNA oligos for spatial barcoding, retrieval of barcoded cDNA using RNaseH, an enzyme that selectively degrades RNA in an RNA-DNA hybrid, preserving the intact tissue section for high-plex protein imaging with CODEX. We developed computational pipelines to register data from two distinct modalities. Performing both DBiT-seq and CODEX on the same tissue slide enables accurate cell typing in each spatial transcriptome spot and subsequently image-guided decomposition to generate single-cell resolved spatial transcriptome atlases. DBiTplus was applied to mouse embryos with limited protein markers but still demonstrated excellent integration for single-cell transcriptome decomposition, to normal human lymph nodes with high-plex protein profiling to yield a single-cell spatial transcriptome map, and to human lymphoma FFPE tissue to explore the mechanisms of lymphomagenesis and progression. DBiTplusCODEX is a unified workflow including integrative experimental procedure and computational innovation for spatially resolved single-cell atlasing and exploration of biological pathways cell-by-cell at genome-scale.

systems biology↗

bioRxiv2024

Tomato roots exhibit distinct, development-specific responses to bacterial-derived peptides

O_LIPlants possess cell-surface recognition receptors that detect molecular patterns from microbial invaders and initiate an immune response. Understanding the conservation of pattern-triggered immunity within different plant organs and across species is crucial to its sustainable and effective use in plant disease management but is currently unclear. C_LIO_LIWe examined the activation and immune response patterns of three pattern recognition receptors (PRRs: SlFLS2, SlFLS3, and SlCORE) in different developmental regions of roots and in leaves of multiple accessions of domesticated and wild tomato (Solanum lycopersicum and S. pimpinellifolium) using biochemical and genetic assays. C_LIO_LIRoots from different tomato accessions differed in the amplitude and dynamics of their immune response, but all exhibited developmental-specific PTI responses in which the root early differentiation zone was the most sensitive to molecular patterns. PRR signaling pathways also showed distinct but occasionally overlapping responses downstream of each immune receptor in tomato roots. C_LIO_LIThese results reveal that each PRR initiates a unique PTI pathway and suggest that the specificity and complexity of tomato root immunity are tightly linked to the developmental stage, emphasizing the importance of spatial and temporal regulation in PTI. C_LI

plant biology↗

bioRxiv2024

A novel male accessory gland peptide reduces female post-mating receptivity in the brown planthopper

Mating in insects commonly induces a profound change in the physiology and behavior of the female that serves to secure numerous and viable offspring and to ensure paternity for the male by reducing receptivity of the female to further mating attempts. Here, we set out to characterize the post-mating response (PMR) in a pest insect, the brown planthopper (BPH) Nilaparvata lugens and to identify a functional analog of sex peptide (SP) and/or other seminal fluid factors that contribute to the PMR in Drosophila. We find that BPHs display a distinct PMR that lasts for about 4 days and includes a change in female behavior with decreased receptivity to males and increased oviposition. Extract from male accessory glands (MAG) injected into virgin females triggers a similar PMR, lasting about 24h. Since SP does not exist in BPHs, we screened for candidate mediators by performing a transcriptional and proteomics analysis of MAG extract. We identified a novel 51 amino acid peptide present only in the MAG and not in female BPHs. This peptide, that we designate maccessin (macc), affects the female PMR. Females mated by males with macc knockdown display receptivity to wild type males in a second mating, which does not occur in controls. However, oviposition is not affected. Injection of recombinant macc reduces female receptivity, with no effect on oviposition. Thus, macc is so far the only candidate seminal fluid peptide that promotes a PMR in BPHs. Our analysis suggests that the gene encoding the macc precursor is restricted to species closely related to BPHs. Author summaryIn insects, mating often induces a long-lasting change in the female behavior and physiology, called a post-mating response (PMR). This ensures numerous and viable offspring, but also serves to secure paternity for the male by inhibiting the female receptivity to further mating attempts. Here, we demonstrate that a pest insect, the brown planthopper (BPH) Nilaparvata lugens, also displays a PMR with decreased receptivity to further mating and increased egg laying. We furthermore find that seminal fluid extracted from the male accessory gland of BPHs injected into females generates a PMR. Next, we identified a novel peptide unique to the male accessory gland (designated maccessin) and demonstrate that this peptide is responsible for the reduced receptivity in the PMR, but does not affect egg laying. The gene encoding maccessin appears unique to close relatives of N. lugens. This is similar to a Drosophila male accessory gland factor, sex peptide, which is known to induce a PMR, and occurs only in a limited number of Drosophila species.

neuroscience↗

bioRxiv2024

KLHDC7B, a novel gene associated with age-related hearing loss in humans, is required for the maintenance of hearing in mice.

BackgroundAge-related hearing loss (ARHL) is the most common sensory loss in older adults, but the underlying pathological mechanisms remain unclear. Recent genome wide association studies (GWAS) have linked variation in a large number of genes with increased risk of ARHL for the first time. Amongst the strongest of these associations is variation in KLHDC7B, a gene of unknown function and one not previously linked to hearing. MethodsTo confirm whether KLHDC7B plays a role in hearing we investigated auditory function in two independent knockout mutant mouse models of Klhdc7b: Klhdc7bIMPC-/-and Klhdc7bRegn{Delta}/{Delta} on the C57BL/6N background and the B6.CAST-Cdh23753A>G background respectively. The B6.CAST-Cdh23753A>G background was backcrossed to correct a known age-related hearing loss (ahl) mutation in cadherin 23 present in both the C57BL/6N and C57BL/6J strains. ResultsWe showed that Klhdc7b is expressed exclusively in inner and outer sensory hair cells within the cochlea of mice at the RNA and protein level. Homozygous mutants for both knockout mouse models display a similar early-onset, progressive and severe hearing loss. Histological characterization of the two mouse models suggests that hair cells develop normally and are present in neonates. However, after the onset of hearing there is a progressive loss of outer hair cells in a gradient from base to apex of the cochlea consistent with the hearing deficit in the mice and the pattern of hearing loss in ARHL. Inner hair cells remain intact up to the latest age examined (~8 weeks). ConclusionsOur data suggests KLHDC7B is required for maintenance of auditory function rather than in its development, supporting the novel association with ARHL in humans detected in recent GWAS. To our knowledge, this is the first validation in mouse of an ARHL association in humans detected in a GWAS. Our work also provides two distinct mouse models to further investigate the role of KLHDC7B in auditory function and for use in the development of therapeutic tools to prevent or treat ARHL.

genetics↗

bioRxiv2024

Pan-Prediction of MHC-II Restricted Epitopes Across Species via an Alphafold-based Quantification Scheme

Predicting MHC-II restricted epitopes across species used to be challenging, but Alphafold (AF) may provide a structure-based pan-prediction solution. In this study, we established the new tool AF-pred with a clear standard for quantitative prediction results. Compared to the sequence-based tools heavily trained with human ligandome, AF-pred does not show advantage in predicting the binding patterns of human HLA-II but has far better performance in predicting binding patterns of other animals MHC-II. Using recently resolved bat MHC-II structures, we analyzed AF-preds prediction capability, logic and limitation. In addition, we also explored the impact of AF algorithm iterations on the prediction of MHC-II restricted epitopes. The results demonstrated that AF-pred is capable of cross-species prediction of MHC-II restricted epitopes and is conducive to the development of novel veterinary vaccines.

immunology↗

bioRxiv2024

Chromatin remodeler BRG1 recruits huntingtin to repair DNA double-strand breaks in neurons

Persistent DNA double-strand breaks (DSBs) are enigmatically implicated in neurodegenerative diseases including Huntingtons disease (HD), the inherited late-onset disorder caused by CAG repeat elongations in Huntingtin (HTT). Here we combine biochemistry, computation and molecular cell biology to unveil a mechanism whereby HTT coordinates a Transcription-Coupled Non-Homologous End-Joining (TC-NHEJ) complex. HTT joins TC-NHEJ proteins PNKP, Ku70/80, and XRCC4 with chromatin remodeler Brahma-related Gene 1 (BRG1) to resolve transcription-associated DSBs in brain. HTT recruitment to DSBs in transcriptionally active gene- rich regions is BRG1-dependent while efficient TC-NHEJ protein recruitment is HTT-dependent. Notably, mHTT compromises TC-NHEJ interactions and repair activity, promoting DSB accumulation in HD tissues. Importantly, HTT or PNKP overexpression restores TC-NHEJ in a Drosophila HD model dramatically improving genome integrity, motor defects, and lifespan. Collective results uncover HTT stimulation of DSB repair by organizing a TC-NHEJ complex that is impaired by mHTT thereby implicating dysregulation of transcription-coupled DSB repair in mHTT pathophysiology. Highlights* BRG1 recruits HTT and NHEJ components to transcriptionally active DSBs. * HTT joins BRG1 and PNKP to efficiently repair transcription related DSBs in brain. * Mutant HTT impairs the functional integrity of TC-NHEJ complex for DSB repair. * HTT expression improves DSB repair, genome integrity and phenotypes in HD flies.

neuroscience↗

bioRxiv2024

Neuroimaging model of visceral manipulation in awake rat

Reciprocal neuronal connections exist between the internal organs of the body and the nervous system. These projections to and from the viscera play an essential role in maintaining and finetuning organ responses in order to sustain homeostasis and allostasis. Functional maps of brain regions participating in this bidirectional communication have been previously studied in awake humans and anesthetized rodents. To further refine the mechanistic understanding of visceral influence on brain states, however, new paradigms that allow for more invasive, and ultimately more informative, measurements and perturbations must be explored. Further, such paradigms should prioritize human translatability. In the current paper, we address these issues by demonstrating the feasibility of non-anesthetized animal imaging during visceral manipulation. More specifically, we used a barostat interfaced with an implanted gastric balloon to cyclically induce distension of a non-anesthetized rats stomach during simultaneous BOLD fMRI. General linear modeling and spatial independent component analysis revealed several regions with BOLD activation temporally coincident with the gastric distension stimulus. The ON-OFF (20 mmHg - 0 mmHg) barostat-balloon pressure cycle resulted in widespread BOLD activation of the inferior colliculus, cerebellum, ventral midbrain, and a variety of hippocampal structures. These results suggest that neuroimaging models of gastric manipulation in the non-anesthetized rat are achievable and provide an avenue for more comprehensive studies involving the integration of other neuroscience techniques like electrophysiology. Significance StatementIt is unclear to what extent measurements of brain activity are affected by background, and experimentally unrelated, interoceptive processes. To advance our understanding of ongoing visceral activitys influence on brain states, here we provide a proof of concept, anesthesia-free animal model of visceral manipulation during simultaneous BOLD fMRI. We successfully demonstrated BOLD activation during gastric distension of the unanesthetized rat in both classically reported (cerebellum, hippocampus) and novel (inferior colliculus) regions. This paradigm establishes an important foundation for further interrogation of viscera-brain interactions.

neuroscience↗

bioRxiv2024

Functional MRI reveals regional changes of brain activity after five days of focal high-density theta burst stimulation (hdTBS) of the rat brain

BackgroundThe therapeutic effects of transcranial magnetic stimulation (TMS) likely stem from neuroplasticity induced by repeated sessions over time. While animal models offer insights into TMS-induced plasticity, a rodent model that faithfully replicates prolonged TMS conditions in humans is still lacking. Objective/HypothesisDevelop a rat model that mimics the spatial and temporal patterns of TMS in humans. MethodsExperiments were conducted on two cohorts of healthy adult rats (N=33). In cohort 1, rats underwent surgical implantation of microelectrodes for motor evoked potential (MEP) recording. With a rodent-specific coil and the high-density theta burst stimulation (hdTBS) paradigm, under awake condition, rats received daily TMS at 100% motor threshold for five days (days 1-5) to the hindlimb motor cortex. Cortical excitability was measured by input-output (I-O) curves on Day 0 (pre-hdTBS baseline) and Day 6 (post-hdTBS). The second cohort received identical TMS and underwent fMRI to map cerebral blood volume (CBV) on Days 0 and 6. ResultsDaily hdTBS session for 5 days significantly up-shifted I-O curves only in the TMS group (N=9), not in the sham group (N=7), indicating enhanced cortical excitability. fMRI data showed that, compared to sham group (N=9), rats receiving hdTBS (N=8) had increased basal CBV in several brain regions proximal and distal to the stimulation site, suggesting enhanced basal metabolism. Conclusion(s)Daily hdTBS session for 5 days focally delivered to the motor cortex of naive rats significantly altered basal brain activity in a network of brain regions, opening a novel platform for further investigating TMS-induced plasticity.

neuroscience↗

bioRxiv2024

Developmental control of E-cadherin junctions by mechanical contractility in Drosophila embryos

Adherens junctions are very plastic structures that change their composition and structure depending on the state of the epithelial tissue, involving mechanical stress and tissue dynamics. In Drosophila embryos, adherens junctions mature only during gastrulation following their formation a few minutes before during cellularization. Although the developmental maturation is obvious during gastrulation, the factors and conditions controlling it have remained unclear. Here, we assay the levels, distribution pattern, and mobility of E-cadherin during Drosophila gastrulation. Indicating a maturation, we find an increase in total levels at junctions and a drop in the mobile fraction of E-cadherin molecules. Both developmental changes depend on Myo-II contractility. Consistent with stereotypic Myo-II regulation, we find that interference with Rho signaling leads to corresponding changes in E-cadherin levels and mobility, at least in part. Besides Rho signaling, Src42A contributes to junction maturation, as tested by both loss-function and gain-of-function situations. Together, we demonstrate developmental maturation of adherens junctions and identify Rho signaling and Src42A as upstream regulatory pathways.

developmental biology↗