Biology subjects

Yu, P.

Publications and source records attributed to Yu, P..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Navigated range expansion promotes migratory culling

Motile organisms can expand into new territories and increase their fitness, while nonmotile viruses usually depend on host migration to spread across long distances. In general, faster host motility facilitates virus transmission. However, recent ecological studies have also shown that animal host migration can reduce viral prevalence by removing infected individuals from the migratory group. Here, we use a bacteria-bacteriophage co-propagation system to investigate how host motility affects viral spread during range expansion. We find that phage spread during chemotaxis-driven navigated range expansion decreases as bacterial migration speed increases. Theoretical and experimental analyses show that the navigated migration leads to a spatial sorting of infected and uninfected hosts in the co-propagating front of bacteria-bacteriophage, with implications for the number of cells left behind. The preferential loss of infected cells in the co-propagating front inhibits viral spread. Further increase in host migration speed leads to a phase transition that eliminates the phage completely. These results illustrate that navigated range expansion of the host can promote the migratory culling of infectious diseases in the migration group. Significance StatementHost migration is commonly believed to accelerate the spread of infectious diseases. However, recent ecological studies suggest that migration may impede this spread. In our study, we developed a synthetic host-virus co-propagation model to explore the impact of host range expansion on the interplay between host mobility and virus spatial distribution. Our experimental and theoretical analysis revealed the spatial sorting of uninfected and infected hosts in the navigated propagating front leads to faster back diffusion of infected hosts. This self-organized structure allowed the migrating host population to eradicate the infectious disease, independent of intricate host-virus dynamics.

systems biology↗

bioRxiv2024

Opposing Motor Memories in the Direct and Indirect Pathways of the Basal Ganglia

Loss of dopamine neurons causes motor deterioration in Parkinsons disease patients. We have previously reported that in addition to acute motor impairment, the impaired motor behavior is encoded into long-term memory in an experience-dependent and task-specific manner, a phenomenon we refer to as aberrant inhibitory motor learning. Although normal motor learning and aberrant inhibitory learning oppose each other and this is manifested in apparent motor performance, in the present study, we found that normal motor memory acquired prior to aberrant inhibitory learning remains preserved in the brain, suggesting the existence of independent storage. To investigate the neuronal circuits underlying these two opposing memories, we took advantage of the RNA-binding protein YTHDF1, an m6A RNA methylation reader involved in the regulation of protein synthesis and learning/memory. Conditional deletion of Ythdf1 in either D1 or D2 receptor-expressing neurons revealed that normal motor memory is stored in the D1 (direct) pathway of the basal ganglia, while inhibitory memory is stored in the D2 (indirect) pathway. Furthermore, fiber photometry recordings of GCaMP signals from striatal D1 (dSPN) and D2 (iSPN) receptor-expressing neurons support the preservation of normal memory in the direct pathway after aberrant inhibitory learning, with activities of dSPN predictive of motor performance. Finally, a computational model based on activities of motor cortical neurons, dSPN and iSPN neurons, and their interactions through the basal ganglia loops supports the above observations. These findings have important implications for novel approaches in treating Parkinsons disease by reactivating preserved normal memory, and in treating hyperkinetic movement disorders such as chorea or tics by erasing aberrant motor memories.

neuroscience↗

bioRxiv2024

Large-scale multi-omics analyses identified root-microbiome associations underlying plant nitrogen nutrition

The microbiome determines the performance and fitness of the host plant. Nevertheless, the causal interaction between host genetic variation, gene regulation and the impact of the microbiome on the host phenotype remain unknown. Here we generated 1,341 paired root transcriptome, rhizosphere microbiome and root ionome samples and performed a multi-omics analyses of the host-microbe association at the root-soil interface using 175 rapeseeds (Brassica napus L.) resequenced ecotypes at two field environments. We observed the highest statistically explained variance for root nitrogen uptake among natural ionomic variation by overall transcriptome-wide gene expression and microbial abundance variation. Moreover, we identified significant genome-wide associations for 203 highly heritable amplicon sequence variants (ASVs) at multiple genetic loci regulated by eQTL hotspots associated with nitrogen metabolism components. These associations involved a central bacterial genus (Sphingopyxis), which plays a dominant role on gene regulatory effect on its variation regulated by eQTL hotspots. In addition, we performed high-throughput bacterial cultivation from rapeseed roots and subjected Sphingopyxis to whole genome sequencing. Finally, targeted metabolite profiling and confocal imaging assays demonstrated a host-microbiome regulatory effect on Sphingopyxis established by lateral root development and plant nitrogen nutrition. In summary, our integrative approach reveals the genetic basis of host-microbiome trait associations in the transcriptional, nutritional and environmental domains and suggests that the microbiome might have causal effects on root development with implications towards the breeding of nutrient-efficient crops.

plant biology↗

bioRxiv2023

Liver Protects Cytoarchitecture, Neuron Viability and Electrocortical Activity in Post-Cardiac Arrest Brain Injury

BACKGROUNDBrain injury is the major reason for patient deaths in victims who survive after cardiac arrest. Clinical studies have shown that the presence of hypoxic hepatitis and pre-cardiac arrest liver disease is associated with increased mortality and inferior neurological recovery. However, how the liver might impact the pathogenesis of post-cardiac arrest is still unknown. METHODSAn in vivo global cerebral ischemia model was established to assess how simultaneous liver ischemia affected the recovery of brain ischemic injury. In addition, an ex vivo brain normothermic machine perfusion (NMP) model was established to evaluate how addition of a functioning liver might impact the circulation, cytoarchitecture, neuron viability and electrocortical activity of the reperfused brain post-cardiac arrest. RESULTSIn the in vivo model, we observed a larger infarct area in the frontal lobe, elevated tissue injury scores in the CA1 region, as well as increased intravascular immune cell adhesion in the reperfused brains with hepatic ischemia, compared to those without simultaneous hepatic ischemia. The results of the ex vivo model demonstrated that the addition of a functioning liver to the brain NMP circuit significantly reduced post-cardiac arrest brain injury, increased neuronal viability and improved electrocortical activity. Furthermore, we observed significant alterations in gene expressions and metabolites in the presence or absence of hepatic ischemia. CONCLUSIONSOur research highlights the crucial role of the liver in the pathogenesis of post-cardiac arrest brain injury. These findings shed lights on a cardio-pulmonary-hepatic brain resuscitation strategy for patients with cardiac arrest.

neuroscience↗

bioRxiv2023

Species- and strain-effects in interferon, innate immunity, and barrier transcriptional response of microbiome interactions of 3D respiratory epithelial cultures

The microbiome modulates the respiratory epitheliums immunomodulatory functions. To explore how the microbiomes biodiversity affects microbe-epithelial interactions, we screened 58 phylogenetically diverse microbes for their transcriptomic effect on tracheobronchial air-liquid interface cell (ALI) cultures. We found distinct species- and strain-level differences in host innate immunity, and epithelial barrier response. Strikingly, we found that host interferon, an antiviral immune response, was one of the most variable host processes, and this variability was not driven by microbial phylogenetic diversity, bioburden, nor by the microbes ability to stimulate other innate immunity pathways. Our study provides a foundation for understanding how the respiratory microbiomes biodiversity affects epithelial, and particularly, antiviral innate immunity.

microbiology↗

bioRxiv2023

Surrogate selection oversamples expanded T cell clonotypes

Inference from immunological data on cells in the adaptive immune system may benefit from modeling specifications that describe variation in the sizes of various clonal sub-populations. We develop one such specification in order to quantify the effects of surrogate selection assays, which we confirm may lead to an enrichment for amplified, potentially disease-relevant T cell clones. Our specification couples within-clonotype birth-death processes with an exchangeable model across clonotypes. Beyond enrichment questions about the surrogate selection design, our framework enables a study of sampling properties of elementary sample diversity statistics; it also points to new statistics that may usefully measure the burden of somatic genomic alterations associated with clonal expansion. We examine statistical properties of immunological samples governed by the coupled model specification, and we illustrate calculations in surrogate selection studies of melanoma and in single-cell genomic studies of T cell repertoires. FundingThis research was supported in part by the National Science Foundation (grant 2023239-DMS), and by grants from the National Institutes of Health: R01 GM102756, P01 CA022443, P01 CA250972, P50 CA278595, UL1 TR002373, P50 CA269011, and P30 CA014520. This work was also supported by resources at the William S. Middleton Memorial Veterans Hospital, Madison, WI, USA, and the UW Carbone Comprehensive Cancer Center. Additional support was provided by Anns Hope Foundation, Taking on Melanoma, the Tim Eagle Memorial, and the Jay Van Sloan Memorial from the Steve Leuthold Family Foundation, philanthropic support in the USA. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the views of the Dept. of Veterans Affairs or the United States Government.

immunology↗

bioRxiv2023

Dynamics and Plasticity of Immune Cells within Tumor Microenvironment

The tumor microenvironment harbors a complex ecosystem of immune cells, the heterogeneity of which has been extensively characterized, yet the developmental trajectories and plasticity of these populations remain poorly understood. Here, by integrating mitochondrial DNA mutations and chromosomal single-nucleotide polymorphisms inferred from single-cell RNA sequencing data, we established a robust lineage tracing framework to precisely reconstruct phylogenetic relationships among immune cells at single-cell resolution across multiple human cancers. This approach enabled us to systematically map the dynamics within the tumor immune landscape, revealing extensive plasticity including transitions between immune cell subtypes, transdifferentiation across lineages, and dedifferentiation toward progenitor states--all occurring with cancer-type specificity. Tumor microenvironment extrinsic factors were identified as key drivers of this plasticity, directing both the acquisition of transitional states and the orientation of fate changes. Mechanistically, these plasticity events were governed by profound epigenetic reprogramming, with global remodeling of chromatin accessibility and DNA methylation patterns underlying identity shifts. Our study provides a comprehensive atlas of immune cell plasticity in human tumors, establishes the molecular principles governing these dynamic processes, and reveals new opportunities for therapeutic intervention through manipulation of immune cell state or fate decisions.

cell biology↗

bioRxiv2023

Spatiotemporally organized immunomodulatory response to SARS-CoV-2 virus in primary human broncho-alveolar epithelia

The COVID-19 pandemic continues to be a health crisis with major unmet medical needs. The early responses from airway epithelial cells, the first target of the virus regulating the progression towards severe disease, are not fully understood. Primary human air-liquid interface cultures representing the broncho-alveolar epithelia were used to study the kinetics and dynamics of SARS-CoV-2 variants infection. The infection measured by nucleoprotein expression, was a late event appearing between day 4-6 post infection for Wuhan-like virus. Other variants demonstrated increasingly accelerated timelines of infection. All variants triggered similar transcriptional signatures, an "early" inflammatory/immune signature preceding a "late" type I/III IFN, but differences in the quality and kinetics were found, consistent with the timing of nucleoprotein expression. Response to virus was spatially organized: CSF3 expression in basal cells and CCL20 in apical cells. Thus, SARS-CoV-2 virus triggers specific responses modulated over time to engage different arms of immune response.

immunology↗

bioRxiv2023

TERT accelerates BRAF mutant-induced thyroid cancer dedifferentiation and progression by regulating ribosome biogenesis

TERT reactivation occurs frequently in human malignancies. While BRAF activating mutation widely existed in cancers at various stages, TERT reactivation mainly occurs in advanced tumors. However, in vivo evidence for TERT role in cancer progression and the underlying mechanism is currently lacking. In this study, we induced TERT and/or BRAF V600E expression in mouse thyroid epithelium. TERT overexpression alone had no evident effect on tumor initiation. BRAFVE expression itself induced mediocre papillary thyroid cancer (PTC). Notably, the co-expression of BRAFVE and TERT resulted in aggressive poorly differentiated thyroid carcinoma (PDTC). Spatial transcriptome revealed that tumors from co-mutant mice were highly heterogeneous and dedifferentiation process significantly correlated with ribosomal pathways. Mechanistically, TERT boosted ribosomal RNA expression and protein synthesis. CX-5461, a rRNA transcription inhibitor, effectively blocked proliferation and induced redifferentiation. Thus, TERT promotes thyroid cancer progression by inducing dedifferentiation, and ribosome biogenesis inhibition represents a potential treatment strategy for TERT-reactivated cancers. Highlights[tpltrtarr] TERT accelerated thyroid cancer dedifferentiation and metastasis in vivo [tpltrtarr]TERT regulated rRNA metabolism and MTORC1/ S6K/RPS6 activities [tpltrtarr]CX-5461 inhibited the progression of TERT-reactivated melanoma and thyroid cancer [tpltrtarr]Inhibition of rRNA induced redifferentiation of advanced thyroid cancer with TERT activation

cancer biology↗

bioRxiv2023

Heritable maize microbiomes contribute to local adaptation and host stress resilience

Beneficial interactions with microorganisms are pivotal for crop performance and resilience. However, it remains unclear how heritable the microbiome is with respect to the host plant genotype and to what extent host genetic mechanisms can modulate plant-microbe interactions in the face of environmental stress. Here, we surveyed the root and rhizosphere microbiome of 129 accessions of locally adapted Zea mays, sourced from diverse habitats and grown under control and different stress conditions. We quantified treatment and host genotype effects on the microbiome. Plant genotype and source environment were predictive of microbiome composition. Genome wide association analysis identified host genetic variants linked to both rhizosphere microbiome composition and source environment. We identified transposon insertions in a candidate gene linked to both the abundance of a keystone microbe Massilia and source total soil nitrogen, finding mutant plants to show a reduction in lateral root density. We conclude that locally adapted maize varieties exert patterns of genetic control on their root and rhizosphere microbiomes that follow variation in their home environments, consistent with a role in tolerance to prevailing stress.

genetics↗

bioRxiv2022

Evaluation of antibody kinetics and durability in health subjects vaccinated with inactivated COVID-19 vaccine (CoronaVac): A cross-sectional and cohort study in Zhejiang, China

BackgroundAlthough inactivated COVID-19 vaccines are proven to be safe and effective in the general population, the dynamic response and duration of antibodies after vaccination in the real world should be further assessed. MethodsWe enrolled 1067 volunteers who had been vaccinated with one or two doses of CoronaVac in Zhejiang Province, China. Another 90 healthy adults without previous vaccinations were recruited and vaccinated with three doses of CoronaVac, 28 days and 6 months apart. Serum samples were collected from multiple timepoints and analyzed for specific IgM/IgG and neutralizing antibodies (NAbs) for immunogenicity evaluation. Antibody responses to the Delta and Omicron variants were measured by pseudovirus-based neutralization tests. ResultsOur results revealed that binding antibody IgM peaked 14-28 days after one dose of CoronaVac, while IgG and NAbs peaked approximately 1 month after the second dose then declined slightly over time. Antibody responses had waned by month 6 after vaccination and became undetectable in the majority of individuals at 12 months. Levels of NAbs to live SARS-CoV-2 were correlated with anti-SARS-CoV-2 IgG and NAbs to pseudovirus, but not IgM. Homologous booster around 6 months after primary vaccination activated anamnestic immunity and raised NAbs 25.5-fold. The NAb inhibition rate subsequently rose to 36.0% for Delta (p=0.03) and 4.3% for Omicron (p=0.004), and the response rate for Omicron rose from 7.9% (7/89) to 17.8% (16/90). ConclusionsTwo doses of CoronaVac vaccine resulted in limited protection over a short duration. The homologous booster slightly increased antibody responses to the Delta and Omicron variants; therefore, the optimization of booster procedures is vital. FundingKey Research and Development Program of Zhejiang Province; Key Program of Health Commission of Zhejiang Province/ Science Foundation of National Health Commission; Major Program of Zhejiang Municipal Natural Science Foundation.

immunology↗

bioRxiv2022

Global mosquito virome profiling and mosquito spatial diffusion pathways revealed by marker-viruses

Mosquitoes are vectors of numerous emergence and reemergence of mosquito-borne diseases, leading to an overwhelming global challenge. The boom in metagenomic studies promoted the increase of mosquito viruses being described, and studies from different regions of the world showed that mosquitoes harbor abundant and diverse viromes. However, there is still a lack of large-scale systematic comparison of viromes among various ecological factors such as the mosquito species/genera, location, etc, and consistent patterns associated with these factors are not clear. Here, we provide an overview of virome profiling that integrated the perspective of mosquito genus, locations, and climates based on the global scale, and redefined the core-virome. Our results also further implicate some mosquito-associated viruses strongly associated with the ecological factors and highlighted the evidence of mosquitoes cross-regional movements by the candidate marker viruses. The study may be helpful in gaining new insights into strategies to prevent arbovirus epidemics.

microbiology↗

bioRxiv2022

Mapping and modeling human colorectal carcinoma interactions with the tumor microenvironment

The initiation and progression of cancer are inextricably linked to the tumor microenvironment (TME). Understanding the function of specific cancer-TME interactions poses a major challenge due in part to the complexity of the in vivo microenvironment. Here we predict cancer-TME interactions from single cell transcriptomic maps of both human colorectal cancers (CRCs) and mouse CRC models, ask how these interactions are altered in established, long-term human tumor organoid (tumoroid) cultures, and functionally recapitulate human myeloid-carcinoma interactions in vitro. Tumoroid cultures suppress gene expression programs involved in promoting inflammation and immune cell migration through receptor-ligand interactions, providing a reductive platform for re-establishing carcinoma-immune cell interactions in vitro. Introduction of human monocyte-derived macrophages into tumoroid cultures instructs macrophages to acquire pro-tumorigenic gene expression programs similar to those observed in vivo. This includes hallmark induction of SPP1, encoding Osteopontin, an extracellular CD44 ligand with established oncogenic effects. Taken together, these findings offer a framework for understanding CRC-TME interactions and provide a reductionist tool for modeling specific aspects of these interactions.

cancer biology↗

bioRxiv2022

Structural insights into the elevator-type transport mechanism of a bacterial ZIP metal transporter

The Zrt-/Irt-like protein (ZIP) family consists of ubiquitously expressed divalent metal transporters critically involved in maintaining systemic and cellular homeostasis of zinc, iron, and manganese. Here, we present a study on a prokaryotic ZIP from Bordetella bronchiseptica (BbZIP) by combining structural biology, evolutionary covariance, computational modeling, and a variety of biochemical assays to tackle the issue of the transport mechanism which has not been established for the ZIP family. The apo state structure in an inward-facing conformation revealed a disassembled transport site, altered inter-helical interactions, and importantly, a rigid body movement of a 4-transmembrane helix (TM) bundle relative to the other TMs. The computationally generated and biochemically validated outward-facing conformation model revealed a slide of the 4-TM bundle, which carries the transport site(s), by approximately 8 [A] toward the extracellular side against the static TMs which mediate dimerization. These findings allowed us to conclude that BbZIP is an elevator-type transporter.

biochemistry↗

bioRxiv2022

Spatiotemporal landscape of SARS-CoV-2 pulmonary infection reveals Slamf9+Spp1+ macrophages promoting viral clearance and inflammation resolution

While SARS-CoV-2 pathogenesis has been intensively investigated, the host mechanisms of viral clearance and inflammation resolution are still elusive because of the ethical limitation of human studies based on COVID-19 convalescents. Here we infected Syrian hamsters by authentic SARS-CoV-2 and built an ideal model to simulate the natural recovery process of SARS-CoV-2 infection from severe pneumonia1,2. We developed and applied a spatial transcriptomic sequencing technique with subcellular resolution and tissue-scale extensibility, i.e., Stereo-seq3, together with single-cell RNA sequencing (scRNA-seq), to the entire lung lobes of 45 hamsters and obtained an elaborate map of the pulmonary spatiotemporal changes from acute infection, severe pneumonia to the late viral clearance and inflammation resolution. While SARS-CoV-2 infection caused massive damages to the hamster lungs, including naive T cell infection and deaths related to lymphopenia, we identified a group of monocyte-derived proliferating Slamf9+Spp1+ macrophages, which were SARS-CoV-2 infection-inducible and cell death-resistant, recruiting neutrophils to clear viruses together. After viral clearance, the Slamf9+Spp1+ macrophages differentiated into Trem2+ and Fbp1+ macrophages, both responsible for inflammation resolution and replenishment of alveolar macrophages. The existence of this specific macrophage subpopulation and its descendants were validated by RNAscope in hamsters, immunofluorescence in hACE2 mice, and public human autopsy scRNA-seq data of COVID-19 patients. The spatiotemporal landscape of SARS-CoV-2 infection in hamster lungs and the identification of Slamf9+Spp1+ macrophages that is pivotal to viral clearance and inflammation resolution are important to better understand the critical molecular and cellular players of COVID-19 host defense and also develop potential interventions of COVID-19 immunopathology.

immunology↗

bioRxiv2022

Dynamic Landscapes of tRNA Transcriptomes and Translatomes in Diverse Mouse Tissues

Although the function of tRNA in translational process is well established, it remains controversial whether tRNA abundance is tightly associated with translational efficiency (TE) in mammals. For example, how critically the expression of tRNAs contributes to the establishment of tissue-specific proteomes in mammals has not been well addressed. Here, we measured both tRNA expression using DM-tRNA-seq and ribosome-associated mRNAs in the brain, heart, and testis of RiboTag mice. Remarkable variation in the expression of tRNA isodecoders was observed among the different tissues. When the statistical effect of isodecoder-grouping on reducing variations is considered through permutating the anticodons, we observed an expected reduction in the tissue-variations of anticodon expression, an unexpected smaller variation of anticodon usage bias, and an unexpected larger variation of tRNA isotype expression. Regardless whether or not they share the same anticodons, isotypes encoding the same amino acids are co-expressed across different tissues. Based on the tRNA expression and TE computed from RiboTag-seq, we find that the tRNA adaptation index (tAI) values and TE are significantly correlated in the same tissues but not among tissues; tRNAs and the amino acid compositions of translating peptides are positively correlated in the same tissues but not between tissues. We therefore hypothesize that the tissue-specific expression of tRNAs might be related to post-transcriptional mechanisms, such as aminoacylation, modification, and tRNA-derived small RNAs (tsRNAs). This study provides a resource for tRNA and translation studies to gain novel insights into the dynamics of tRNAs and their role in translational regulation.

cell biology↗

bioRxiv2022

Comparative transcriptomics and metabolomics reveal specialized metabolite drought stress responses in switchgrass (Panicum virgatum L.)

O_LISwitchgrass (Panicum virgatum) is a bioenergy model crop valued for its energy efficiency and drought tolerance resilience. The related monocot species rice (Oryza sativa) and maize (Zea mays) deploy species-specific, specialized metabolites as core stress defenses. By contrast, specialized chemical defenses in switchgrass are largely unknown. C_LIO_LITo investigate specialized metabolic drought responses in switchgrass, we integrated tissue-specific transcriptome and metabolite analyses of the genotypes Alamo and Cave-in-Rock that feature different drought tolerance. C_LIO_LIThe more drought-susceptible Cave-in-Rock featured an earlier onset of transcriptomic changes and significantly more differentially expressed genes in response to drought compared to Alamo. Specialized pathways showed moderate differential expression compared to pronounced transcriptomic alterations in carbohydrate and amino acid metabolism. However, diterpenoid-biosynthetic genes showed drought-inducible expression in Alamo roots, contrasting largely unaltered triterpenoid and phenylpropanoid pathways. Metabolomic analyses identified common and genotype-specific flavonoids and terpenoids. Consistent with transcriptomic alterations, several root diterpenoids showed significant drought-induced accumulation, whereas triterpenoid abundance remained predominantly unchanged. Structural analysis of drought-responsive root diterpenoids verified these metabolites as oxygenated furanoditerpenoids. C_LIO_LIDrought-dependent transcriptome and metabolite profiles provide the foundation to understand the molecular mechanisms underlying switchgrass environmental resilience. Accumulation of specialized root diterpenoids and corresponding pathway transcripts supports a role in drought stress tolerance for these compounds. C_LI Significance statementWith an increasing demand for renewable energy opposed by rising climate-driven crop losses, understanding, and leveraging plant natural defenses can enable the development of sustainable crop production systems. Here, we integrated comparative transcriptomics and metabolomics analyses to gain a detailed understanding of the diversity and physiological relevance of specialized metabolites in upland and lowland switchgrass ecotypes and provide resources for future investigations of drought response mechanisms in switchgrass.

plant biology↗

bioRxiv2022

LTD-inducing low frequency stimulation enhances p-Tau181 and p-Tau217 in an age-dependent manner in live rats

The progressive cognitive decline in Alzheimers disease (AD) patients correlates with the extent of tau pathology, in particular tau hyperphosphorylation, which is strongly age-associated. Although elevation of phosphorylated tau (p-Tau) on residues Thr181 (p-Tau181), Thr217 (p-Tau217), and Thr231 (p-Tau231) in cerebrospinal fluid or blood are recently proposed to be particularly sensitive markers of early AD, the generation of p-Tau during brain activity is poorly understood. A major form of synaptic plasticity, long-term depression (LTD), has recently been linked to the enhancement of tau phosphorylation. Here we show that low frequency stimulation (LFS), used to induce LTD, enhances p-Tau181 and p-Tau217 in an age-dependent manner in the hippocampus of live rats. In contrast, phosphorylation at residues Thr231, Ser202/Thr205, and Ser396 is less sensitive to LFS. Pharmacological antagonism of either NMDA or metabotropic glutamate 5 (mGluR5) receptors inhibits the elevation of both p-Tau181 and p-Tau217. Targeting ageing with a small molecule cognitive enhancer ISRIB (trans-isomer) prevents the enhancement of p-Tau by LFS in aged rats. Together, our data provide an in vivo means to uncover brain plasticity-related cellular and molecular processes of tau phosphorylation in health and ageing conditions.

neuroscience↗