Biology subjects

Ren, N.

Publications and source records attributed to Ren, N..

12 recordsLinked to original sources

bioRxiv2026

Decoding instrumental lever pressing from prefrontal, accumbens, and hippocampal local field potentials: conservation across sex, task, and dopamine depletion

During operant behavior, oscillatory activity is coordinated across multiple brain regions and can change under different task conditions. In this study, we use a decoding approach to characterize these patterns and predict lever pressing behavior in rats from local field potentials (LFP) recorded bilaterally in the hippocampus, nucleus accumbens, and prefrontal cortex. We extract LFP features for band power and peak frequency and predict behavior across animals and conditions with a Poisson Generalized Linear Model (GLM). We use data from both male and female rats performing either fixed-ratio (FR40) or progressive (PROG) operant lever-pressing tasks, under vehicle (VEH) or tetrabenazine (TBZ), a vesicular monoamine transport (VMAT-2) inhibitor that depletes dopamine and induces depressive-like motivation dysfunction. We find that we can accurately predict lever pressing from multi-region LFP within-animals on a timescale of seconds with >30% variance explained. Although within-animal and within-condition predictions are highest, we also find, interestingly, that these decoders generalize across animals and across drug, sex, and task conditions, suggesting a stable association between LFP and behavior. We then evaluate whether LFP features can be used to decode long-term task variables, such as the number of presses since or until the next reinforcer. We find that LFP features can predict these long-term task variables, but that decoding relies on different LFP features for prediction than those used for immediate lever pressing. Altogether these results suggest that there are robust distributed patterns of LFP associated with lever-pressing behavior under multiple drug, task, and sex conditions.

neuroscience↗

bioRxiv2026

Disrupted Mitochondrial Copper Homeostasis Promotes Ferroptotic Stress, Senescence and MASLD Progression

Background & AimsSystemic metabolic dysfunction promotes degenerative diseases in many organs, including liver and kidney. The liver is a master regulator of systemic metal ion homeostasis. Hepatic copper deficiency is increasingly observed in metabolic dysfunction associated steatotic liver disease (MASLD) and is associated with greater disease severity and poor outcomes. However, mechanisms linking copper dysregulation to MASLD and its co-morbidities remain poorly defined. We investigated whether impaired mitochondrial copper homeostasis contributes to MASLD-related pathobiology and represents a modifiable therapeutic axis. Methods & ResultsUsing dietary mouse models of MASLD and in vitro systems, we found that dietary copper deficiency induces lipotoxicity and suppresses mitochondrial metabolic programs. MASLD livers exhibited marked depletion of copper, impaired cytochrome c oxidase integrity, and bioenergetic failure. Targeted restoration of mitochondrial copper with the copper ionophore elesclomol normalized copper-handling programs, improved mitochondrial function, and suppressed ferroptotic stress, hepatocyte senescence, and fibroinflammatory remodeling. Mechanistically, reduced expression of the mitochondrial copper transporter SLC25A3 and MT-CO1 disrupted the SLC25A3-SCO1-MT-CO1-CTR1 axis, limited copper uptake and destabilized copper-iron balance, promoting maladaptive cell fate changes. Across multiple human cohorts and mouse models, copper-iron imbalance tracks with MASLD progression, clinical outcomes, and multiple extrahepatic comorbidities; restoring copper homeostasis in mice with MASLD attenuates both liver and kidney inflammation and fibrosis. ConclusionsMitochondrial copper deficiency is a mechanistically actionable driver of MASLD that promotes bioenergetic failure, ferroptosis, senescence and fibroinflammatory damage in the liver and other organs. Targeting copper-centered mitochondrial regulation represents a novel biomarker and therapeutic strategy for MASLD and its systemic complications.

pathology↗

bioRxiv2026

Tracking long-term natural changes in hippocampal excitatory to inhibitory synapses from spikes

Although long-term synaptic plasticity is often studied using controlled electrical or optogenetic stimulation, it also occurs spontaneously during natural, ongoing brain activity. Here, using large-scale spike recordings in mice from the Allen Institute Visual Coding Neuropixels dataset, we examine to what extent fluctuations in putative synaptic efficacy can be tracked and explained by models of activity-dependent long-term plasticity. We first detect putative excitatory synaptic connections within the hippocampus based on cross-correlations between the spike trains of thousands of pairs of neurons. Most of these putative connections are between presynaptic neurons with broad spike waveforms and postsynaptic neurons with narrow spike waveforms and are consistent with synapses from excitatory to inhibitory units. For the subset of pairs where a transient, excitatory effect was detected, we use a model-based approach to track fluctuations in synaptic efficacy. Previous work found that these fluctuations can be partially predicted from pre- and postsynaptic firing rates and models of short-term plasticity. Here we model naturally occurring long-term potentiation and depression using rate-based learning rules. We find that modeling the covariance of pre- and postsynaptic activity improves prediction of efficacy fluctuations. We also examine synaptic changes associated with hippocampal sharp-wave ripples, but do not find clear evidence of systematic SWR-associated changes for the putative synapses studied here.

neuroscience↗

bioRxiv2023

The Synaptic Architecture of Layer 5 Thick Tufted Excitatory Neurons in the Visual Cortex of Mice

The neocortex is one of the most critical structures that makes us human, and it is involved in a variety of cognitive functions from perception to sensory integration and motor control. Composed of repeated modules, or microcircuits, the neocortex relies on distinct cell types as its fundamental building blocks. Despite significant progress in characterizing these cell types 1-5, an understanding of the complete synaptic partners associated with individual excitatory cell types remain elusive. Here, we investigate the connectivity of arguably the most well recognized and studied excitatory neuron in the neocortex: the thick tufted layer 5 pyramidal cell 6-10 also known as extra telencephalic (ET) 11 neurons. Although the synaptic interactions of ET neurons have been extensively explored, a comprehensive characterization of their local connectivity remains lacking. To address this knowledge gap, we leveraged a 1 mm3 electron microscopic (EM) dataset. We found that ET neurons primarily establish connections with inhibitory cells in their immediate vicinity. However, when they extend their axons to other cortical regions, they tend to connect more with excitatory cells. We also find that the inhibitory cells targeted by ET neurons are a specific group of cell types, and they preferentially inhibit ET cells. Finally, we observed that the most common excitatory targets of ET neurons are layer 5 IT neurons and layer 6 pyramidal cells, whereas synapses with other ET neurons are not as common. These findings challenge current views of the connectivity of ET neurons and suggest a circuit design that involves local competition among ET neurons and collaboration with other types of excitatory cells. Our results also highlight a specific circuit pattern where a subclass of excitatory cells forms a network with specific inhibitory cell types, offering a framework for exploring the connectivity of other types of excitatory cells.

neuroscience↗

bioRxiv2022

Predictable fluctuations in excitatory synaptic strength due to natural variation in presynaptic firing rate

Many controlled, in vitro studies have demonstrated how postsynaptic responses to presynaptic spikes are not constant but depend on short-term synaptic plasticity (STP) and the detailed timing of presynaptic spikes. However, the effects of short-term plasticity (depression and facilitation) are not limited to short, sub-second timescales. The effects of STP appear on long timescales as changes in presynaptic firing rates lead to changes in steady-state synaptic transmission. Here we examine the relationship between natural variations in the presynaptic firing rates and spike transmission in vivo. Using large-scale spike recordings in awake mice from the Allen Institute Neuropixels dataset, we first detect putative excitatory synaptic connections based on cross-correlations between the spike trains of millions of pairs of neurons. For the subset of pairs where a transient, excitatory effect was detected, we use a model-based approach to track fluctuations in synaptic efficacy and find that efficacy varies substantially on slow ([~]1 minute) timescales over the course of these recordings. For many connections, the efficacy fluctuations are correlated with fluctuations in the presynaptic firing rate. To understand the potential mechanisms underlying this relationship, we then model the detailed probability of postsynaptic spiking on a millisecond timescale, including both slow changes in postsynaptic excitability and monosynaptic inputs with short-term plasticity. The detailed model reproduces the slow efficacy fluctuations observed with many putative excitatory connections, suggesting that these fluctuations can be both directly predicted based on the time-varying presynaptic firing rate and, at least partly, explained by the cumulative effects of STP.

neuroscience↗

bioRxiv2022

Efficient rescue of a newly classified Ebinur lake orthobunyavirus with GFP reporter and its application in rapid antiviral screening

Orthobunyaviruses have been reported to cause severe diseases in humans or animals, posing a threat to human health and social economy. Ebinur lake virus (EBIV) is a newly classified orthobunyavirus, which needs further intensive study and therapies to cope with its potential infection risk to human and animals. Here, through the reverse genetics system, the recombinant EBIV of wild type (rEBIV/WT) and NP-conjugated-eGFP (rEBIV/eGFP/S) were rescued for the application of the rapid antiviral drug screening. The eGFP fluorescence signal of the rEBIV/eGFP/S was stable in the process of successive passage in BHK-21 cells (over 10 passages) and this recombinant virus could replicate in various cell lines. Compared to the wild type EBIV, the rEBIV/eGFP/S caused the smaller plaques and its peak titers were lower, suggesting attenuation due to the eGFP insertion. Through the high-content screening (HCS) system, ribavirin showed an inhibitory effect on the rEBIV/eGFP/S with an EC50 of 21.91 M, while favipiravir did not inhibit, even at high concentrations. In addition, five of ninety-six natural compounds had antiviral against EBIV. The robust reverse genetics system for EBIV will facilitate investigation into replication and assembly mechanisms and assist drug and vaccine development.

molecular biology↗

bioRxiv2021

Dynamic surveillance of mosquitoes and their viromes in Wuhan during 2020.

Mosquitoes are medically important arthropod vectors and harbor a great variety of viruses. The population density, species and virome of mosquitoes varies according to geography and climate. To investigate the dynamic changes in the species composition and diversity of mosquitoes and their viromes in Wuhan, China, a total of 2,345 adult mosquitoes collected from different habitats including an urban residential area, two hospitals, a scenic area, and a pig farm in a rural region from April to October 2020 were subjected to morphological identification, RT-qPCR and metagenomic sequencing. The results indicated that the dominant presence of Culex mosquitoes was observed in both urban regions (90.32%, 1538/1703) and the pig farm (54.98%, 353/642). Viromes of Culex showed dynamic changes during the collection time. Several viruses, such as Culex flavivirus, Alphamesonivirus 1, Hubei mosquito virus 2 and Hubei mosquito virus 4, had seasonal changes and unimodal increases or declines. Other viruses, such as Wuhan mosquito virus 6, Hubei virga-like virus 2 and Zhejiang mosquito virus 3, were stable in all collected Culex and should be potential members of "core viromes". This study improves the understanding of the dynamic composition of mosquitoes and the viromes they carry and provides useful information for informing mosquito control and mosquito-borne disease prevention strategies.

microbiology↗

bioRxiv2021

A dinucleotide tag-based parallel reporter gene assay method

The causal SNPs leading to increased cancer predisposition mainly function as gene regulatory elements, the evaluation of which largely rely on the parallel reporter gene assay system. However, the common DNA barcode-based parallel reporter gene assay systems are troubled with tag bias, mainly due to the tag nucleotide composition. Here we describe a versatile dinucleotide-tag reporter system (DiR) that enables parallel analysis of regulatory elements with minimized bias based on the next-generation sequencing. The DiR system is also more robust than the classical luciferase assay method, especially in the investigation of moderate-level regulatory elements. We applied DiR-seq assay in the functional evaluation of the prostate cancer risk SNPs in prostate cancer cell lines and disclosed 2, and 6 regulatory SNPs in PC-3 and LNCaP cells. The DiR system has great potential to advance the functional study of risk SNPs that have associations with polygenic diseases.

molecular biology↗

bioRxiv2020

Characterization of LC-MS based urine metabolomics in healthy subjects across the life span

Previous studies reported that gender and age could influence urine metabolomics, which should be considered in biomarker discovery. As a consequence, for the baseline of urine metabolomics characteristics, it becomes critical to avoid confounding effects in clinical cohort studies. In this study, we provided a comprehensive lifespan characterization of urine metabolomics in a cohort of 348 healthy children and 315 adults aged 1 to 70 years using liquid chromatography coupled with high resolution mass spectrometry. Our results suggested that gender-dependent urine metabolites are much greater in adults than in children. The pantothenate and CoA biosynthesis and alanine metabolism pathways were enriched in early life. Androgen and estrogen metabolism showed high activity during adolescence and youth stages. Pyrimidine metabolism was enriched in the old stage. Based on the above analysis, metabolomic characteristics of each age stage were provided. This work could help us understand the baseline of urine metabolism characteristics and contribute to further studies of clinical disease biomarker discovery.

biochemistry↗

bioRxiv2020

Model-based detection of putative synaptic connections from spike recordings with latency and type constraints

Detecting synaptic connections using large-scale extracellular spike recordings presents a statistical challenge. While previous methods often treat the detection of each putative connection as a separate hypothesis test, here we develop a modeling approach that infers synaptic connections while incorporating circuit properties learned from the whole network. We use an extension of the Generalized Linear Model framework to describe the cross-correlograms between pairs of neurons and separate correlograms into two parts: a slowly varying effect due to background fluctuations and a fast, transient effect due to the synapse. We then use the observations from all putative connections in the recording to estimate two network properties: the presynaptic neuron type (excitatory or inhibitory) and the relationship between synaptic latency and distance between neurons. Constraining the presynaptic neurons type, synaptic latencies, and time constants improves synapse detection. In data from simulated networks, this model outperforms two previously developed synapse detection methods, especially on the weak connections. We also apply our model to in vitro multielectrode array recordings from mouse somatosensory cortex. Here our model automatically recovers plausible connections from hundreds of neurons, and the properties of the putative connections are largely consistent with previous research. New & NoteworthyDetecting synaptic connections using large-scale extracellular spike recordings is a difficult statistical problem. Here we develop an extension of a Generalized Linear Model that explicitly separates fast synaptic effects and slow background fluctuations in cross-correlograms between pairs of neurons while incorporating circuit properties learned from the whole network. This model outperforms two previously developed synapse detection methods in the simulated networks, and recovers plausible connections from hundreds of neurons in in vitro multielectrode array data.

neuroscience↗

bioRxiv2019

Trophoblast proliferation, migration, and invasion is regulated by the miR-195/EGFR signaling pathway in recurrent spontaneous abortion patients

OBJECTIVETo investigate the effect of the miR-195/EGFR signaling pathway on trophoblasts in patients with recurrent spontaneous abortion, thus providing a clinical basis for the diagnosis and treatment of recurrent spontaneous abortion.\n\nMETHODSRT-qPCR, western blot, flow cytometry, CCK8, cell scratch assay, transwell, and a dual Luciferase reporter assay were used to detect changes in the miR-195/EGFR signaling pathways in clinical samples and in vitro cultured cells and to explore how these changes affect trophoblasts in affected patients.\n\nRESULTSExpression of miR-195 was elevated in villus tissues of patients with recurrent spontaneous abortion, while the expression levels of EGFR and its downstream genes p38 and AKT phosphorylation were down-regulated. In vitro cultured cell experiments showed that miR-195 inhibited the proliferation, migration, and invasion of trophoblast cells. EGFR is a target gene of miR-195, and miR-195 suppresses the expression of EGFR.\n\nConclusionThe miR-195/EGFR signaling pathway regulates the proliferation, migration, and invasion of trophoblast cells, thus playing an important role in recurrent spontaneous abortion.

cell biology↗

bioRxiv2018

Functional connectivity with short-term dynamics explains diverse patterns of excitatory spike transmission in vivo

Information transmission in neural networks is influenced by both short-term synaptic plasticity (STP) as well as non-synaptic factors, such as after-hyperpolarization currents and changes in excitability. Although these effects have been widely characterized in vitro using intracellular recordings, how they interact in vivo is unclear. Here we develop a statistical model of the short-term dynamics of spike transmission that aims to disentangle the contributions of synaptic and non-synaptic effects based only on observed pre- and postsynaptic spiking. The model includes a dynamic functional connection with short-term plasticity as well as effects due to the recent history of postsynaptic spiking and slow changes in postsynaptic excitability. Using paired spike recordings, we find that the model accurately describes the short-term dynamics of in vivo spike transmission at a diverse set of identified and putative excitatory synapses, including a thalamothalamic connection in mouse, a thalamocortical connection in a female rabbit, and an auditory brainstem synapse in a female gerbil. We illustrate the utility of this modeling approach by showing how the spike transmission patterns captured by the model may be sufficient to account for stimulus-dependent differences in spike transmission in the auditory brainstem (endbulb of Held). Finally, we apply this model to large-scale multi-electrode recordings to illustrate how such an approach has the potential to reveal cell-type specific differences in spike transmission in vivo. Although short-term synaptic plasticity parameters estimated from ongoing pre- and postsynaptic spiking are highly uncertain, our results are partially consistent with previous intracellular observations in these synapses. Significance StatementAlthough synaptic dynamics have been extensively studied and modeled using intracellular recordings of post-synaptic currents and potentials, inferring synaptic effects from extracellular spiking is challenging. Whether or not a synaptic current contributes to postsynaptic spiking depends not only on the amplitude of the current, but also on many other factors, including the activity of other, typically unobserved, synapses, the overall excitability of the postsynaptic neuron, and how recently the postsynaptic neuron has spiked. Here we developed a model that, using only observations of pre- and postsynaptic spiking, aims to describe the dynamics of in vivo spike transmission by modeling both short-term synaptic plasticity and non-synaptic effects. This approach may provide a novel description of fast, structured changes in spike transmission.

neuroscience↗