Biology subjects

Lu, H.

Publications and source records attributed to Lu, H..

At least 289 records · Page 16Linked to original sources

bioRxiv2019

Angle-tuned Coil: A Focal Spot-size Adjustable Transcranial Magnetic Stimulator

BackgroundConventional transcranial magnetic stimulation (TMS) coils are limited by the depth-focality tradeoff rule and the emission field intensity from coils with either small or large apertures will diverge quickly at less than one aperture diameter distance away from the coil. To utilize a better depth-focality tradeoff rule and accomplish deep and focused stimulation, a new approach needs to be employed.\n\nObjectivesWe report a new TMS coil design that can deliver deep and spot size adjustable stimulation to deep brain regions.\n\nMethodsIn our design, we introduce a magnetic core at the center of a coil to help confine the magnetic field and prevent leakage. We further tilted the wire wrapping angle of the coil to break its ring symmetry and accomplish tunable focusing by adjusting the tilting angle.\n\nResultsBy comparing the electric field decay curves of five types of coils, our results concluded the proposed novel method to improve the coils depth-focality profile. Both theoretical calculations and experimental data collectively demonstrated that by using a larger tilting angle, we were able to accomplish a more tightly focused stimulation at any distance away from the coil.\n\nConclusionEnlarging the tilting angle of the coil wire wrapping and applying magnetic core significantly improved the spatial resolution of the field without inducing considerable effect on field decay speed. Our novel TMS coil design plots a new curve in the depth-focality profile with better performance than the existing conventional coil designs in the tradeoff rule.

bioengineering↗

bioRxiv2019

Mutational signatures in upper tract urothelial carcinoma define etiologically distinct subtypes with prognostic relevance

Parts of East Asia have a very high upper tract urothelial carcinoma (UTUC) prevalence, and an etiological link between the medicinal use of herbs containing aristolochic acid (AA) and UTUC has been established. The mutational signature of AA, which is characterized by a particular pattern of A:T to T:A transversions, can be detected by genome sequencing. Thus, integrating mutational signatures analysis with clinicopathological data may be a crucial step toward personalized treatment strategies for the disease. Therefore, we performed whole-genome sequencing (WGS) of 90 UTUC patients from China. Mutational signature analysis via nonnegative matrix factorization method defined three etiologically distinct subtypes with prognostic relevance: (i) AA, the typical AA mutational signature characterized by signature 22, had the highest tumor mutation burden, the best clinical outcomes; (ii) Age, an age-related group featured by signatures 1 and 5, had the lowest weighted genome instability index score, the worst clinical outcomes; and (iii) DSB, signature with deficiencies in DNA double strand break-repair featured by signatures 3, the intermediate clinical outcomes. Additionally, the distinct AA subtype was associated with AA exposure, the highest number of predicted neoantigens and heavier lymphocytes infiltrating. Thus, it may be good candidate for immune checkpoint blockade therapy. Notably, we showed AA-mutational signature was also identified in histologically \"normal\" urothelial cells. Thus, non-invasive urine test based on the AA-mutational signature could take advantage of this \"field effect\" to screen individuals at increased risk of recurrence due to exposure to herbal remedies containing the carcinogen AA. Collectively, the findings here may accelerate the development of novel prognostic markers and personalized therapeutic approaches for UTUC patients in China.

genomics↗

bioRxiv2019

Loss of SHMT2 mediates 5-FU chemoresistance by inducing autophagy in colorectal cancer

Serine hydroxymethyltransferase 2 (SHMT2) plays a vital role in one-carbon metabolism and drives colorectal carcinogenesis. In our study, loss of SHMT2 induced 5-Fluorouracil (5-FU) chemoresistance and was associated with poor prognosis in colorectal cancer (CRC). To elucidate the possible mechanism and generate a strategy to sensitize CRC to 5-FU chemotherapy, we first identified the binding proteins of SHMT2 in cancer cells by mass spectrometry. We found that SHMT2 inhibited autophagy through binding cytoplasmic p53. In fact, SHMT2 prevented cytoplasmic p53 degradation by inhibiting the binding of p53 and HDM2. Under treatment with 5-FU, depletion of SHMT2 promoted autophagy and inhibited apoptosis. Autophagy inhibitors CQ decreased low SHMT2-induced 5-FU resistance in vitro and in vivo. Finally, we enhanced the lethality of 5-FU treatment to CRC cells through the autophagy inhibitor or knockdown of SHMT2 in patient-derived and CRC cell xenograft models. Our findings identified the low SHMT2-induced autophagy on 5-FU resistance in CRC. These results reveal SHMT2-p53 as a novel cancer therapeutic target to reduce chemotherapeutic drug resistance.

cancer biology↗

bioRxiv2019

APOC2 accelerates colorectal cancer progression via modulating lipid metabolism and transcriptional activity of PHF8

The apolipoproteins (APOs) are the major proteins in blood lipid transportation. Emerging evidence has demonstrated that APOs might exert important function in tumor cells, but the underlying mechanism remains inclusive. In this study, we aim to explore the relationship between APOC2 dysfunction and colorectal cancer (CRC) malignancy. By analyzing the expression of APOC2 in 507 patients with CRC, we demonstrated that the APOC2 was overexpressed and associated with poor prognosis in CRC. We then found that high levels of APOC2 resulted in proliferation, invasion and metastasis of CRC cells in vitro and in vivo. Mechanistically, we revealed that APOC2 directly interacted with FASN which resulted in decreased levels of omega-3 fatty acids and increased levels of alpha-ketoglutarate (-KG). Both RNA-seq and ChIP-seq analysis revealed that APOC2 overexpression resulted accumulation of -KG leads to activation on the transcriptional program of PHF8 and thereby contributed to activation on genes involved in cell proliferation, invasion and metastasis. Together, our study unveiled the oncogenic role of APOC2 in tumor cells, which sheds new light on the potential of APOC2 as a biomarker in the prognosis of CRC.

cancer biology↗

bioRxiv2019

Mass Spectrometry based Metabolomics Deciphered Metabolic Reprogramming That Was Required for Biofilm formation in Uropathogenic Escherichia coli

Biofilm formation plays a key role in many bacteria causing infections, which mostly accounts for high-frequency infectious recurrence and antibiotics resistance. In this study, we sought to compare modified metabolism of biofilm and planktonic populations with UIT89, a predominant agent of urinary tract infection, by combining mass spectrometry based untargeted and targeted metabolomics methods, as well as cytological visualization, which enable us to identify the driven metabolites and associated metabolic pathways underlying biofilm formation. Surprisingly, our finding revealed distinct differences in both phenotypic morphology and metabolism between two patterns. Furthermore, we identified and characterized 38 differential metabolites and associated three metabolic pathways involving glycerolipid metabolism, amino acid metabolism and carbohydrate metabolism that were altered mostly during biofilm formation. This discovery in metabolic phenotyping permitted biofilm formation shall provide us a novel insight into the desperation of biofilm, which enable to develop novel biofilm based treatments against pathogen causing infections, with lower antibiotic resistance.

microbiology↗

bioRxiv2019

Phase separation of TAZ compartmentalizes the transcription machinery to promote gene expression

TAZ promotes cell proliferation, development, and tumorigenesis by regulating target gene transcription. However, how TAZ orchestrates the transcriptional responses remains poorly defined. Here we demonstrate that TAZ forms nuclear condensates via liquid-liquid phase separation to compartmentalize its DNA binding co-factor TEAD4, the transcription co-activators BRD4 and MED1 and the transcription elongation factor CDK9 for activation of gene expression. TAZ, but not its paralog YAP, forms phase-separated droplets in vitro and liquid-like nuclear condensates in vivo, and this ability is negatively regulated by Hippo signaling via LATS-mediated phosphorylation and mediated by the coiled-coil domain. Deletion of the TAZ coiled-coil domain or substitution with the YAP coiled-coil domain does not affect the interaction of TAZ with its partners, but prevents its phase separation and more importantly, its ability to induce target gene expression. Thus, our study identifies a novel mechanism for the transcriptional activation by TAZ and demonstrates for the first time that pathway-specific transcription factors also engage the phase separation mechanism for efficient transcription activation.

cell biology↗

bioRxiv2019

Chromosome level draft genomes of the fall armyworm, Spodoptera frugiperda (Lepidoptera: Noctuidae), an alien invasive pest in China

The fall armyworm (FAW), Spodoptera frugiperda (J.E. Smith) is a severely destructive pest native to the Americas, but has now become an alien invasive pest in China, and causes significant economic loss. Therefore, in order to make effective management strategies, it is highly essential to understand genomic architecture and its genetic background. In this study, we assembled two chromosome scale genomes of the fall armyworm, representing one male and one female individual procured from Yunnan province of China. The genome sizes were identified as 542.42 Mb with N50 of 14.16 Mb, and 530.77 Mb with N50 of 14.89 Mb for the male and female FAW, respectively. We predicted about 22,201 genes in the male genome. We found the expansion of cytochrome P450 and glutathione s-transferase gene families, which are functionally related to the intensified detoxification and pesticides tolerance. Further population analyses of corn strain (C strain) and rice strain (R strain) revealed that the Chinese fall armyworm was most likely invaded from Africa. These strain information, genome features and possible invasion source described in this study will be extremely important for making effective strategies to manage the fall armyworms.

genomics↗

bioRxiv2019

FALCONET: an R package to accelerate automatic visualisation of genome scale metabolic models

SummaryFALCONET (FAst visuaLisation of COmputational NETworks) enables the automatic for-mation and visualisation of metabolic maps from genome-scale models with R and CellDesigner, readily facilitating the visualisation of multi-layers omics datasets in the context of metabolic networks.\n\nMotivationUntil now, numerous GEMs have been reconstructed and used as scaffolds to conduct integrative omics analysis and in silico strain design. Due to the large network size of GEMs, it is challenging to produce and visualize these networks as metabolic maps for further in-depth analyses.\n\nResultsHere, we presented the R package - FALCONET, which facilitates drawing and visualizing metabolic maps in an automatic manner. This package will benefit the research community by allowing a wider use of GEMs in systems biology.\n\nAvailability and implementationFALCONET is available on https://github.com/SysBioChalmers/FALCONET and released under the MIT License.\n\nContactnielsenj@chalmers.se\n\nSupplementary informationSupplementary data are available online.

systems biology↗

bioRxiv2019

Down regulation of Hmgcr in response to Influenza A infection is independent of the IFN response in human cells

Previous studies have demonstrated that the product of the Interferon stimulated gene Ch25h, 25-Hydroxycholestrol, provides an immediate and rapid mechanism for down-regulating sterol biosynthesis, through the inhibition of Hmgcr gene expression and proteolytic degradation of HMGCR protein. Further studies provide evidence that inhibition of the sterol biosynthesis pathway by 25-HC has broad antiviral effects. In this study, Influenza A virus (IAV) replication was inhibited in cells treated with Fluvastatin or where Hmgcr expression was inhibited with an siRNA. Treatment of A549 cells with 25-HC however, resulted in a 2-fold enhancement of IAV replication despite the fact that 25-HC promotes the proteolytic degradation of HMGCR. A549 cells infected with IAV revealed a rapid loss of HMGCR protein, a reduction in Hmgcr gene expression as well as an increase in the expression of Ch25h, that were all independent of the IFN pathway. Infection of both wild-type and Ch25h-/- murine BMDMs with IAV also revealed a rapid loss of HMGCR abundance indicating that 25-HC independent mechanisms exist for promoting proteolytic degradation of HMGCR. These data for the human A549 cell line contrast with the induction of Ch25h and subsequent loss of HMGCR in murine cells that has been shown to be dependent on IFN signalling.\n\nImportanceCholesterol, a lipid, is mainly produced by the liver or obtained from everyday foods. It is an essential element of the structure of cells and is vital for maintaining the normal function of human body. In cells, cholesterol can be oxidised to oxysterols by biological catalysts, known as enzymes. Certain oxysterols have recently emerged as important elements in the immune response to micro-organisms. This project studied a key enzyme, which is a component of the cholesterol metabolism, known as 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). A set of experiments were designed and performed to study the behaviour of HMGCR following viral infections. This study lays the foundation for re-building a map of cholesterol metabolism and the immune response to viral infection. It will be useful for understanding the importance of cholesterol metabolism in infection and exploring novel antiviral strategies.

immunology↗

bioRxiv2019

UHPLC/MS based large-scale targeted metabolomics method for multiple-biological matrix assay

This new method has the capacity to dynamically analyse the metabolome of interest in diverse biological matrixes by offering coverage of rat urine, plasma, liver, brain, intestine, stomach, heart, spleen, lung, faeces, fresh plant tissues, cells and microbes. In addition, this new method enables specific and efficient analysis of microdontia metabolomes, non-microdontia and whole cell metabolomes, as well as can engage in absolute determination of 84 key clinical-wide metabolites in different biological matrixes, to enable the complementary support of clinical diagnosis and classification of diseases. To demonstrate the applicable capacity of this new method, multiple-matrixes differential metabolomes were firstly characterized using this new method to coordinate metabolic modifications underlie hepatitis induced by carbon tetrachloride (CCL4) in rats, such finding provides novel insight into the pathogenesis and therapeutics of hepatitis in clinic. Altogether, we are fully confident that this new metabolomics method will be widely welcomed by scientists in different niches to solve their key questions accordingly.

biochemistry↗

bioRxiv2019

Palmitoylation is critically required for cancer intrinsic PD-1 expression and functions

Programmed cell death protein 1 (PD-1) is a crucial anticancer target, but the relatively low response rate and acquired resistance to existing antibody drugs highlight an urgent need to develop alternative targeting strategies. Here we report the palmitoylation of PD-1, discovered the main DHHC enzyme for this modification, revealed the mechanism for its effect on PD-1 expression, and rationally developed a peptide for targeting PD-1 expression. Palmitoylation promoted the trafficking of PD-1 to recycling endosome, thus preventing its lysosome-dependent degradation. Palmitoylation was required for the activation of PD-1 downstream signaling, and targeting palmitoylation by pharmacological inhibitor or depleting the modification enzyme caused significant anti-tumor effects. A peptide was designed to competitively inhibit PD-1 palmitoylation and expression, opening a new route for developing PD-1 inhibitors as a strategy for cancer immunotherapy.\n\nSignificanceWe show for the first time that PD-1 is palmitoylated, identify DHHC9 as the predominant enzyme for its palmitoylation, and reveal the molecular mechanisms underlying its effects on PD-1 stability and functions. Importantly, we also designed a competitive inhibitor targeting PD-1 palmitoylation, and this first-in-class molecule may inspire the development of new checkpoint inhibitors.

cancer biology↗

bioRxiv2019

Neural and computational mechanisms of analogical reasoning

The ability to generate and process semantic relations is central to many aspects of human cognition. Theorists have long debated whether such relations are coded as atomistic links in a semantic network, or as distributed patterns over some core set of abstract relations. The form and content of the conceptual and neural representations of semantic relations remains to be empirically established. The present study combined computational modeling and neuroimaging to investigate the representation and comparison of abstract semantic relations in the brain. By using sequential presentation of verbal analogies, we decoupled the neural activity associated with encoding the representation of the first-order semantic relation between words in a pair from that associated with the second-order comparison of two relations. We tested alternative computational models of relational similarity in order to distinguish between rival accounts of how semantic relations are coded and compared in the brain. Analyses of neural similarity patterns supported the hypothesis that semantic relations are coded, in the parietal cortex, as distributed representations over a pool of abstract relations specified in a theory-based taxonomy. These representations, in turn, provide the immediate inputs to the process of analogical comparison, which draws on a broad frontoparietal network. This study sheds light not only on the form of relation representations but also on their specific content.\n\nSignificanceRelations provide basic building blocks for language and thought. For the past half century, cognitive scientists exploring human semantic memory have sought to identify the code for relations. In a neuroimaging paradigm, we tested alternative computational models of relation processing that predict patterns of neural similarity during distinct phases of analogical reasoning. The findings allowed us to draw inferences not only about the form of relation representations, but also about their specific content. The core of these distributed representations is based on a relatively small number of abstract relation types specified in a theory-based taxonomy. This study helps to resolve a longstanding debate concerning the nature of the conceptual and neural code for semantic relations in the mind and brain.

neuroscience↗

bioRxiv2019

Autistic traits lower the flexibility of information sampling: insights from a two-stage decision model

Information sampling can reduce uncertainty in future decisions but is often costly. To maximize reward, people need to balance sampling cost and information gain. Here we aimed to understand how autistic traits influence the optimality of information sampling and to identify the particularly affected cognitive processes. Healthy human adults with different levels of autistic traits performed a probabilistic inference task, where they could sequentially sample information to increase their likelihood of correct inference and may choose to stop at any moment. We manipulated the cost and evidence associated with each sample and compared participants performance to strategies that maximize expected gain. We found that participants were overall close to optimal but also showed autistic-trait-related differences. Participants with higher autistic traits had a higher efficiency of winning rewards when the sampling cost was zero but a lower efficiency when the cost was high and the evidence was more ambiguous.\n\nComputational modeling of participants sampling choices and decision times revealed a two-stage decision process, with the second stage being an optional second thought. Participants may consider cost in the first stage and evidence in the second stage, or in the reverse order. The probability of choosing stopping at a specific stage increases with increasing cost or increasing evidence. Surprisingly, autistic traits did not influence the decision in either stage. However, participants with higher autistic traits inclined to consider cost first, while those with lower autistic traits considered cost or evidence first in a more balanced way. This would lead to the observed autistic-trait-related advantages or disadvantages in sampling optimality, depending on whether the optimal sampling strategy is determined only by cost or jointly by cost and evidence.\n\nAuthor SummaryChildren with autism can spend hours practicing lining up toys or learning all about cars or lighthouses. This kind of behaviors, we think, may reflect suboptimal information sampling strategies, that is, a failure to balance the gain of information with the cost (time, energy, or money) of information sampling. We hypothesized that suboptimal information sampling is a general characteristic of people with autism or high level of autistic traits. In our experiment, we tested how participants may adjust their sampling strategies with the change of sampling cost and information gain in the environment. Though all participants were healthy young adults who had similar IQs, higher autistic traits were associated with higher or lower efficiency of winning rewards under different conditions. Counterintuitively, participants with different levels of autistic traits did not differ in the general tendency of oversampling or undersampling, or in the decision they would reach when a specific set of sampling cost or information gain was considered. Instead, participants with higher autistic traits consistently considered sampling cost first and only weighed information gain during a second thought, while those with lower autistic traits had more diverse sampling strategies that consequently better balanced sampling cost and information gain.

neuroscience↗

bioRxiv2019

Static and Dynamic Functional Connectivity Analysis of Cerebrovascular Reactivity: An fMRI Study

The human brain, as a finely-tuned system, needs a constant flow of oxygen to function properly. To accomplish this, the cerebrovascular system ensures a steady stream of oxygenation to brain cells. One tool that the cerebrovascular system uses is cerebrovascular reactivity (CVR), which is the systems ability to react to vasoactive stimuli. Understanding CVR can provide unique information about cerebrovascular diseases and general brain function. CVR can be evaluated by scanning subjects with blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) while they periodically inhale room air and CO2-enriched gas, a powerful and widely-used vasodilator. Our goal is to understand the effect of vasodilation on individual intrinsic connectivity networks (ICNs), as well as how functional network connectivity (FNC) adapts to the same vasodilation. To achieve this goal, we first developed an innovative metric to measure the effect of CVR on ICNs, which contrasts to the commonly used voxel-wise CVR. Furthermore, for the first time, we studied static (sFNC) and dynamic (dFNC) FNC in the context of CVR. Our results show that network connectivity is generally weaker during vascular dilation, and these results are more pronounced in dFNC analysis. dFNC analysis reveals that participants did not return to the pre-CO2 inhalation state, suggesting that the one-minute period of room-air inhalation is not enough for the CO2 effect to fully dissipate in humans. Overall, we see new relationships between CVR and ICNs, as well as how FNC adapts to vascular system changes.

neuroscience↗

bioRxiv2019

A beneficial genomic rearrangement creates multiple versions of calcipressin in C. elegans

Gene duplication is a major source of genetic novelty and evolutionary adaptation, providing a molecular substrate that can generate biological complexity and diversity (Ohno 1967, Taylor and Raes 2004). Despite an abundance of genomic evidence from extant organisms suggesting the importance of gene duplication, consensus about how they arise and functionally diversify is lacking (Innan and Kondrashov 2010). In the process of studying the adaptation of laboratory strains of C. elegans to new food sources, we identified a recombinant inbred line (RIL) with higher relative fitness and hyperactive exploration behavior compared to either parental strain. Using bulk-segregant analysis and short-read resequencing, we identified a de novo beneficial, complex rearrangement of the rcan-1 gene, which we resolved into five new unique tandem inversion/duplications using Oxford Nanopore long-read sequencing. rcan-1 encodes an ortholog to human RCAN1/DSCR1, which has been implicated as a causal gene for Down syndrome (Fuentes, Genesca et al. 2000). The genomic rearrangement in rcan-1 causes two complete and two truncated versions of the rcan-1 coding region, with a variety of modified promoter and 3 regions, which ultimately reduce whole-body gene expression. This rearrangement does not phenocopy a loss-of-function allele, which indicates that the rearrangement was necessary for the observed fitness gains. Our results demonstrate that adaptation can occur through unexpectedly complex genetic changes that can simultaneously duplicate and diversify a gene, providing the molecular substrate for future evolutionary change.

evolutionary biology↗

bioRxiv2019

Interaction Effects of Apolipoprotein E ε 4 and Cognitive Status on the Functional Connectivity within Default Mode Network in Individuals at Risk of Cognitive Impairments

BackgroundDisturbance of intrinsic brain networks is often associated with APOE{varepsilon} 4 allele and cognitive dysfunction. However, little is known about the functional connectivity strength (FCS) within default mode network (DMN).\n\nObjectiveWe aimed to examine the independent effects APOE{varepsilon} 4 and cognitive status and the interaction effect on the functional connectivity within DMN.\n\nMethodsResting-state functional MRI was conducted for sixty-five senior adults who had normal cognition or cognitive decline with or without APOE{varepsilon} 4. Regions within DMN include mPFC, IPL, LTC, hippocampus and PCC. The absolute values of correlation coefficient between DMN regions were employed as the measures of FCS for quantifying the functional connectivity.\n\nResultsMain effect of APOE{varepsilon} 4 was found on the FCS of bilateral PCC (F = 6.133, p = 0.016), while the main effect of cognitive status was found on the FCS of left IPL and right mPFC (F = 4.585, p = 0.036). Interaction effect was found in the FCS of right mPFC and left LTC (F = 4.698, p = 0.034), right hippocampus and left LTC (F = 7.673, p = 0.008), left PCC and left LTC (F = 6.719, p = 0.012), right IPL and right LTC (F = 4.516, p = 0.038).\n\nConclusionsAPOE{varepsilon} 4 carriers with cognitive impairment denote a preclinical status characterized by aberrant inter-hemispheric FC within DMN. The network-level connectivity may be useful in the evaluation of the individuals at risk for developing AD and affiliate network-guided brain stimulation.

neuroscience↗

bioRxiv2019

MAP7 recruits kinesin-1 to microtubules to direct organelle transport

Microtubule-associated proteins (MAPs) play well-characterized roles in regulating microtubule polymerization, dynamics, and organization. In addition, MAPs control trans-port along microtubules by regulating the motility of kinesin and dynein. MAP7 (ensconsin, E-MAP-115) is a ubiquitous MAP that organizes the microtubule cytoskeleton in mitosis and neuronal branching. MAP7 also promotes the interaction of kinesin-1 with microtubules. We expressed and purified full-length kinesin-1 and MAP7 in Sf9 cells. In single-molecule motiity assays, MAP7 recruits kinesin-1 to microtubules, increasing the frequency of both diffusive and processive runs. Optical trapping assays on beads transported by single and teams of kinesin-1 motors indicate that MAP7 increases the relative binding rate of kinesin-1 and the number of motors simultaneously engaged in ensembles. To examine the role of MAP7 in regulating bidirectional transport, we isolated late phagosomes along with their native set of kinesin-1, kinesin-2, and dynein motors. Bidirectional cargoes exhibit a clear shift towards plus-end directed motility on MAP7-decorated microtubules due to increased forces exerted by kinesin teams. Collectively, our results indicate that MAP7 enhances kinesin-1 recruitment to microtubules and targets organelle transport to the plus end.

biophysics↗

bioRxiv2019

A null model of the mouse whole-neocortex micro-connectome

1Connectomics, the study of the structure of networks of synaptically connected neurons, is one of the most important frontiers of neuroscience. Great advances are being made on the level of macro- and meso-scale connectomics, that is the study of how and which populations of neurons are wired together by tracing axons of anatomically and genetically defined neurons throughout the brain. Similarly, the use of electron-microscopy and statistical connectome models has improved our understanding of micro-connectomics, that is the study of connectivity patterns between individual neurons. We have combined these two complementary views of connectomics to build a first draft statistical model of the neuron-to-neuron micro-connectome of a whole mouse neocortex. We combined available data on region-to-region connectivity and individual whole-brain axon reconstructions to model in addition to the meso-scale trends also the innervation of individual neurons by individual axons, within and across regions. This process revealed a novel targeting principle that allowed us to predict the innervation logic of individual axons from meso-scale data. The resulting micro-connectome of 10 million neurons and 88 billion synapses recreates biological trends of targeting on the macro-meso- and micro-scale, i.e. targeting of brain regions, domains and layers within a brain region down to individual neurons. This openly accessible connectome can serve as a powerful null model to compare experimental findings to and as a substrate for whole-brain simulations of detailed neural networks.

neuroscience↗