Biology subjects

Sorek, M.

Publications and source records attributed to Sorek, M..

11 recordsLinked to original sources

bioRxiv2026

Uncovering Sex Differences in the Drosophila Ventral Nerve Cord Through Connectome Alignment

There are now multiple Drosophila connectomes available, comprising both its brain and spinal cord - comparing these connectomes requires first classifying neurons into cell types. Existing approaches for cell typing typically require extensive manual curation. Here we present a new method that automatically aligns connectomes via network topology alone. Using two complete male ventral nerve cord (VNC) connectomes as references, we assign cell types to [~]13,000 neurons intrinsic to the female VNC, and automatically identify sex-specific and sexually dimorphic cell types. We not only provide a comprehensive census of cell types across male and female nerve cords, but we uncover connectivity differences that underlie differences in function. We focus on circuits underlying song production in males and oviposition behaviors in females, and investigate the counterparts of these circuits across sexes. Our automated methods and analyses provide insights into sex differences in circuits that connect the brain and body, and pave the way for comparative connectomics at scale.

neuroscience↗

bioRxiv2026

Eyewire II - A connectomic resource for resolving cell types and circuits of the mouse retina

Comprehensive wiring diagrams from electron microscopy (EM) are a powerful tool to understand the inner workings of the brain. The retina is an easily accessible part of the brain that performs complex visual computations. Its thin, layered structure offers a unique opportunity to decipher neural cell types and map their connectivity. A major obstacle has been the limited size of existing retinal EM datasets, which could not resolve rare cell types and neurons with large dendritic arbors. Here, we describe Eyewire II, a large-scale EM dataset covering nearly 1 mm2 of the adult mouse retina - roughly 10-100 times larger than previous retinal EM volumes. Human proofreading of an automated reconstruction has so far yielded more than 8, 000 bipolar cells, 13, 000 amacrine cells, and 4, 000 retinal ganglion cells. Automated detection is complete for synaptic ribbons and in progress for conventional synapses. Prior to EM imaging, visual responses to diverse stimuli - including natural movies - were recorded in a subset of neurons using two-photon Ca2+ imaging, enabling direct alignment of morphological and functional cell type identity. To enable high-throughput, automatic cell typing, we devised a human-in-the-loop approach that combines deep learning with human expert annotations. As a proof-of-principle, we show that morphological features of reconstructed bipolar cells are sufficient to recover all 15 known bipolar cell types with regular, non-overlapping mosaics. Together, these data and tools establish Eyewire II as a shared resource for the field of retina research. Already now, more than 30 laboratories worldwide are contributing proofreading, expert annotations, and software tools, advancing Eyewire II towards a complete cell type catalog and synaptic wiring diagram of a mammalian retina.

neuroscience↗

bioRxiv2025

Distributed control circuits across a brain-and-cord connectome

Just as genomes revolutionized molecular genetics, connectomes (maps of neurons and synapses) are transforming neuroscience. To date, the only species with complete connectomes are worms1-3 and sea squirts4 (103-104 synapses). By contrast, the fruit fly is more complex (108 synaptic connections), with a brain that supports learning and spatial memory5,6 and an intricate ventral nerve cord analogous to the vertebrate spinal cord7-11. Here we report the first densely reconstructed adult fly connectome that unites the brain and ventral nerve cord, and we leverage this resource to investigate principles of neural control. We show that effector neurons (motor neurons, endocrine cells and efferent neurons targeting the viscera) are primarily influenced by sensory neurons in the same body part, forming local feedback loops. These local loops are linked by long-range circuits involving ascending and descending neurons organized into behavior-centric modules. Single ascending and descending neurons are often positioned to influence the voluntary movements of multiple body parts, together with the endocrine cells or visceral organs that support those movements. Brain regions involved in learning and navigation supervise these circuits. These results reveal an architecture that is distributed, parallelized and embodied, reminiscent of distributed control architectures in engineered systems12,13.

neuroscience↗

bioRxiv2025

Connectomic reconstruction from hippocampal CA3 reveals spatially graded mossy fiber inputs and selective feedforward inhibition to pyramidal cells

The mossy fiber (MF) connections to pyramidal cells in hippocampal CA3 are hypothesized to participate in pattern separation and memory encoding, yet no large-scale neuronal wiring diagram exists for these connections. We assembled a 3D electron microscopy volume ([~]1x1x0.1mm3) from mouse hippocampal CA3. By proofreading and automated segmentation, we reconstructed and classified all soma-containing neurons--including 1,815 pyramidal cells and 229 inhibitory cells--and over 55,000 MFs. Pyramidal cells receive more numerous MF inputs along a proximodistal gradient. Some distal cells show surprisingly high convergence via relatively small terminals with fewer vesicles. Pyramidal cells share significantly more MF inputs than networks randomized by degree-preserving swap, and are better approximated by networks randomized by proximity-preserving swap. We identify a feedforward inhibitory circuit from MFs via perisomatic interneurons that selectively target a pyramidal subtype. We demonstrated large-scale mapping across levels in the hippocampus--from circuits to cell types to vesicles. The dataset is shared through Pyr, an online platform for hippocampal connectomics.

neuroscience↗

bioRxiv2024

Neuropeptides specify and reprogram division of labor in the leafcutter ant Atta cephalotes

Social insects offer powerful models to investigate the mechanistic foundation of elaborate individual behaviors comprising a cooperative community. Workers of the leafcutter ant genus Atta provide an extreme example of behavioral segregation among many phenotypically distinct worker types. We utilize the complex worker system of Atta cephalotes to test the molecular underpinnings of behavioral programming and, in particular, the extent of plasticity to reprogramming. We identify specific neuropeptides as mediators of worker division of labor in A. cephalotes, finding two neuropeptides associated with characteristic behaviors of leafcutting and of brood care. Manipulation via genetic knockdown or by injection of these neuropeptides led to stark loss or gain of each behavior and to transcriptomic shifts in the predicted direction, that is, towards gene pathways expressed in the natural caste. We also compare specific A. cephalotes worker transcriptomes with those of orthologous workers of the eusocial mammal, the naked mole rat H. gaber, revealing global similarities between caste-biased expression and link to specific roles of our studied neuropeptides in ants. This work underscores the essential function of neuropeptides in establishing complex social behavior and a remarkable plasticity among individual behavioral types.

molecular biology↗

bioRxiv2023

Neuronal "parts list" and wiring diagram for a visual system

A catalog of neuronal cell types has often been called a "parts list" of the brain, and regarded as a prerequisite for understanding brain function. In the optic lobe of Drosophila, rules of connectivity between cell types have already proven essential for understanding fly vision. Here we analyze the fly connectome to complete the list of cell types intrinsic to the optic lobe, as well as the rules governing their connectivity. We more than double the list of known types. Most new cell types contain between 10 and 100 cells, and integrate information over medium distances in the visual field. Some existing type families (Tm, Li, and LPi) at least double in number of types. We introduce a new Sm interneuron family, which contains more types than any other, and three new families of cross-neuropil types. Self-consistency of cell types is demonstrated through automatic assignment of cells to types by distance in high-dimensional feature space, and further validation is provided by algorithms that select small subsets of discriminative features. Cell types with similar connectivity patterns divide into clusters that are interpretable in terms of motion, object, and color vision. Our work showcases the advantages of connectomic cell typing: complete and unbiased sampling, a rich array of features based on connectivity, and reduction of the connectome to a drastically simpler wiring diagram of cell types, with immediate relevance for brain function and development.

neuroscience↗

bioRxiv2023

Neuronal wiring diagram of an adult brain

Connections between neurons can be mapped by acquiring and analyzing electron microscopic (EM) brain images. In recent years, this approach has been applied to chunks of brains to reconstruct local connectivity maps that are highly informative, yet inadequate for understanding brain function more globally. Here, we present the first neuronal wiring diagram of a whole adult brain, containing 5x107 chemical synapses between [~]130,000 neurons reconstructed from a female Drosophila melanogaster. The resource also incorporates annotations of cell classes and types, nerves, hemilineages, and predictions of neurotransmitter identities. Data products are available by download, programmatic access, and interactive browsing and made interoperable with other fly data resources. We show how to derive a projectome, a map of projections between regions, from the connectome. We demonstrate the tracing of synaptic pathways and the analysis of information flow from inputs (sensory and ascending neurons) to outputs (motor, endocrine, and descending neurons), across both hemispheres, and between the central brain and the optic lobes. Tracing from a subset of photoreceptors all the way to descending motor pathways illustrates how structure can uncover putative circuit mechanisms underlying sensorimotor behaviors. The technologies and open ecosystem of the FlyWire Consortium set the stage for future large-scale connectome projects in other species.

neuroscience↗

bioRxiv2022

Special Nuclear Layer Contacts Among Starburst Amacrine Cells in the Mouse Retina

We observed novel classes of cell-cell contacts between retinal starburst amacrine neurons, from finely detailed morphological reconstructions of cells from an electron microscopic image volume of a mouse retina. These contacts have peculiar morphological patterns and traits, different among the respective On and Off starburst amacrine subpopulations, but both occur within the soma layers as opposed to their regular laminae of contact within the inner plexiform layer.

neuroscience↗

bioRxiv2021

Transposable elements as sensors of SARS-CoV-2 infection

Transposable element (TE) transcription is induced in response to viral infections. TE induction triggers a robust and durable interferon (IFN) response, providing a host defense mechanism. Still, the connection between SARS-CoV-2 IFN response and TEs remains largely unknown. Here, we analyzed TE expression changes in response to SARS-CoV-2 infection in different human cellular models. We find that compared to other viruses, which cause global upregulation of TEs, SARS-CoV-2 infection results in a significantly milder TE response in both primary lung epithelial cells and in iPSC-derived lung alveolar type 2 cells. TE activation precedes, and correlates with, the induction of IFN-related genes, suggesting that the limited activation of TEs following SARS-CoV-2 infection may be the reason for the weak IFN response. Diminished TE activation was not observed in lung cancer cell lines with very high viral load. Moreover, we identify two variables which explain most of the observed diverseness in immune responses: basal expression levels of TEs in the pre-infected cells, and the viral load. Finally, analyzing the SARS-CoV-2 interactome, as well as the epigenetic landscape around the TEs that are activated following infection, we identify SARS-CoV-2 interacting proteins, which may regulate chromatin structure and TE transcription in response to a high viral load. This work provides a functional explanation for SARS-CoV-2s success in its fight against the host immune system, and suggests that TEs could be used as sensors and serve as potential drug targets for COVID-19. Key points O_LIUnlike other viruses, SARS-CoV-2 invokes a weak and inefficient transposable element (TE) response C_LIO_LITE induction precedes and predicts IFN response C_LIO_LIBasal TE expression and viral load explain immune responses C_LIO_LIDistinct chromatin and enhancer binding factors occupancy on TEs induced by SARS-CoV-2 C_LI

bioinformatics↗

bioRxiv2020

Pluripotent stem cell derived models of neurological diseases reveal early transcriptional heterogeneity

BackgroundMany neurodegenerative diseases (NDs) develop only later in life, when cells in the nervous system lose their structure or function. In genetic forms of NDs, this late onset phenomenon remains largely unexplained. ResultsAnalyzing single cell RNA sequencing (scRNA-seq) from Alzheimers disease (AD) patients, we find increased transcriptional heterogeneity in AD excitatory neurons. We hypothesized that transcriptional heterogeneity precedes ND pathologies. To test this idea experimentally, we used juvenile forms (72Q; 180Q) of Huntingtons disease (HD) iPSCs, differentiated them into committed neuronal progenitors, and obtained single cell expression profiles. We show a global increase in gene expression variability in HD. Autophagy genes become more stable, while energy and actin-related genes become more variable in the mutant cells. Knocking-down several differentially-variable genes resulted in increased aggregate formation, a pathology associated with HD. We further validated the increased transcriptional heterogeneity in CHD8+/- cells, a model for autism spectrum disorder. ConclusionsOverall, our results suggest that although NDs develop over time, transcriptional regulation imbalance is present already at very early developmental stages. Therefore, an intervention aimed at this early phenotype may be of high diagnostic value.

molecular biology↗

bioRxiv2017

Structural and functional diversity of a dense sample of retinal ganglion cells

To aid understanding of retinal structure and function, we present as an online resource the dendritic arbors and visual responses of ganglion cells in a single patch of mouse retina. We divide the inner plexiform layer, which contains the dendritic arbors of ganglion cells, into four sublaminae defined by a purely anatomical principle of arbor segregation. The sublaminae serve as the starting point for a hierarchical clustering of our ganglion cells. We propose and apply a quantitative criterion for validating a cluster as a ganglion cell type: the aggregate neurite density of a type should be approximately uniform (\"density conservation\"). Finally, we find that ganglion cells arborizing in the inner marginal sublamina of the inner plexi-form layer exhibit significantly more sustained visual responses on average.

neuroscience↗