Biology subjects

Behrens, C.

Publications and source records attributed to Behrens, C..

13 recordsLinked to original sources

bioRxiv2026

A single-cell transcriptomic atlas of paper wasp brains highlights Kenyon cells' role in social behavior

Social insects provide unique opportunities for studying social interactions, but the cellular and molecular mechanisms underlying these behaviors are poorly understood. Here, we performed single-cell sequencing to profile the transcriptomes of 96,310 cells across four phenotypes of Polistes fuscatus paper wasps: foundresses, workers, gynes, and males, to determine how social states and social interactions are encoded in the physiology of the central brain. We characterized the cellular diversity of the Polistes brain and demonstrate that a substantial portion of the brain is composed of diverse populations of Kenyon cell neurons. The composition and gene-expression profiles of these Kenyon cells, as well other neural and non-neural cell populations, vary across sex, caste, and season. We also demonstrate that social interactions, and even the mere observation of a social interaction, induce significant transcriptomic responses, including signatures of neural activation, across populations of Kenyon cell neurons. Notably, the transcriptional and activational signatures elicited by observing a social interaction frequently overlapped with those induced by direct social interaction, suggesting that a shared neural program underlies both direct social interactions and social observation.

genomics↗

bioRxiv2025

Strong but diffuse genetic divergence underlies differentiation in an incipient species of marine stickleback

Understanding how lineages proceed along the "speciation continuum" and how species boundaries are maintained over time remain central questions in evolutionary biology. Populations early in the speciation process can give us detailed insight into the reproductive barriers that first initiate speciation. In this study, we explore the nature of genomic divergence between two sympatric marine stickleback ecotypes from Atlantic Canada, "whites" and "commons". Males of each ecotype exhibit distinct nuptial colorations, nesting habits, and parental care strategies. Using population genomic analyses of SNPs and copy number variants (CNVs; deletions and duplications) we show that whites and commons consistently form distinct populations. We uncover genomic differentiation in the white ecotype characteristic of an incipient species, showing extremely low genome-wide differentiation (FST) and very recent divergence ([~]1 kya). Demographic analysis detected very low levels of ongoing gene flow between populations. Our results and prior genomic studies suggest that reproductive isolation is being maintained between ecotypes despite recent evidence that hybridization in nature does occur. Contrary to other systems, we found many small, but dispersed regions of high differentiation throughout the genome rather than explicitly within chromosomal inversions or the sex chromosomes. On chromosomes VII and XVI, we identified CNVs overlapping genes enriched for olfaction, which may play a role in differences in reproductive strategies between ecotypes. Ultimately, our results demonstrate that genome-wide rather than localized differences can underlie the early stages of divergence, and that this pattern is corroborated by both SNPs and CNVs.

evolutionary biology↗

bioRxiv2025

Discrete genetic modules underlie divergent reproductive strategies in three-spined stickleback

A central challenge in biology is to understand how complex behaviors evolve. Given their importance to fitness, complex behavioral traits often evolve as an integrated package, but it is unclear whether suites of traits evolve through a few pleiotropic genetic changes, each affecting many behaviors, or by accumulating several changes that, when combined, give rise to an entire package of correlated traits. Typically, three-spined stickleback exhibit paternal care, a behavior that characterizes the entire Gasterosteidae family. However, an unusual "white" three-spined stickleback ecotype exhibits a suite of traits associated with the evolutionary loss of paternal care. In the white ecotype, males disperse embryos from their nests rather than care for them, build loose nests, exhibit high rates of courtship, and are relatively small in body size. These behavioral differences are apparent in stickleback reared in a common garden environment, suggesting the differences have a heritable basis. In an F2 intercross, we show that these traits are genetically uncorrelated and map to different genomic regions, suggesting that components of the white reproductive strategy segregate independently and evolved through the addition of multiple genetic changes. These results contribute to the growing body of evidence that the behavioral diversity observed in nature may often evolve by accumulating and combining alleles, each with modular effects, and show that this principle applies to a suite of behavioral traits that together form an integrated and adaptive strategy.

evolutionary biology↗

bioRxiv2025

Evidence of parental care as a novel reproductive isolating mechanism

Variation in behavior can contribute to reproductive isolation by preventing gene flow among populations. Here, we tested the novel hypothesis that parental care, when dysregulated, can function as a reproductive isolating mechanism in three-spined stickleback fish (Gasterosteus aculeatus). In the typical "common" stickleback ecotype, males provide care to their offspring by fanning with their pectoral fins and defending their nest. In contrast, a divergent "white" stickleback ecotype has evolutionarily lost care and disperses embryos into the surrounding environment. We examined how paternal care from common, white, and F1 hybrid fathers influenced offspring survival. We detected no intrinsic incompatibilities in embryos, but F1 hybrid fathers exhibited dysregulated parental care that coincided with decreased survival of parented offspring. The increased offspring mortality may be explained by further dysregulation of feeding and parenting circuitry, as F2 hybrids exhibited significantly higher rates of post-fertilization filial cannibalism than common or white fathers. Additionally, despite strong divergence in nesting-building and courtship behavior, F1 hybrids achieved mating success at a similar rate as male commons and whites, suggesting that prezygotic barriers against hybrids may be weak. The observed postzygotic isolation, and potentially weak prezygotic isolation in lab-based studies, suggest that hybridization is likely occurring at low rates in the wild. Population genetic analysis supported this, as low proportions of putative hybrids were detected in sympatric sites. Together, these results may help explain why genetic divergence between these phenotypically distinct ecotypes is low and provide evidence that dysregulated parental behavior can act as a newly discovered postzygotic reproductive isolating barrier.

evolutionary biology↗

bioRxiv2022

A chromatic feature detector in the retina signals visual context changes

The retina transforms patterns of light into visual feature representations supporting behaviour. These representations are distributed across various types of retinal ganglion cells (RGCs), whose spatial and temporal tuning properties have been studied extensively in many model organisms, including the mouse. However, it has been difficult to link the potentially nonlinear retinal transformations of natural visual inputs to specific ethological purposes. Here, we discover a nonlinear selectivity to chromatic contrast in an RGC type that allows the detection of changes in visual context. We trained a convolutional neural network (CNN) model on large-scale functional recordings of RGC responses to natural mouse movies, and then used this model to search in silico for stimuli that maximally excite distinct types of RGCs. This procedure predicted centre colour-opponency in transient Suppressed-by-Contrast RGCs (tSbC), a cell type whose function is being debated. We confirmed experimentally that these cells indeed responded very selectively to Green-OFF, UV-ON contrasts. This type of chromatic contrast was characteristic of transitions from ground to sky in the visual scene, as might be elicited by heador eye-movements across the horizon. Because tSbC cells performed best among all RGC types at reliably detecting these transitions, we suggest a role for this RGC type in providing contextual information (i.e. sky or ground) necessary for the selection of appropriate behavioural responses to other stimuli, such as looming objects. Our work showcases how a combination of experiments with natural stimuli and computational modelling allows discovering novel types of stimulus selectivity and identifying their potential ethological relevance.

neuroscience↗

bioRxiv2021

Targeting de novo lipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer

Mutant KRAS (KM) is the most common oncogene in lung cancer (LC). KM regulates several metabolic networks, but their role in tumorigenesis is still not sufficiently characterized to be exploited in cancer therapy. To identify metabolic networks specifically deregulated in KMLC, we characterized the lipidome of genetically engineered LC mice, cell lines, patient derived xenografts and primary human samples. We also determined that KMLC, but not EGFR-mutant (EGFR-MUT) LC, is enriched in triacylglycerides (TAG) and phosphatidylcholines (PC). We also found that KM upregulates fatty acid synthase (FASN), a rate-limiting enzyme in fatty acid (FA) synthesis promoting the synthesis of palmitate and PC. We determined that FASN is specifically required for the viability of KMLC, but not of LC harboring EGFR-MUT or wild type KRAS. Functional experiments revealed that FASN inhibition leads to ferroptosis, a reactive oxygen species (ROS)-and iron-dependent cell death. Consistently, lipidomic analysis demonstrated that FASN inhibition in KMLC leads to accumulation of PC with polyunsaturated FA (PUFA) chains, which are the substrate of ferroptosis. Integrating lipidomic, transcriptome and functional analyses, we demonstrated that FASN provides saturated (SFA) and monounsaturated FA (MUFA) that feed the Lands cycle, the main process remodeling oxidized phospholipids (PL), such as PC. Accordingly, either inhibition of FASN or suppression of the Lands cycle enzymes PLA2 and LPCAT3, promotes the intracellular accumulation of lipid peroxides and ferroptosis in KMLC both in vitro and in vivo. Our work supports a model whereby the high oxidative stress caused by KM dictates a dependency on newly synthesized FA to repair oxidated phospholipids, establishing a targetable vulnerability. These results connect KM oncogenic signaling, FASN induction and ferroptosis, indicating that FASN inhibitors already in clinical trial in KMLC patients (NCT03808558) may be rapidly deployed as therapy for KMLC.

cancer biology↗

bioRxiv2021

The histologic phenotype of lung cancers may be driven by transcriptomic features rather than genomic characteristics

Histology plays an essential role in therapeutic decision-making for lung cancer patients. However, the molecular determinants of lung cancer histology are largely unknown. We conducted whole-exome sequencing(WES) and microarray profiling on 19 micro-dissected tumor regions of different histologic subtypes from 9 patients with lung cancers of mixed histology. A median of 68.9% of point mutations and 83% of copy number aberrations were shared between different histologic components within the same tumors. Furthermore, different histologic components within the tumors demonstrated similar subclonal architecture. On the other hand, transcriptomic profiling revealed shared pathways between the same histologic subtypes from different patients, which was supported by the analyses of the transcriptomic data from 141 cell lines and 343 lung cancers of different histologic subtypes. These data suggest that histology of lung cancers may be determined at the transcriptomic level rather than the genomic level.

genomics↗

bioRxiv2020

Resolving the spatial and cellular architecture of lung adenocarcinoma by multi-region single-cell sequencing

Little is known of the geospatial architecture of individual cell populations in lung adenocarcinoma (LUAD) evolution. Here, we perform single-cell RNA sequencing of 186,916 cells from 5 early-stage LUADs and 14 multi-region normal lung tissues of defined spatial proximities from the tumors. We show that cellular lineages, states, and transcriptomic features geospatially evolve across normal regions to LUADs. LUADs also exhibit pronounced intratumor cell heterogeneity within single sites and transcriptional lineage-plasticity programs. T regulatory cell phenotypes are increased in normal tissues with proximity to LUAD, in contrast to diminished signatures and fractions of cytotoxic CD8+ T cells, antigen-presenting macrophages and inflammatory dendritic cells. We further find that the LUAD ligand-receptor interactome harbors increased expression of epithelial CD24 which mediates pro-tumor phenotypes. These data provide a spatial atlas of LUAD evolution, and a resource for identification of targets for its treatment. Statement of significanceThe geospatial ecosystem of the peripheral lung and early-stage LUAD is not known. Our multi-region single-cell sequencing analyses unravel cell populations, states, and phenotypes in the spatial and ecological evolution of LUAD from the lung that comprise high-potential targets for early interception.

cancer biology↗

bioRxiv2020

Genomic and TCR Repertoire Intratumor Heterogeneity of Small-cell Lung Cancer and its Impact on Survival

Small-cell lung cancer (SCLC) is speculated to harbor complex genomic intratumor heterogeneity (ITH) associated with high recurrence rate and suboptimal response to immunotherapy. Here, we revealed a rather homogeneous mutational landscape but extremely suppressed and heterogeneous T cell receptor (TCR) repertoire in SCLCs. Higher mutational burden, lower chromosomal copy number aberration (CNA) burden, less CNA ITH and less TCR ITH were associated with longer overall survival of SCLC patients. Compared to non-small cell lung cancers (NSCLCs), SCLCs had similar predicted neoantigen burden and mutational ITH, but significantly more suppressed and heterogeneous TCR repertoire that may be associated with higher CNA burden and CNA ITH in SCLC. Novel therapeutic strategies targeting CNA could potentially improve the tumor immune microenvironment and response to immunotherapy in SCLC.

genomics↗

bioRxiv2020

Single-cell analysis of human lung epithelia reveals concomitant expression of the SARS-CoV-2 receptor ACE2 with multiple virus receptors and scavengers in alveolar type II cells

The novel coronavirus SARS-CoV-2 was identified as the causative agent of the ongoing pandemic COVID 19. COVID-19-associated deaths are mainly attributed to severe pneumonia and respiratory failure. Recent work demonstrated that SARS-CoV-2 binds to angiotensin converting enzyme 2 (ACE2) in the lung. To better understand ACE2 abundance and expression patterns in the lung we interrogated our in-house single-cell RNA-sequencing dataset containing 70,085 EPCAM+ lung epithelial cells from paired normal and lung adenocarcinoma tissues. Transcriptomic analysis revealed a diverse repertoire of airway lineages that included alveolar type I and II, bronchioalveolar, club/secretory, quiescent and proliferating basal, ciliated and malignant cells as well as rare populations such as ionocytes. While the fraction of lung epithelial cells expressing ACE2 was low (1.7% overall), alveolar type II (AT2, 2.2% ACE2+) cells exhibited highest levels of ACE2 expression among all cell subsets. Further analysis of the AT2 compartment (n = 27,235 cells) revealed a number of genes co-expressed with ACE2 that are important for lung pathobiology including those associated with chronic obstructive pulmonary disease (COPD; HHIP), pneumonia and infection (FGG and C4BPA) as well as malarial/bacterial (CD36) and viral (DMBT1) scavenging which, for the most part, were increased in smoker versus light or non-smoker cells. Notably, DMBT1 was highly expressed in AT2 cells relative to other lung epithelial subsets and its expression positively correlated with ACE2. We describe a population of ACE2-positive AT2 cells that co-express pathogen (including viral) receptors (e.g. DMBT1) with crucial roles in host defense thus comprising plausible phenotypic targets for treatment of COVID-19.

genomics↗

bioRxiv2020

Bayesian inference for biophysical neuron models enables stimulus optimization for retinal neuroprosthetics

Multicompartment models have long been used to study the biophysical mechanisms underlying neural information processing. However, it has been challenging to infer the parameters of such models from data. Here, we build on recent advances in Bayesian simulation-based inference to estimate the parameters of detailed models of retinal neurons whose anatomical structure was based on electron microscopy data. We demonstrate how parameters of a cone, an OFF- and an ON-cone bipolar cell model can be inferred from standard two-photon glutamate imaging with simple light stimuli. The inference method starts with a prior distribution informed by literature knowledge and yields a posterior distribution over parameters highlighting parameters consistent with the data. This posterior allows determining how well parameters are constrained by the data and to what extent changes in one parameter can be compensated for by changes in another. To demonstrate the potential of such data-driven mechanistic neuron models, we created a simulation environment for external electrical stimulation of the retina as used in retinal neuroprosthetic devices. We used the framework to optimize the stimulus waveform to selectively target OFF- and ON-cone bipolar cells, a current major problem of retinal neuroprothetics. Taken together, this study demonstrates how a data-driven Bayesian simulation-based inference approach can be used to estimate parameters of complex mechanistic models with high-throughput imaging data.

neuroscience↗

bioRxiv2019

Retinal horizontal cells use different synaptic sites for global feedforward and local feedback signaling

In the outer plexiform layer (OPL) of the mouse retina, two types of cone photoreceptors (cones) provide input to more than a dozen types of cone bipolar cells (CBCs). This transmission is modulated by a single horizontal cell (HC) type, the only interneuron in the outer retina. Horizontal cells form feedback synapses with cones and feedforward synapses with CBCs. However, the exact computational role of HCs is still debated. Along with performing global signaling within their laterally coupled network, HCs also provide local, cone-specific feedback. Specifically, it has not been clear which synaptic structures HCs use to provide local feedback to cones and global forward signaling to CBCs.\n\nHere, we reconstructed in a serial block-face electron microscopy volume the dendritic trees of five HCs as well as cone axon terminals and CBC dendrites to quantitatively analyze their connectivity. In addition to the fine HC dendritic tips invaginating cone axon terminals, we also identified \"bulbs\", short segments of increased dendritic diameter on the primary dendrites of HCs. These bulbs are located well below the cone axon terminal base and make contact to other cells mostly identified as other HCs or CBCs. Using immunolabeling we show that HC bulbs express vesicular gamma-aminobutyric acid transporters and co-localize with GABA receptor {gamma}2 subunits. Together, this suggests the existence of two synaptic strata in the mouse OPL, spatially separating cone-specific feedback and feedforward signaling to CBCs. A biophysics-based computational model of a HC dendritic branch supports the hypothesis that the spatial arrangement of synaptic contacts allows simultaneous local feedback and global feedforward signaling.

neuroscience↗

bioRxiv2019

The temporal structure of the inner retina at a single glance

The retina decomposes visual stimuli into parallel channels that encode different features of the visual environment. Central to this computation is the synaptic processing in a dense and thick layer of neuropil, the so-called inner plexiform layer (IPL). Here, different types of bipolar cells stratifying at distinct depths relay the excitatory feedforward drive from photoreceptors to amacrine and ganglion cells. Current experimental techniques for studying processing in the IPL do not allow imaging the entire IPL simultaneously in the intact tissue. Here, we extend a two-photon microscope with an electrically tunable lens allowing us to obtain optical vertical slices of the IPL, which provide a complete picture of the response diversity of bipolar cells at a \"single glance\". The nature of these axial recordings additionally allowed us to isolate and investigate batch effects, i.e. inter-experimental variations resulting in systematic differences in response speed. As a proof of principle, we developed a simple model that disentangles biological from experimental causes of variability, and allowed us to recover the characteristic gradient of response speeds across the IPL with higher precision than before. Our new framework will make it possible to study the computations performed in the central synaptic layer of the retina more efficiently.

neuroscience↗