Biology subjects

Nicholas, S.

Publications and source records attributed to Nicholas, S..

9 recordsLinked to original sources

bioRxiv2026

Parallel descending neurons differentially encode target and looming information in the hoverfly visual system

Detecting small, fast-moving objects is crucial for behaviors such as pursuit, territorial defence, and predator avoidance. At long range, however, potential mates, rivals, and predators produce remarkably similar visual signals, potentially making them difficult to distinguish. Nevertheless, many flying insects, including the hoverfly Eristalis tenax, can respond rapidly and appropriately to these ambiguous visual cues, implying specialised neural pathways that extract behaviorally relevant information. Descending neurons link visual processing to motor output, thus transforming visual signals into behavioral actions. In E. tenax, both target selective descending neurons (TSDNs) and looming-sensitive descending neurons respond to small targets, yet their respective contributions to target processing remain unclear. Using electrophysiological recordings, we compared receptive field organization and sensitivity to target size and motion direction across these neuronal populations. Although TSDNs and looming-sensitive descending neurons differed systematically in their target coding, a subset of looming-sensitive descending neurons closely resembled TSDNs, sharing small receptive fields and sharp target tuning despite retaining sensitivity to looming stimuli. These findings reveal previously unrecognized diversity among descending neurons tuned to small targets and suggest that parallel descending pathways encode distinct information from similar visual cues. Such an organization may enable common visual inputs to support both target pursuit and the detection of approaching threats.

neuroscience↗

bioRxiv2026

Hepatobiliary Progenitor-like Reprogramming in Liver Metastases

Metastatic progression requires cancer cells to adapt to the unique constraints of distant organ microenvironments, yet the mechanisms that drive organ-specific adaptations remain poorly understood. Here, we show that the liver actively rewrites metastatic cancer cell identity, driving tumor cells toward a hepatobiliary progenitor-like state. Through integrated transcriptomic, proteomic, metabolomic, and epigenomic analyses of patient-derived rapid-autopsy samples and experimental models, we identify this state as selectively enriched in liver metastases. It is characterized by co-activation of hepatic and biliary/progenitor regulators HNF4A and SOX9 and is observed across multiple epithelial cancers, indicating a conserved response to the hepatic niche. Mechanistically, hepatocyte-derived TGF-{beta} and hypoxia converge to activate a HIF-1-ACLY axis, increasing nuclear acetyl-coenzyme A availability and histone acetylation at hepatic lineage regulatory elements to drive hepatobiliary reprogramming. This coordinated niche-response program can be captured transcriptionally and is associated with inferior overall survival. Disruption of this pathway suppresses hepatic reprogramming and impairs liver metastatic fitness. These findings identify the liver as an active determinant of metastatic cell fate, linking microenvironmental signaling to metabolic and chromatin remodeling programs that enable lineage plasticity. More broadly, they reveal organ-specific reprogramming as a fundamental principle of metastasis and a therapeutic vulnerability in liver metastases.

cancer biology↗

bioRxiv2025

Sexual dimorphism in sensorimotor transformation of optic flow

Motion vision underpins a wide range of adaptive behaviours essential for individual and species survival. In hoverflies, some visual behaviours are sexually dimorphic, including for example male high-speed pursuit of conspecifics, matched by improved optics, and faster photoreceptors. Other visual behaviours are sexually monomorphic, with for example similar foraging flight speeds in male and female hoverflies. However, whether the descending neurons responsible for sensorimotor transformation of optic flow are sexually dimorphic is unknown. To address this, we combined morphological analysis with electrophysiology of optic flow sensitive descending neurons and compared neural responses to the behavioural output in tethered hoverflies. We found that while optomotor flight behaviour is largely sexually monomorphic, the underlying neural responses are sexually dimorphic, especially at higher optic flow velocities. Additionally, behavioural responses were noticeably slower than neural responses. Together, our findings uncover a nuanced, sex- and stimulus- dependant sensorimotor transformation, shaped by both neural architecture and behavioural demands.

neuroscience↗

bioRxiv2025

Conserved but mechanistically diverse piRNA defence against gypsy LTR retrotransposons in insect ovaries

Organisms have evolved highly adaptable defence systems to silence mobile genetic elements such as transposons. While individual transposons may emerge and vanish over time, the long-term evolutionary stability of the pathways that suppress them remains poorly understood. In the ovarian somatic cells of Drosophila, envelope-carrying gypsy long terminal repeat (LTR) retrotransposons are silenced by the Piwi-interacting RNA (piRNA) pathway, which depends exclusively on Piwi - an evolutionary derivative of an Aubergine/Piwi gene duplication unique to flies. Recent studies, however, have revealed that envelope-carrying gypsy elements are widespread across metazoans and particularly abundant in insect genomes, raising questions about the origin of ovarian somatic piRNA defence. Here we demonstrate that Aedes and Anopheles mosquitoes, as well as stingless bees and crickets, all produce piRNAs targeting gypsy elements in ovarian somatic cells, indicating a continuous arms race in this cellular niche for more than 400 million years of insect evolution. Notably, in Aedes aegypti, ovarian somatic cells express the same piRNA clusters as other somatic tissues, where they are known to target RNA viruses - suggesting a shared origin of anti-viral and anti-retrotransposon defences. Furthermore, we reveal striking lineage-specific differences in ovarian somatic piRNA biogenesis: slicing-independent phasing dominates in dipterans, ping-pong amplification in bees, and slicing-dependent phasing in crickets. Together, these findings indicate that distinct piRNA pathways have independently evolved at different timepoints to silence the same class of retrotransposons in insect evolution.

evolutionary biology↗

bioRxiv2025

Understanding the mechanism of facilitation in hoverfly TSDNs

Many animals use visual motion cues to track and pursue small, fast-moving targets, such as prey or conspecifics. In target-pursuing insects, including dragonflies and hoverflies, Small Target Motion Detector (STMD) neurons are found in the optic lobes and are believed to be presynaptic to Target Selective Descending Neurons (TSDNs) that project to motor command centres. While STMDs respond robustly to target motion - even when displayed against moving backgrounds - TSDN target responses are modulated by background motion. Depending on whether the background motion is syn- or contra-directional to the target motion, the response of the TSDNs is either suppressed or facilitated (amplified). This suggests that TSDNs not only receive input from STMDs but also from neurons sensitive to background motion, but this neural circuit is not clearly understood. To explore the underlying neural mechanisms, we developed three candidate TSDN circuit models - which combine input from bio-plausible STMDs and optic flow-sensitive Lobula Plate Tangential Cells (LPTCs) in different ways - and fitted them to published electrophysiology data from hoverfly TSDNs. We then tested the best-fitting models against new electrophysiological data using different background patterns. We found that the overall best model suggests simple inhibition from LPTCs with the same preferred direction as the STMDs feeding into the TSDN. This parsimonious mechanism can explain the facilitation and suppression of TSDN responses to small targets, may inform similar studies in other animals and open new avenues for bio-inspired robotics. Author summaryMany human sports, including tennis, football, and basketball, rely on the ability to visually detect and respond to the motion of a small, rapidly moving object. Indeed, some sports stars seem to have an uncanny ability to predict the future location of a ball. Similarly, many animals also need to detect the motion of small objects, as these may represent an approaching predator, prey, or a conspecific that needs to be avoided or pursued. Interestingly, while the detection of small visual targets is computationally a hard problem, insects, which have small brains with very modest power requirements, appear to solve this effortlessly. Thus, understanding how target detection is performed in insects can open up avenues for bio-inspired robotics. Male hoverflies naturally engage in complex pursuit behavior, and since they have specialised neurons for target tracking, hoverflies are ideal for understanding the underlying neural circuitry. Here, we combine neural recordings from hoverflies with computational modelling to show how neurons that respond selectively to target motion are combined with neurons that respond to widefield optic-flow to generate behaviourally relevant sensorimotor responses. Importantly, our model does not involve learning and hence suggests that these behaviours can be innate.

neuroscience↗

bioRxiv2023

Neural responses to reconstructed target pursuits

Many animals use motion vision information to control dynamic behaviors. Predatory animals, for example, show an exquisite ability to detect rapidly moving prey followed by pursuit and capture. Such target detection is not only used by predators but can also play an important role in conspecific interactions. Male hoverflies (Eristalis tenax), for example, vigorously defend their territories against conspecific intruders. Visual target detection is believed to be subserved by specialized target tuned neurons that are found in a range of species, including cats, zebrafish, and insects. However, how these target-tuned neurons respond to actual pursuit trajectories is currently not well understood. To redress his, we recorded extracellularly from target selective descending neurons (TSDNs) in male Eristalis tenax hoverflies. We show that the neurons have dorso-frontal receptive fields, with a preferred direction up and away from the visual midline. We next reconstructed visual flow-fields as experienced during pursuits of artificial targets (black beads). We recorded TSDN responses to six reconstructed pursuits and found that each neuron responded consistently at remarkably specific time points, but that these time points differed between neurons. We compared the observed spike probability with the spike probability predicted from each neurons receptive field and size tuning, and found a correlation coefficient of 0.35. Interestingly, however, the overall response rate was low, with individual neurons responding to only a small part of each reconstructed pursuit. In contrast, the TSDN population responded to a substantially larger proportion of the pursuits (up to a median of 23%). This large variation between neurons could be useful if different neurons control different parts of the behavioral output. Significance statementDescending neurons constitute less than 1% of the nervous system, yet have to convey all requisite information from the brain to the body. They are therefore a crucial bottleneck in sensorimotor transformation. Descending target tuned neurons in male hoverflies (Eristalis tenax), for example, are believed to play a key role in territory defense and pursuit of conspecifics. However, this has not been tested using visual stimuli resembling reconstructed target pursuits. We here found that the observed neural responses to reconstructed pursuits are stronger than those predicted from responses to simpler stimuli. In addition, while the responses to simple stimuli suggested a homogenous population of neurons, the reconstructed pursuits showed important differences between individual neurons. Our data thus highlight the need for using more naturalistic stimuli when deciphering neural function.

neuroscience↗

bioRxiv2023

Cellos: High-throughput deconvolution of 3D organoid dynamics at cellular resolution for cancer pharmacology

Three-dimensional (3D) culture models, such as organoids, are flexible systems to interrogate cellular growth and morphology, multicellular spatial architecture, and cell interactions in response to drug treatment. However, new computational methods to segment and analyze 3D models at cellular resolution with sufficiently high throughput are needed to realize these possibilities. Here we report Cellos (Cell and Organoid Segmentation), an accurate, high throughput image analysis pipeline for 3D organoid and nuclear segmentation analysis. Cellos segments organoids in 3D using classical algorithms and segments nuclei using a Stardist-3D convolutional neural network which we trained on a manually annotated dataset of 3,862 cells from 36 organoids confocally imaged at 5 m z-resolution. To evaluate the capabilities of Cellos we then analyzed 74,450 organoids with 1.65 million cells, from multiple experiments on triple negative breast cancer organoids containing clonal mixtures with complex cisplatin sensitivities. Cellos was able to accurately distinguish ratios of distinct fluorescently labelled cell populations in organoids, with <3% deviation from the seeding ratios in each well and was effective for both fluorescently labelled nuclei and independent DAPI stained datasets. Cellos was able to recapitulate traditional luminescence-based drug response quantifications by analyzing 3D images, including parallel analysis of multiple cancer clones in the same well. Moreover, Cellos was able to identify organoid and nuclear morphology feature changes associated with treatment. Finally, Cellos enables 3D analysis of cell spatial relationships, which we used to detect ecological affinity between cancer cells beyond what arises from local cell division or organoid composition. Cellos provides powerful tools to perform high throughput analysis for pharmacological testing and biological investigation of organoids based on 3D imaging.

bioinformatics↗

bioRxiv2022

Dual receptive fields underlying target and motion sensitivity in looming sensitive descending neurons

Responding rapidly to visual stimuli is fundamental for many animals. For example, predatory birds and insects alike have amazing target detection abilities, with incredibly short neural and behavioral delays, enabling efficient prey capture. Similarly, looming objects need to be rapidly avoided to ensure immediate survival, as these could represent approaching predators. Male Eristalis tenax hoverflies are non-predatory, highly territorial insects, that perform high-speed pursuits of conspecifics and other territorial intruders. During the initial stages of the pursuit the retinal projection of the target is very small, but grows to a larger object before physical interaction. Supporting such behaviors, E. tenax and other insects have both target-tuned and loom-sensitive neurons in the optic lobes and the descending pathways. We here show that these visual stimuli are not necessarily encoded in parallel. Indeed, we describe a class of descending neurons that respond to small targets, to looming and to widefield stimuli. We show that these neurons have two distinct receptive fields where the dorsal receptive field is sensitive to the motion of small targets and the ventral receptive field responds to larger objects or widefield stimuli. Our data suggest that the two receptive fields have different pre-synaptic input, where the inputs are not linearly summed. This novel and unique arrangement could support different behaviors, including obstacle avoidance, flower landing, target pursuit or capture. Significance StatementIf you are playing baseball, when the ball is far away, it appears as a very small object on your retina. However, as the ball gets closer, its image becomes a rapidly expanding object. Here, we show that within the hoverfly visual system, a single neuron could respond to both of these images. Indeed, we found a class of descending neurons with dual sensitivity, separated into two distinct parts of the visual field. The neurons have a more dorsal receptive field that is sensitive to small targets and a more ventral receptive field that is sensitive to larger objects.

neuroscience↗

bioRxiv2020

Now you see me, now you don't: Modulation of neural responses to targets moving in three-dimensional optic flow

For the human observer, it can be difficult to follow the motion of small objects, especially when they move against background clutter. In contrast, insects efficiently do this, as evidenced by their ability to capture prey, pursue conspecifics, or defend territories, even in highly textured surrounds. We here recorded from target selective descending neurons (TSDNs) which likely subserve these impressive behaviors. To simulate the type of background optic flow that would be generated by the pursuers own movements through the world, we used the coherent motion of a perspective distorted sparse dot field. We show that hoverfly TSDN responses to target motion are suppressed when such background optic flow moves in the same direction as the target. Indeed, the neural responses are strongly attenuated against both translational sideslip as well as rotational yaw. More strikingly, we show that TSDNs are facilitated by background optic flow in the opposite direction to the target, if the target moves horizontally. Furthermore, we show that a small, frontal spatial window of background optic flow is enough to fully facilitate or attenuate TSDN responses to target motion. We argue that the TSDN response facilitation could be beneficial in modulating corrective turns during target pursuit. Significance statementTarget detection in visual clutter is a difficult computational task that insects, with their poor resolution compound eyes and small brains, do successfully and with extremely short behavioral delays. We here show that the responses of target selective descending neurons are attenuated by background motion in the same direction as target motion, but facilitated by opposite direction background motion. This finding is important for understanding conspecific pursuit behavior, since these descending neurons likely control behavioral output. The facilitation that we describe would come into effect if the hoverfly is subjected to background motion in one direction, but the target it is pursuing moves in the opposite direction, and could therefore be used to modulate gaze stabilizing corrective turns.

neuroscience↗