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Stephens, G. J.

Publications and source records attributed to Stephens, G. J..

14 recordsLinked to original sources

Psilocybin ameliorates neuropathic pain-like behaviour in mice and facilitates gabapentin-mediated analgesia

Chronic pain states are challenging to control with current drug therapies. Here, we demonstrate that a single dose of psilocybin can produce a sustained anti-nociceptive effect in a model of chronic neuropathic pain in male and female mice. Psilocybin anti-nociceptive effects were mediated by 5-HT2A receptors, although additional mechanisms might also be involved. Furthermore, a single dose of psilocybin caused a significant increase in the anti-nociceptive potential of gabapentin, a widely used treatment for neuropathic pain consistent with the establishment of longer lasting changes in network processing. Overall, these findings present the first preclinical evidence that psilocybin could be a valuable approach for treating chronic pain from nerve injury and serve as a new therapeutic addition for pain management.

neuroscience↗

The First of Us: Ophiocordyceps use a novel scramblase-binding peptide to manipulate zombie ants

Parasite-adaptive manipulation of behavior is a widespread natural phenomenon. While Ophiocordyceps zombie fungi are well-known for hijacking ant behavior to increase their fitness, functionally characterizing the biomolecules involved in behavior manipulation remains difficult in these non-model organisms. To circumvent this problem, we have adopted the powerful genetics toolbox of Caenorhabditis elegans to identify molecular targets and neurophysiological effects of candidate Ophiocordyceps effectors. With this approach, we discovered a novel cysteine-rich, small secreted fungal peptide that binds to well-conserved calcium-dependent scramblase channels in neurons, particularly those associated with sensory tissues. This binding suppressed nematode motor coordination and dampened ant olfactory systems vital for communication. Our findings are the first to directly connect an Ophiocordyceps effector with its extended phenotype, while demonstrating the neuroethological role of Scramblase-1.

molecular biology↗

Decomposing Predictive Information in Social Dynamics

Social behaviors include some of the most interesting interactions in living systems yet their principled characterization remains unsolved. Here we suggest that at the core of social interactions is the notion of mutual prediction, which we analyze in the context of two male zebrafish engaged in a dominance contest. Using 3D velocity trajectories, we construct the mutual information between a two-animal past and one-animal future, and we quantify the redundant, unique, and synergistic components using partial information decomposition across time windows. We find that predictive information decomposition naturally aligns with important social concepts, such as mirroring and dominance. At contest end, we find asymmetries in self-unique and redundant information that reflect the emergent dominance relationship. Applied to mecp2 zebrafish mutants, an autism model, we find that predictive information is reduced overall, but especially for synergistic flows, which is indicative of difficulties in more complex social dynamics. Significance StatementSocial interactions are rich and diverse, ranging from mirroring to complementary actions. A unifying framework for defining and analyzing such interaction types has long been needed. Here, based on modern information theory, we formulate how the past state of interacting organisms encodes the future state of an individual. This framework provides a natural decomposition of pairwise social dynamics into mirroring, independent action, directed influence, and joint action. Applied to dominance contests in zebrafish, these modes of interaction capture distinct phases of conflict, their assessment strategies, and the resulting dominance relationships. Moreover, our analysis reveals a specific disruption in the social behavior of mutant zebrafish linked to autism, shedding new light on impairments in communication and social learning.

biophysics↗

Deep Imputation for Skeleton Data (DISK) for Behavioral Science

AbstractPose estimation methods and motion capture systems have opened doors to quan- titative measurements of animal kinematics. However, these methods are not perfect and contain missing data. Our method, Deep Imputation for Skeleton data (DISK), leverages deep learning algorithms to learn dependencies between keypoints and their dynamics to impute missing tracking data. We developed an unsupervised training scheme, which does not rely on manual annotations, and tested several neural network architectures for the imputation task. We found that transformer outperforms other architectures including graph con- volutional networks that were developed specifically for skeleton-based action recognition. We demonstrate the usability and performance of our imputation method on seven different animal skeletons including two multi-animal set-ups. With an optional estimated imputation error, DISK enables behavior scien- tists to assess the reliability of the imputed data. The imputed recordings allow to detect more episodes of motion, such as steps, and to obtain more sta- tistically robust results when comparing these episodes between experimental conditions. While animal behavior experiments are expensive and complex, track- ing errors make sometimes large portions of the experimental data unusable. DISK allows for filling in the missing information and for taking full advantage of the rich behavioral data. This stand-alone imputation package, freely available at https://github.com/bozeklab/DISK.git, is applicable to results of any track- ing method (marker-based or markerless) and allows for any type of downstream analysis.

animal behavior and cognition↗

A Markovian dynamics for C. elegans behavior across scales

How do we capture the breadth of behavior in animal movement, from rapid body twitches to aging? Using high-resolution videos of the nematode worm C. elegans, we show that a single dynamics connects posture-scale fluctuations with trajectory diffusion, and longer-lived behavioral states. We take short posture sequences as an instantaneous behavioral measure, fixing the sequence length for maximal prediction. Within the space of posture sequences we construct a fine-scale, maximum entropy partition so that transitions among microstates define a high-fidelity Markov model, which we also use as a means of principled coarse-graining. We translate these dynamics into movement using resistive force theory, capturing the statistical properties of foraging trajectories. Predictive across scales, we leverage the longest-lived eigenvectors of the inferred Markov chain to perform a top-down subdivision of the worms foraging behavior, revealing both "runs-and-pirouettes" as well as previously uncharacterized finer-scale behaviors. We use our model to investigate the relevance of these fine-scale behaviors for foraging success, recovering a trade-off between local and global search strategies. SIGNIFICANCE STATEMENTComplex phenotypes, such as an animals behavior, generally depend on an overwhelming number of processes that span a vast range of scales. While there is no reason that behavioral dynamics permit simple models, by subsuming inherent nonlinearities and memory into maximally-predictive microstates, we find one for C. elegans foraging. The resulting "Markov worm" is effectively indistinguishable from real worm motion across a range of timescales, and we can decompose our model dynamics both to recover and discover behavioral states. Employing a simple form of substrate interactions, we connect postures to trajectories, illuminating how worms explore the environment. In more complex organisms, our approach can also link behaviors across time, from rapid muscular control to neuromodulation.

animal behavior and cognition↗

Maximally predictive ensemble dynamics from data

We leverage the interplay between microscopic variability and macroscopic order to connect physical descriptions across scales directly from data, without underlying equations. We reconstruct a state space by concatenating measurements in time, building a maximum entropy partition of the resulting sequences, and choosing the sequence length to maximize predictive information. Trading non-linear trajectories for linear, ensemble evolution, we analyze reconstructed dynamics through transfer operators. The evolution is parameterized by a transition time{tau} : capturing the source entropy rate at small{tau} and revealing timescale separation with collective, coherent states through the operator spectrum at larger{tau} . Applicable to both deterministic and stochastic systems, we illustrate our approach through the Langevin dynamics of a particle in a double-well potential and the Lorenz system. Applied to the behavior of the nematode worm C. elegans, we derive a "run-and-pirouette" navigation strategy directly from posture dynamics. We demonstrate how sequences simulated from the ensemble evolution capture both fine scale posture dynamics and large scale effective diffusion in the worms centroid trajectories and introduce a top-down, operator-based clustering which reveals subtle subdivisions of the "run" behavior. POPULAR SUMMARYComplex structure is often composed from a limited set of relatively simple building blocks; such as novels from letters or proteins from amino acids. In musical composition, e.g., sounds and silences combine to form longer time scale structures; motifs form passages which in turn form movements. The challenge we address is how to identify collective variables which distinguish structures across such disparate time scales. We introduce a principled framework for learning effective descriptions directly from observations. Just as a musical piece transitions from one movement to the next, the collective dynamics we infer consists of transitions between macroscopic states, like jumps between metastable states in an effective potential landscape. The statistics of these transitions are captured compactly by transfer operators. These operators play a central role, guiding the construction of maximally-predictive short-time states from incomplete measurements and identifying collective modes via eigenvalue decomposition. We demonstrate our analysis in both stochastic and deterministic systems, and with an application to the movement dynamics of an entire organism, unravelling new insight in long time scale behavioral states directly from measurements of posture dynamics. We can, in principle, also make connections to both longer or shorter timescales. Microscopically, postural dynamics result from the fine scale interactions of actin and myosin in the muscles, and from electrical impulses in the brain and nervous system. Macroscopically, behavioral dynamics may be extended to longer time scales, to moods or dispositions, including changes during aging, or over generations due to ecological or evolutionary adaptation. The generality of our approach provides opportunity for insights on long term dynamics within a wide variety of complex systems.

biophysics↗

Functional modules from variable genes: Leveraging percolation to analyze noisy, high-dimensional data

While measurement advances now allow extensive surveys of gene activity (large numbers of genes across many samples), interpretation of these data is often confounded by noise — expression counts can differ strongly across samples due to variation of both biological and experimental origin. Complimentary to perturbation approaches, we extract functionally related groups of genes by analyzing the standing variation within a sampled population. To distinguish biologically meaningful patterns from uninterpretable noise, we focus on correlated variation and develop a novel density-based clustering approach that takes advantage of a percolation transition generically arising in random, uncorrelated data. We apply our approach to two contrasting RNA sequencing data sets that sample individual variation — across single cells of fission yeast and whole animals of C. elegans worms — and demonstrate robust applicability and versatility in revealing correlated gene clusters of diverse biological origin, including cell cycle phase, development/reproduction, tissue-specific functions, and feeding history. Our technique exploits generic features of noisy high-dimensional data and is applicable, beyond gene expression, to feature-rich data that sample population-level variability in the presence of noise.Significance Statement Gene expression largely determines the fate of each cell and ultimately the development and behavior of the whole organism. Whereas most of our knowledge on gene regulatory networks has been obtained from perturbation experiments (e.g. manipulating environmental conditions, genotype, or other physiological variables), here we develop an alternative approach based on the analysis of naturally occurring variations across individuals within a population. Using both single-cell and whole-animal RNA sequencing data, we demonstrate how a rich set of co-regulated gene modules can be uncovered from transcriptomic variability of individuals within unperturbed populations. To robustly extract interpretable clusters from the strong noise background, we devise a novel, versatile clustering approach based on network theory. With a foundation in the generic behavior of random networks near their percolation critical point, our method is broadly applicable, beyond gene expression, to any noisy, high-dimensional data that sample variation across individuals within a population.Competing Interest StatementThe authors have declared no competing interest.View Full Text

systems biology↗

Flow-Mediated Olfactory Communication in Honey Bee Swarms

Honey bee swarms are a landmark example of collective behavior. To become a coherent swarm, bees locate their queen by tracking her pheromones, but how can distant individuals exploit these chemical signals which decay rapidly in space and time? Here, we combine a novel behavioral assay with the machine vision detection of organism location and scenting behavior to track the search and aggregation dynamics of the honey bee Apis mellifera L. We find that bees collectively create a communication network to propagate pheromone signals, by arranging in a specific spatial distribution where there is a characteristic distance between individuals and a characteristic direction in which individuals broadcast the signals. To better understand such a flow-mediated directional communication strategy, we connect our experimental results to an agent-based model where virtual bees with simple, local behavioral rules, exist in a flow environment. Our model shows that increased directional bias leads to a more efficient aggregation process that avoids local equilibrium configurations of isotropic communication, such as small bee clusters that persist throughout the simulation. Our results highlight a novel example of extended classical stigmergy: rather than depositing static information in the environment, individual bees locally sense and globally manipulate the physical fields of chemical concentration and airflow.

animal behavior and cognition↗

Markerless tracking of an entire insect colony

We present a comprehensive, computational method for tracking an entire colony of the honey bee Apis mellifera using high-resolution video on a natural honeycomb background. We adapt a convolutional neural network (CNN) segmentation architecture to automatically identify bee and brood cell positions, body orientations and within-cell states. We achieve high accuracy (~10% body width error in position, ~10{degrees} error in orientation, and true positive rate > 90%) and demonstrate months-long monitoring of sociometric colony fluctuations. We combine extracted positions with rich visual features of organism-centered images to track individuals over time and through challenging occluding events, recovering ~79% of bee trajectories from five observation hives over a span of 5 minutes. The resulting trajectories reveal important behaviors, including fast motion, comb-cell activity, and waggle dances. Our results provide new opportunities for the quantitative study of collective bee behavior and for advancing tracking techniques of crowded systems.

bioinformatics↗

OrganoidTracker: efficient cell tracking using machine learning and manual error correction

Time-lapse microscopy is routinely used to follow cells within organoids, allowing direct study of division and differentiation patterns. There is an increasing interest in cell tracking in organoids, which makes it possible to study their growth and homeostasis at the single-cell level. As tracking these cells by hand is prohibitively time consuming, automation using a computer program is required. Unfortunately, organoids have a high cell density and fast cell movement, which makes automated cell tracking difficult. In this work, a semi-automated cell tracker has been developed. To detect the nuclei, we use a machine learning approach based on a convolutional neural network. To form cell trajectories, we link detections at different time points together using a min-cost flow solver. The tracker raises warnings for situations with likely errors. Rapid changes in nucleus volume and position are reported for manual review, as well as cases where nuclei divide, appear and disappear. When the warning system is adjusted such that virtually error-free lineage trees can be obtained, still less than 2% of all detected nuclei positions are marked for manual analysis. This provides an enormous speed boost over manual cell tracking, while still providing tracking data of the same quality as manual tracking.

bioinformatics↗

Capturing the Continuous Complexity of Behavior in C. elegans

Animal behavior is often quantified through subjective, incomplete variables that may mask essential dynamics. Here, we develop a behavioral state space in which the full instantaneous state is smoothly unfolded as a combination of short-time posture dynamics. Our technique is tailored to multivariate observations and extends previous reconstructions through the use of maximal prediction. Applied to high-resolution video recordings of the roundworm C. elegans, we discover a low-dimensional state space dominated by three sets of cyclic trajectories corresponding to the worms basic stereotyped motifs: forward, backward, and turning locomotion. In contrast to this broad stereotypy, we find variability in the presence of locally-unstable dynamics, and this unpredictability shows signatures of deterministic chaos: a collection of unstable periodic orbits together with a positive maximal Lyapunov exponent. The full Lyapunov spectrum is symmetric with positive, chaotic exponents driving variability balanced by negative, dissipative exponents driving stereotypy. The symmetry is indicative of damped, driven Hamiltonian dynamics underlying the worms movement control.

animal behavior and cognition↗

Modeling the ballistic-to-diffusive transition in nematode motility reveals variation in exploratory behavior across species

A quantitative understanding of organism-level behavior requires predictive models that can capture the richness of behavioral phenotypes, yet are simple enough to connect with underlying mechanistic processes. Here we investigate the motile behavior of nematodes at the level of their translational motion on surfaces driven by undulatory propulsion. We broadly sample the nematode behavioral repertoire by measuring motile trajectories of the canonical lab strain C. elegans N2 as well as wild strains and distant species. We focus on trajectory dynamics over timescales spanning the transition from ballistic (straight) to diffusive (random) movement and find that salient features of the motility statistics are captured by a random walk model with independent dynamics in the speed, bearing and reversal events. We show that the model parameters vary among species in a correlated, low-dimensional manner suggestive of a common mode of behavioral control and a trade-off between exploration and exploitation. The distribution of phenotypes along this primary mode of variation reveals that not only the mean but also the variance varies considerably across strains, suggesting that these nematode lineages employ contrasting \"bet-hedging\" strategies for foraging.

biophysics↗

Pixel personality for dense object tracking in a 2D honeybee hive

Tracking large numbers of densely-arranged, interacting objects is challenging due to occlusions and the resulting complexity of possible trajectory combinations, as well as the sparsity of relevant, labeled datasets. Here we describe a novel technique of collective tracking in the model environment of a 2D honeybee hive in which sample colonies consist of N [~] 103 highly similar individuals, tightly packed, and in rapid, irregular motion. Such a system offers universal challenges for multiobject tracking, while being conveniently accessible for image recording. We first apply an accurate, segmentation-based object detection method to build initial short trajectory segments by matching object configurations based on class, position and orientation. We then join these tracks into full single object trajectories by creating an object recognition model which is adaptively trained to recognize honeybee individuals through their visual appearance across multiple frames, an attribute we denote as pixel personality. Overall, we reconstruct [~] 46% of the trajectories in 5 min recordings from two different hives and over 71% of the tracks for at least 2 min. We provide validated trajectories spanning 3, 000 video frames of 876 unmarked moving bees in two distinct colonies in different locations and filmed with different pixel resolutions, which we expect to be useful in the further development of general-purpose tracking solutions.

animal behavior and cognition↗

Affective bonding explains post-traumatic behavioral development in adult mice

In human post-traumatic stress disorder (PTSD), a major psychiatry challenge is how diverse stress reactions emerge after a protracted symptom-free period. Here, we study the behavioral development in mice isolated after observing an aggressive encounter inflicted upon their pair-housed partners and compared the results with those in multiple control paradigms. Compared with mice plainly isolated, mice isolated following the acute witnessing social stress gradually developed a wide range of long-term differences of their physiological conditions, spontaneous behaviors, and social interactions, including paradoxical results if interpreted in traditional ways. To address this developmental diversity, we applied fine-scale behavioral analysis to standard behavioral tests and showed that the seemingly sudden emergent behavioral differences developed gradually. Mice showed different developmental patterns in different zones of a behavior testing apparatus. However, the results of the fine-scale analysis together with state-space behavioral characterization allow a consistent interpretation of the seemingly conflicting observations among multiple tests. Interestingly, these behavioral differences were not observed if the aggressive encounter happened to a stranger mouse. Additionally, traumatized mice showed rebound responses to their partners after the long separation. In contrast, mice pair-housed with their attacked partners after the aggressive encounters still showed a difference in social interactions, while a difference in spontaneous behaviors did not occur. Accordingly, we propose that social relationship is the single common factor underlying the otherwise independent development of behavioral differences in this mouse paradigm and that the gained insights could have parallels in human PTSD development.

neuroscience↗