Biology subjects

Flavell, S. W.

Publications and source records attributed to Flavell, S. W..

14 recordsLinked to original sources

bioRxiv2026

Deconstructing a behavioral state: parallel neural integrators control distinct features of an aversive behavioral state in C. elegans

Transient sensory stimuli can trigger long-lasting changes in behavior and cognition. For example, repeated aversive experiences can lead to persistent changes in arousal and mood. Specialized integrator circuits can store information about recent experiences, but how they are embedded within the architecture of the brain to control internal brain states remains poorly understood. We find that C. elegans accumulates evidence of past aversive experiences over minutes to generate a scalable behavioral state consisting of multiple behavioral changes. Using a brain-wide imaging screen, we identified a set of neurons that integrate aversive sensory stimuli over different timescales, from seconds to minutes. Neuronal perturbations show that these integrator neurons are critical for the aversive behavioral state. They control distinct behavioral features, such as changes in locomotion speed or increased responsiveness to subsequent aversive stimuli. Moreover, the integrator neurons function in parallel to one another, utilize different mechanisms to generate persistent neural activity, and signal through different transmitters. Our result show how a behavioral state can be decomposed into distinct behavioral features that map onto different neural integrators that act in parallel. Combined action of the integrators then generates the full set of behaviors that comprise the global state.

neuroscience↗

bioRxiv2025

Identification of bacterial signals that modulate enteric sensory neurons to influence behavior in C. elegans

The bacterial microbiome influences many aspects of animal health and disease. Some bacteria have beneficial functions, for example providing nutrients, whereas others act as pathogens. These bacteria are sensed by host cells to induce adaptive changes in physiology and behavior. While immune and intestinal cells detect bacterial signals through well-characterized mechanisms, recent studies indicate that neurons can also directly sense bacterial signals. However, the bacterial sensory mechanisms in neurons are less well understood. In the nematode Caenorhabditis elegans, the enteric sensory neuron NSM innervates the pharyngeal lumen and is directly activated by bacterial food ingestion; in turn, NSM releases serotonin to induce feeding-related behaviors. However, the molecular identities of the bacterial signals that activate NSM are unknown. To identify these signals, we systematically probed bacterial macromolecules from nutritive bacteria using biochemical approaches and GC-MS identification. We find that polysaccharides from gram-positive and gram-negative bacteria are sufficient to activate NSM. We further identify peptidoglycan from gram-positive bacteria as a specific component capable of activating NSM. NSM responses to polysaccharides require the acid-sensing ion channels DEL-3 and DEL-7, which localize to its sensory dendrite in the pharyngeal lumen. Ingestion of bacterial polysaccharides enhances feeding rates and reduces locomotion, matching the known effects of NSM on behavior. We also examine bacterial signals from pathogenic bacteria that can infect and kill C. elegans. This approach identifies prodigiosin, a metabolite from pathogenic Serratia marcescens, as a bacterial cue that prevents NSM activation by nutritive bacterial signals. This study identifies molecular signals that underlie neuronal recognition of nutritive bacteria in the alimentary canal and competing signals from a pathogenic bacterial strain that mask this form of recognition.

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bioRxiv2024

Neural Sequences Underlying Directed Turning in C. elegans

Complex behaviors like navigation rely on sequenced motor outputs that combine to generate effective movement. The brain-wide organization of the circuits that integrate sensory signals to select and execute appropriate motor sequences is not well understood. Here, we characterize the architecture of neural circuits that control C. elegans olfactory navigation. We identify error-correcting turns during navigation and use whole-brain calcium imaging and cell-specific perturbations to determine their neural underpinnings. These turns occur as motor sequences accompanied by neural sequences, in which defined neurons activate in a stereotyped order during each turn. Distinct neurons in this sequence respond to sensory cues, anticipate upcoming turn directions, and drive movement, linking key features of this sensorimotor behavior across time. The neuromodulator tyramine coordinates these sequential brain dynamics. Our results illustrate how neuromodulation can act on a defined neural architecture to generate sequential patterns of activity that link sensory cues to motor actions.

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bioRxiv2024

Deep Neural Networks to Register and Annotate the Cells of the C. elegans Nervous System

Aligning and annotating the heterogeneous cell types that make up complex cellular tissues remains a major challenge in the analysis of biomedical imaging data. Here, we present a series of deep neural networks that allow for automatic non-rigid registration and cell identification, developed in the context of freely moving and deforming invertebrate nervous systems. A semi-supervised learning approach was used to train a C. elegans registration network (BrainAlignNet) that aligns pairs of images of the bending C. elegans head with single pixel-level accuracy. When incorporated into an image analysis pipeline, this network can link neurons over time with 99.6% accuracy. This network could also be readily purposed to align neurons from the jellyfish Clytia hemisphaerica, an organism with a vastly different body plan and set of movements. A separate network (AutoCellLabeler) was trained to annotate >100 neuronal cell types in the C. elegans head based on multi-spectral fluorescence of genetic markers. This network labels >100 different cell types per animal with 98% accuracy, exceeding individual human labeler performance by aggregating knowledge across manually labeled datasets. Finally, we trained a third network (CellDiscoveryNet) to perform unsupervised discovery of >100 cell types in the C. elegans nervous system: by comparing multi-spectral imaging data from many animals, it can automatically identify and annotate cell types without using any human labels. The performance of CellDiscoveryNet matched that of trained human labelers. These tools should be immediately useful for a wide range of biological applications and should be straightforward to generalize to many other contexts requiring alignment and annotation of dense heterogeneous cell types in complex tissues.

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bioRxiv2024

Pathogen infection induces sickness behaviors by recruiting neuromodulatory systems linked to stress and satiety in C. elegans

When animals are infected by a pathogen, peripheral sensors of infection signal to the brain to coordinate a set of adaptive behavioral changes known as sickness behaviors. While the pathways that signal from the periphery to the brain have been intensively studied in recent years, how central circuits are reconfigured to elicit sickness behaviors is not well understood. Here we find that neuromodulatory systems linked to stress and satiety are recruited upon infection to drive sickness behaviors in C. elegans. Upon chronic infection by the bacterium Pseudomonas aeruginosa PA14, C. elegans decrease their feeding behavior, then display reversible bouts of quiescence, and eventually die. The ALA neuron and its neuropeptides FLP-7, FLP-24, and NLP-8, which control stress-induced sleep in uninfected animals, promote the PA14-induced feeding reduction. However, the ALA neuropeptide FLP-13 instead acts to delay quiescence and death in infected animals. Cell-specific genetic perturbations show that the neurons that release FLP-13 to delay quiescence in infected animals are distinct from ALA. A brain-wide imaging screen reveals that infection-induced quiescence involves ASI and DAF-7/TGF-beta, which control satiety-induced quiescence in uninfected animals. Our results suggest that a common set of neuromodulators are recruited across different physiological states, acting from distinct neural sources and in distinct combinations to drive state-dependent behaviors.

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bioRxiv2023

Programmed Cell Death Modifies Neural Circuits and Tunes Intrinsic Behavior

Programmed cell death (PCD) is a common feature of animal development. During development of the C. elegans hermaphrodite, programmed cell death eliminates 131 cells in stereotyped positions in the cell lineage, mostly in neuronal lineages. Blocking cell death results in supernumerary "undead" neurons. We find that undead neurons can be wired into circuits, can display activity, and can modify specific behaviors. The two undead RIM-like neurons participate in the RIM-containing circuit that computes movement. The presence of these two extra neurons results in animals that initiate fewer reversals and lengthens the duration of those reversals that do occur. We describe additional behavioral alterations of cell-death mutants, including in locomotory turning angle and pharyngeal pumping. These findings indicate that physiological or evolutionary variations in PCD might reveal latent neuronal elements that the nervous system can incorporate to modify nervous system function and animal behavior.

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bioRxiv2023

A single neuron in C. elegans orchestrates multiple motor outputs through parallel modes of transmission

Animals generate a wide range of highly coordinated motor outputs, which allows them to execute purposeful behaviors. Individual neuron classes in the circuits that generate behavior have a remarkable capacity for flexibility, as they exhibit multiple axonal projections, transmitter systems, and modes of neural activity. How these multi-functional properties of neurons enable the generation of highly coordinated behaviors remains unknown. Here we show that the HSN neuron in C. elegans evokes multiple motor programs over different timescales to enable a suite of behavioral changes during egg-laying. Using HSN activity perturbations and in vivo calcium imaging, we show that HSN acutely increases egg-laying and locomotion while also biasing the animals towards low-speed dwelling behavior over longer timescales. The acute effects of HSN on egg-laying and high-speed locomotion are mediated by separate sets of HSN transmitters and different HSN axonal projections. The long-lasting effects on dwelling are mediated by HSN release of serotonin that is taken up and re-released by NSM, another serotonergic neuron class that directly evokes dwelling. Our results show how the multi-functional properties of a single neuron allow it to induce a coordinated suite of behaviors and also reveal for the first time that neurons can borrow serotonin from one another to control behavior.

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bioRxiv2023

Dissecting the Functional Organization of the C. elegans Serotonergic System at Whole-Brain Scale

Serotonin controls many aspects of animal behavior and cognition. But how serotonin acts on its diverse receptor types in neurons across the brain to modulate global activity and behavior is unknown. Here, we examine how serotonin release from a feeding-responsive neuron in C. elegans alters brain-wide activity to induce foraging behaviors, like slow locomotion and increased feeding. A comprehensive genetic analysis identifies three core serotonin receptors that collectively induce slow locomotion upon serotonin release and three others that interact with them to further modulate this behavior. The core receptors have different functional roles: some induce behavioral responses to sudden increases in serotonin release, whereas others induce responses to persistent release. Whole-brain calcium imaging reveals widespread serotonin-associated brain dynamics, impacting different behavioral networks in different ways. We map out all sites of serotonin receptor expression in the connectome, which, together with synaptic connectivity, helps predict serotonin-associated brain-wide activity changes. These results provide a global view of how serotonin acts at defined sites across a connectome to modulate brain-wide activity and behavior.

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bioRxiv2022

Brain-wide representations of behavior spanning multiple timescales and states in C. elegans

Changes in an animals behavior and internal state are accompanied by widespread changes in activity across its brain. However, how neurons across the brain encode behavior and how this is impacted by state is poorly understood. We recorded brain-wide activity and the diverse motor programs of freely-moving C. elegans and built probabilistic models that explain how each neuron encodes quantitative features of the animals behavior. By determining the identities of the recorded neurons, we created, for the first time, an atlas of how the defined neuron classes in the C. elegans connectome encode behavior. Many neuron classes have conjunctive representations of multiple behaviors. Moreover, while many neurons encode current motor actions, others encode recent actions. Changes in behavioral state are accompanied by widespread changes in how neurons encode behavior, and we identify these flexible nodes in the connectome. Our results provide a global map of how the cell types across an animals brain encode its behavior.

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bioRxiv2022

Developmental history modulates adult olfactory behavioral preferences via regulation of chemoreceptor expression in C. elegans

Developmental experiences play critical roles in shaping adult physiology and behavior. We and others previously showed that adult C. elegans which transiently experienced dauer arrest during development (PD: post-dauer) exhibit distinct gene expression profiles as compared to control adults which bypassed the dauer stage. In particular, the expression patterns of subsets of chemoreceptor genes are markedly altered in PD adults. Whether altered chemoreceptor levels drive behavioral plasticity in PD adults is unknown. Here we show that PD adults exhibit enhanced attraction to a panel of food-related attractive volatile odorants including the bacterially-produced chemical diacetyl. Diacetyl-evoked responses in the AWA olfactory neuron pair are increased in both dauer larvae and PD adults, and we find that these increased responses are correlated with upregulation of the diacetyl receptor ODR-10 in AWA likely via both transcriptional and post-transcriptional mechanisms. We show that transcriptional upregulation of odr-10 expression in dauer larvae is in part mediated by the DAF-16 FOXO transcription factor. Via transcriptional profiling of sorted populations of AWA neurons from control and PD adults, we further show that the expression of a subset of additional chemoreceptor genes in AWA is regulated similarly to odr-10 in PD animals. Our results suggest that developmental experiences may be encoded at the level of olfactory receptor regulation, and provide a simple mechanism by which C. elegans is able to precisely modulate its behavioral preferences as a function of its current and past experiences.

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bioRxiv2022

Diverse states and stimuli tune olfactory receptor expression levels to modulate food-seeking behavior

Animals must weigh competing needs and states to generate adaptive behavioral responses to the environment. Sensorimotor circuits are thus tasked with integrating diverse external and internal cues relevant to these needs to generate context-appropriate behaviors. However, the mechanisms that underlie this integration are largely unknown. Here, we show that a wide range of states and stimuli converge upon a single C. elegans olfactory neuron to modulate food-seeking behavior. Using an unbiased ribotagging approach, we find that the expression of olfactory receptor genes in the AWA olfactory neuron is influenced by a wide array of states and stimuli, including feeding state, physiological stress, and recent sensory cues. We identify odorants that activate these state-dependent olfactory receptors and show that altered expression of these receptors influences food-seeking and foraging. Further, we dissect the molecular and neural circuit pathways through which these diverse cues are integrated by AWA. This reveals a modular organization in which state-related signals arising from different cell types in the body converge on AWA and independently control chemoreceptor expression. The synthesis of these signals by AWA allows animals to generate sensorimotor responses that reflect the animals overall state. Our findings suggest a general model in which state-dependent transcriptional changes at the sensory periphery modulate animals sensorimotor responses to meet their ongoing needs and states.

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bioRxiv2021

The nematode worm C. elegans chooses between bacterial foods exactly as if maximizing economic utility

In value-based decision making, options are selected according to subjective values assigned by the individual to available goods and actions. Despite the importance of this faculty of the mind, the neural mechanisms of value assignments, and how choices are directed by them, remain obscure. To investigate this problem, we used a classic measure of utility maximization, the Generalized Axiom of Revealed Preference, to quantify internal consistency of food preferences in Caenorhabditis elegans, a nematode worm with a nervous system of only 302 neurons. Using a novel combination of microfluidics and electrophysiology, we found that C. elegans food choices fulfill the necessary and sufficient conditions for utility maximization, indicating that nematodes behave as if they maintain, and attempt to maximize, an underlying representation of subjective value. Food choices are well-fit by a utility function widely used to model human consumers. Moreover, as in many other animals, subjective values in C. elegans are learned, a process we find requires intact dopamine signaling. Differential responses of identified chemosensory neurons to foods with distinct growth potentials are amplified by prior consumption of these foods, suggesting that these neurons may be part of a value-assignment system. The demonstration of utility maximization in an organism with a very small nervous system sets a new lower bound on the computational requirements for utility maximization and offers the prospect of an essentially complete explanation of value-based decision making at single neuron resolution in this organism.

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bioRxiv2020

A neural circuit for flexible control of persistent behavioral states

To adapt to their environments, animals must generate behaviors that are closely aligned to a rapidly changing sensory world. However, behavioral states such as foraging or courtship typically persist over long time scales to ensure proper execution. It remains unclear how neural circuits generate persistent behavioral states while maintaining the flexibility to select among alternative states when the sensory context changes. Here, we elucidate the functional architecture of a neural circuit controlling the choice between roaming and dwelling states, which underlie exploration and exploitation during foraging in C. elegans. By imaging ensemble-level neural activity in freely-moving animals, we identify stable, circuit-wide activity patterns corresponding to each behavioral state. Combining circuit-wide imaging with genetic analysis, we find that mutual inhibition between two antagonistic neuromodulatory systems underlies the persistence and mutual exclusivity of the opposing network states. Through machine learning analysis and circuit perturbations, we identify a sensory processing neuron that can transmit information about food odors to both the roaming and dwelling circuits and bias the animal towards different states in different sensory contexts, giving rise to context-appropriate state transitions. Our findings reveal a potentially general circuit architecture that enables flexible, sensory-driven control of persistent behavioral states.

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bioRxiv2018

Parallel multimodal circuits control an innate foraging behavior

Foraging strategies that enable animals to locate food efficiently are composed of highly conserved behavioral states with characteristic features. Here, we identify parallel multimodal circuit modules that control an innate foraging state -- local search behavior -- after food removal in the nematode Caenorhabditis elegans. Two parallel groups of chemosensory and mechanosensory glutamatergic neurons that detect food-related cues trigger local search by inhibiting separate integrating neurons through a metabotropic glutamate receptor, MGL-1. The chemosensory and mechanosensory modules are separate and redundant, as glutamate release from either can drive the full behavior. Spontaneous activity in the chemosensory module encodes information about the time since the last food encounter and correlates with the foraging behavior. In addition, the ability of the sensory modules to control local search is gated by the internal nutritional state of the animal. This multimodal circuit configuration provides robust control of an innate adaptive behavior.

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