RESUMO
Serotonin influences many aspects of animal behavior. But how serotonin acts on its diverse receptors across the brain to modulate global activity and behavior is unknown. Here, we examine how serotonin release in C. elegans alters brain-wide activity to induce foraging behaviors, like slow locomotion and increased feeding. Comprehensive genetic analyses identify three core serotonin receptors (MOD-1, SER-4, and LGC-50) that induce slow locomotion upon serotonin release and others (SER-1, SER-5, and SER-7) that interact with them to modulate this behavior. SER-4 induces behavioral responses to sudden increases in serotonin release, whereas MOD-1 induces responses to persistent release. Whole-brain imaging reveals widespread serotonin-associated brain dynamics, spanning many behavioral networks. We map all sites of serotonin receptor expression in the connectome, which, together with synaptic connectivity, helps predict which neurons show serotonin-associated activity. These results reveal how serotonin acts at defined sites across a connectome to modulate brain-wide activity and behavior.
Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/metabolismo , Serotonina/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismo , Comportamento Animal/fisiologia , Encéfalo/metabolismoRESUMO
Changes in an animal's 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 behavioral features. By determining the identities of the recorded neurons, we created 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, although many neurons encode current motor actions, others integrate 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 animal's brain encode its behavior.
Assuntos
Caenorhabditis elegans , Conectoma , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Modelos Estatísticos , Neurônios/metabolismoRESUMO
Animals must respond to the ingestion of food by generating adaptive behaviors, but the role of gut-brain signaling in behavioral regulation is poorly understood. Here, we identify conserved ion channels in an enteric serotonergic neuron that mediate its responses to food ingestion and decipher how these responses drive changes in foraging behavior. We show that the C. elegans serotonergic neuron NSM acts as an enteric sensory neuron that acutely detects food ingestion. We identify the novel and conserved acid-sensing ion channels (ASICs) DEL-7 and DEL-3 as NSM-enriched channels required for feeding-dependent NSM activity, which in turn drives slow locomotion while animals feed. Point mutations that alter the DEL-7 channel change NSM dynamics and associated behavioral dynamics of the organism. This study provides causal links between food ingestion, molecular and physiological properties of an enteric serotonergic neuron, and adaptive feeding behaviors, yielding a new view of how enteric neurons control behavior.
Assuntos
Canais Iônicos Sensíveis a Ácido/metabolismo , Sistema Nervoso Entérico/metabolismo , Comportamento Alimentar/fisiologia , Canais Iônicos Sensíveis a Ácido/fisiologia , Animais , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/metabolismo , Sistema Nervoso Entérico/fisiologia , Alimentos , Canais Iônicos/metabolismo , Canais Iônicos/fisiologia , Locomoção , Neurônios/metabolismo , Células Receptoras Sensoriais/metabolismo , Neurônios Serotoninérgicos/metabolismo , Neurônios Serotoninérgicos/fisiologia , Serotonina , Transdução de SinaisRESUMO
Variability is a prominent feature of behavior and is an active element of certain behavioral strategies. To understand how neuronal circuits control variability, we examined the propagation of sensory information in a chemotaxis circuit of C. elegans where discrete sensory inputs can drive a probabilistic behavioral response. Olfactory neurons respond to odor stimuli with rapid and reliable changes in activity, but downstream AIB interneurons respond with a probabilistic delay. The interneuron response to odor depends on the collective activity of multiple neurons-AIB, RIM, and AVA-when the odor stimulus arrives. Certain activity states of the network correlate with reliable responses to odor stimuli. Artificially generating these activity states by modifying neuronal activity increases the reliability of odor responses in interneurons and the reliability of the behavioral response to odor. The integration of sensory information with network states may represent a general mechanism for generating variability in behavior.
Assuntos
Caenorhabditis elegans/fisiologia , Condutos Olfatórios , Animais , Comportamento Animal , Sinalização do Cálcio , Neurônios/metabolismo , OdorantesRESUMO
Foraging animals have distinct exploration and exploitation behaviors that are organized into discrete behavioral states. Here, we characterize a neuromodulatory circuit that generates long-lasting roaming and dwelling states in Caenorhabditis elegans. We find that two opposing neuromodulators, serotonin and the neuropeptide pigment dispersing factor (PDF), each initiate and extend one behavioral state. Serotonin promotes dwelling states through the MOD-1 serotonin-gated chloride channel. The spontaneous activity of serotonergic neurons correlates with dwelling behavior, and optogenetic modulation of the critical MOD-1-expressing targets induces prolonged dwelling states. PDF promotes roaming states through a Gαs-coupled PDF receptor; optogenetic activation of cAMP production in PDF receptor-expressing cells induces prolonged roaming states. The neurons that produce and respond to each neuromodulator form a distributed circuit orthogonal to the classical wiring diagram, with several essential neurons that express each molecule. The slow temporal dynamics of this neuromodulatory circuit supplement fast motor circuits to organize long-lasting behavioral states.
Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Neuropeptídeos/metabolismo , Serotonina/metabolismo , Transdução de Sinais , Animais , Comportamento Animal , Canais de Cloreto/metabolismo , AMP Cíclico/metabolismo , Neurônios/metabolismo , Receptores Acoplados a Proteínas G/metabolismoRESUMO
Angelman Syndrome is a debilitating neurological disorder caused by mutation of the E3 ubiquitin ligase Ube3A, a gene whose mutation has also recently been associated with autism spectrum disorders (ASDs). The function of Ube3A during nervous system development and how Ube3A mutations give rise to cognitive impairment in individuals with Angleman Syndrome and ASDs are not clear. We report here that experience-driven neuronal activity induces Ube3A transcription and that Ube3A then regulates excitatory synapse development by controlling the degradation of Arc, a synaptic protein that promotes the internalization of the AMPA subtype of glutamate receptors. We find that disruption of Ube3A function in neurons leads to an increase in Arc expression and a concomitant decrease in the number of AMPA receptors at excitatory synapses. We propose that this deregulation of AMPA receptor expression at synapses may contribute to the cognitive dysfunction that occurs in Angelman Syndrome and possibly other ASDs.
Assuntos
Síndrome de Angelman/fisiopatologia , Proteínas do Citoesqueleto/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Células Cultivadas , Cognição , Humanos , Camundongos , Camundongos Knockout , Receptores de AMPA/metabolismo , Sinapses/metabolismo , UbiquitinaçãoRESUMO
Spectral mode representations play an essential role in various areas of physics, from quantum mechanics to fluid turbulence, but they are not yet extensively used to characterize and describe the behavioral dynamics of living systems. Here, we show that mode-based linear models inferred from experimental live-imaging data can provide an accurate low-dimensional description of undulatory locomotion in worms, centipedes, robots, and snakes. By incorporating physical symmetries and known biological constraints into the dynamical model, we find that the shape dynamics are generically governed by Schrödinger equations in mode space. The eigenstates of the effective biophysical Hamiltonians and their adiabatic variations enable the efficient classification and differentiation of locomotion behaviors in natural, simulated, and robotic organisms using Grassmann distances and Berry phases. While our analysis focuses on a widely studied class of biophysical locomotion phenomena, the underlying approach generalizes to other physical or living systems that permit a mode representation subject to geometric shape constraints.
Assuntos
Robótica , LocomoçãoRESUMO
Microbes are ubiquitous in the natural environment of Caenorhabditis elegans. Bacteria serve as a food source for C. elegans but may also cause infection in the nematode host. The sensory nervous system of C. elegans detects diverse microbial molecules, ranging from metabolites produced by broad classes of bacteria to molecules synthesized by specific strains of bacteria. Innate recognition through chemosensation of bacterial metabolites or mechanosensation of bacteria can induce immediate behavioral responses. The ingestion of nutritive or pathogenic bacteria can modulate internal states that underlie long-lasting behavioral changes. Ingestion of nutritive bacteria leads to learned attraction and exploitation of the bacterial food source. Infection, which is accompanied by activation of innate immunity, stress responses, and host damage, leads to the development of aversive behavior. The integration of a multitude of microbial sensory cues in the environment is shaped by experience and context. Genetic, chemical, and neuronal studies of C. elegans behavior in the presence of bacteria have defined neural circuits and neuromodulatory systems that shape innate and learned behavioral responses to microbial cues. These studies have revealed the profound influence that host-microbe interactions have in governing the behavior of this simple animal host.
Assuntos
Caenorhabditis elegans/fisiologia , Interações entre Hospedeiro e Microrganismos/fisiologia , Animais , Aprendizagem da Esquiva/fisiologia , Bactérias/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/microbiologia , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/fisiologia , Dióxido de Carbono/metabolismo , Sinais (Psicologia) , Escherichia coli , Comportamento Alimentar/fisiologia , Vias Neurais/fisiologia , Oxigênio/metabolismo , Pseudomonas aeruginosa/patogenicidade , Serotonina/fisiologiaRESUMO
In the version of this article originally published, the bottom of Figure 4f,g was partially truncated in the PDF. The error has been corrected in the PDF version of this article.
RESUMO
We developed a new way to engineer complex proteins toward multidimensional specifications using a simple, yet scalable, directed evolution strategy. By robotically picking mammalian cells that were identified, under a microscope, as expressing proteins that simultaneously exhibit several specific properties, we can screen hundreds of thousands of proteins in a library in just a few hours, evaluating each along multiple performance axes. To demonstrate the power of this approach, we created a genetically encoded fluorescent voltage indicator, simultaneously optimizing its brightness and membrane localization using our microscopy-guided cell-picking strategy. We produced the high-performance opsin-based fluorescent voltage reporter Archon1 and demonstrated its utility by imaging spiking and millivolt-scale subthreshold and synaptic activity in acute mouse brain slices and in larval zebrafish in vivo. We also measured postsynaptic responses downstream of optogenetically controlled neurons in C. elegans.
Assuntos
Evolução Molecular Direcionada/métodos , Proteínas Luminescentes/química , Engenharia de Proteínas/métodos , Robótica , Peixe-Zebra/embriologia , Animais , Encéfalo/diagnóstico por imagem , Caenorhabditis elegans , Separação Celular , Feminino , Citometria de Fluxo , Fluorescência , Biblioteca Gênica , Genes Reporter , Células HEK293 , Hipocampo/citologia , Humanos , Masculino , Camundongos , Microscopia de Fluorescência , Neurônios/citologia , OptogenéticaRESUMO
A hub-and-spoke circuit of neurons connected by gap junctions controls aggregation behavior and related behavioral responses to oxygen, pheromones, and food in Caenorhabditis elegans The molecular composition of the gap junctions connecting RMG hub neurons with sensory spoke neurons is unknown. We show here that the innexin gene unc-9 is required in RMG hub neurons to drive aggregation and related behaviors, indicating that UNC-9-containing gap junctions mediate RMG signaling. To dissect the circuit in detail, we developed methods to inhibit unc-9-based gap junctions with dominant-negative unc-1 transgenes. unc-1(dn) alters a stomatin-like protein that regulates unc-9 electrical signaling; its disruptive effects can be rescued by a constitutively active UNC-9::GFP protein, demonstrating specificity. Expression of unc-1(dn) in RMG hub neurons, ADL or ASK pheromone-sensing neurons, or URX oxygen-sensing neurons disrupts specific elements of aggregation-related behaviors. In ADL, unc-1(dn) has effects opposite to those of tetanus toxin light chain, separating the roles of ADL electrical and chemical synapses. These results reveal roles of gap junctions in a complex behavior at cellular resolution and provide a tool for similar exploration of other gap junction circuits.
Assuntos
Caenorhabditis elegans/metabolismo , Sinapses Elétricas/metabolismo , Junções Comunicantes/metabolismo , Células Receptoras Sensoriais/metabolismo , Comportamento Social , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Sinapses Elétricas/genética , Junções Comunicantes/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Atividade Motora/genética , Feromônios/metabolismo , Transdução de Sinais/genéticaRESUMO
Electrophysiological recordings have enabled identification of physiologically distinct yet behaviorally similar states of mammalian sleep. In contrast, sleep in nonmammals has generally been identified behaviorally and therefore regarded as a physiologically uniform state characterized by quiescence of feeding and locomotion, reduced responsiveness, and rapid reversibility. The nematode Caenorhabditis elegans displays sleep-like quiescent behavior under two conditions: developmentally timed quiescence (DTQ) occurs during larval transitions, and stress-induced quiescence (SIQ) occurs in response to exposure to cellular stressors. Behaviorally, DTQ and SIQ appear identical. Here, we use optogenetic manipulations of neuronal and muscular activity, pharmacology, and genetic perturbations to uncover circuit and molecular mechanisms of DTQ and SIQ. We find that locomotion quiescence induced by DTQ- and SIQ-associated neuropeptides occurs via their action on the nervous system, although their neuronal target(s) and/or molecular mechanisms likely differ. Feeding quiescence during DTQ results from a loss of pharyngeal muscle excitability, whereas feeding quiescence during SIQ results from a loss of excitability in the nervous system. Together these results indicate that, as in mammals, quiescence is subserved by different mechanisms during distinct sleep-like states in C. elegans.
Assuntos
Caenorhabditis elegans/fisiologia , Sono/fisiologia , Torpor/fisiologia , Animais , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/fisiologia , Comportamento Alimentar/fisiologia , Larva/crescimento & desenvolvimento , Larva/fisiologia , Locomoção/fisiologia , Músculos/fisiologia , Rede Nervosa/fisiologia , Vias Neurais/crescimento & desenvolvimento , Vias Neurais/fisiologia , Neurônios/fisiologia , Neuropeptídeos/fisiologia , Optogenética , Músculos Faríngeos/inervação , Músculos Faríngeos/fisiologia , Estresse FisiológicoRESUMO
The selection and execution of context-appropriate behaviors is controlled by the integrated action of neural circuits throughout the brain. However, how activity is coordinated across brain regions, and how nervous system structure enables these functional interactions, remain open questions. Recent technical advances have made it feasible to build brain-wide maps of nervous system structure and function, such as brain activity maps, connectomes, and cell atlases. Here, we review recent progress in this area, focusing on C. elegans and D. melanogaster, as recent work has produced global maps of these nervous systems. We also describe neural circuit motifs elucidated in studies of specific networks, which highlight the complexities that must be captured to build accurate models of whole-brain function.
Assuntos
Encéfalo , Caenorhabditis elegans , Animais , Encéfalo/fisiologia , Caenorhabditis elegans/fisiologia , Conectoma , Rede Nervosa/fisiologia , Mapeamento Encefálico , Drosophila melanogaster/fisiologia , Invertebrados/fisiologia , Fenômenos Fisiológicos do Sistema NervosoRESUMO
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.
RESUMO
Neuronal activity orchestrates the proper development of the neuronal circuitry by regulating both transcriptional and post-transcriptional gene expression programmes. How these programmes are coordinated, however, is largely unknown. We found that the transcription of miR379-410, a large cluster of brain-specific microRNAs (miRNAs), is induced by increasing neuronal activity in primary rat neurons. Results from chromatin immunoprecipitation and luciferase reporter assays suggest that binding of the transcription factor myocyte enhancing factor 2 (Mef2) upstream of miR379-410 is necessary and sufficient for activity-dependent transcription of the cluster. Mef2-induced expression of at least three individual miRNAs of the miR379-410 cluster is required for activity-dependent dendritic outgrowth of hippocampal neurons. One of these miRNAs, the dendritic miR-134, promotes outgrowth by inhibiting translation of the mRNA encoding for the translational repressor Pumilio2. In summary, we have described a novel regulatory pathway that couples activity-dependent transcription to miRNA-dependent translational control of gene expression during neuronal development.
Assuntos
Dendritos/metabolismo , Proteínas de Domínio MADS/metabolismo , MicroRNAs/genética , Família Multigênica , Fatores de Regulação Miogênica/metabolismo , Organogênese , Proteínas de Ligação a RNA/metabolismo , Transcrição Gênica , Animais , Sequência de Bases , Sítios de Ligação , Regulação para Baixo , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Fatores de Transcrição MEF2 , Dados de Sequência Molecular , Proteínas de Ligação a RNA/genética , Ratos , Ratos Sprague-DawleyRESUMO
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.
RESUMO
Animals generate a wide range of highly coordinated motor outputs, which allows them to execute purposeful behaviors. Individual neurons in the circuits that generate behaviors 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 adaptive 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 toward low-speed dwelling behavior over minutes. The acute effects of HSN on egg laying and high-speed locomotion are mediated by separate sets of HSN transmitters and different HSN axonal compartments. The long-lasting effects on dwelling are mediated in part by HSN release of serotonin, which 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 that neurons can borrow serotonin from one another to control behavior.
Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/fisiologia , Neurônios Motores/fisiologia , Serotonina/fisiologia , Oviposição/fisiologia , Neurônios SerotoninérgicosRESUMO
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.
RESUMO
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.
Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/metabolismo , Alimentos , Preferências Alimentares , Transdução de SinaisRESUMO
Studies of C. elegans behavior have been crucial in identifying genetic pathways that control nervous system development and function, as well as basic principles of neural circuit function. Modern analysis of C. elegans behavior commonly relies on video recordings of animals, followed by automated image analysis and behavior quantification. Here, we describe two methods for recording and quantifying C. elegans behavior: a single-worm tracking approach that provides high-resolution behavioral data for individual animals and a multi-worm tracking approach that allows for quantification of the behavior of many animals in parallel. These approaches should be useful to a wide range of researchers studying the nervous system and behavior of C. elegans.