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[
Neuron,
2024]
In an interview with Neuron, Cori Bargmann discusses C.&#
xa0;elegans as a model organism, the importance of considering the animal's own world (thinking like a worm), choosing a scientific problem, and her experience as head of science at the Chan Zuckerberg Initiative and co-chair of the BRAIN Initiative.
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[
Cold Spring Harb Symp Quant Biol,
2014]
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[
International Worm Meeting,
2021]
The ability to discriminate between nutritious and harmful food is essential to survival. As a result, learned avoidance to harmful food sources is conserved from invertebrates to humans. The mechanisms enabling the nervous system to associate sensory cues from a food source with an internal state of sickness to trigger aversive memory formation remain elusive. After prolonged exposure to pathogenic food, C. elegans can learn to avoid the pathogen upon subsequent encounter1. This learned aversion requires infection; non virulent forms of bacteria are not sufficient for memory formation. In response to exposure to pathogenic food, serotonin is induced in a pair of sensory neurons called ADF and remodels downstream circuits2. Learned aversion to pathogen requires serotonin signaling from ADF, suggesting that ADF serves as a site of integration for detecting bacterial cues and internal sickness caused by the pathogen. We seek to understand how internal state changes the coupling between sensory activation and serotonin release in ADF neurons. As a first step, we are using calcium imaging to examine ADF responses to bacterial cues in both naive and pathogen-exposed animals. ADF responds robustly to conditioned media from both pathogenic and non-pathogenic bacteria in a dose-dependent fashion, and ADF activity can be modulated by previous odor history. We are screening mutants using these quantitative parameters to assess ADF responses to direct chemosensory stimuli, indirect signaling from other sensory neurons, and signaling from non-neuronal tissues indicating bacterial infection. Our goal is to uncover cell-biological mechanisms through which ADF neurons mediate learned pathogenic behavior in C. elegans. 1. Zhang, Y., Lu, H., & Bargmann, C.I. (2005). Pathogenic bacteria induce aversive olfactory learning in Caenorhabditis elegans. Nature, 438(7065), 179. 2. Morud, J., Hardege, I., Liu, H., Wu, T., Basu, S., Zhang, Y., & Schafer, W. (2020). Deoprhanisation of novel biogenic amine-gated ion channels identifies a new serotonin receptor for learning. bioRxiv. doi: https://doi.org/10.1101/2020.09.17.301382.
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[
Nature,
1998]
Bilaterally symmetrical animals must be able to integrate sensory inputs and coordinate motor control on both sides of the body. Thus, many neurons in the central nervous system (CNS) project their axons to the opposite side of the body, whereas others project axons that remain on the same side. In the latest issues of Cell and Neuron, the groups of Corey Goodman, Guy Tear, Marc Tessier-Lavigne and Cori Bargmann report that, from worms and flies to rats and humans, a common mechanism determines which axons cross the midline and which do not.
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[
International Worm Meeting,
2021]
Identifying the environmental information and computations that drive sensory detection is key for understanding animal behavior. A variety of different coding strategies have been proposed to mediate sensory detection across organisms and systems, including readouts of the signal absolute level, derivatives, or fold change, low-pass-filtered signal variables, and Linear-Nonlinear models. Differentiating between various models can be challenging without a deliberate systematic experimental design. Here we measure responses in the C. elegans olfactory neuron AWCON over a wide range of stimulus conditions. We find that previous sensation models could only match subsets of experimental observations. We formulate an alternative adaptive concentration threshold model in which sensory activity is regulated by an absolute signal threshold that continuously adapts to odor history. The activation threshold is extracted from a non-linear function of the signal followed by a low pass filter. The model fits the measured sensory threshold and latency over a broad stimulus range and accurately predicts sensory activity and probabilistic behavior during animal navigation in odor gradients. At a molecular level, the rate of the threshold adaptation is regulated by EGL-4, a cGMP-dependent protein kinase. The adaptive-threshold model generality was demonstrated by predicting activity of larval zebrafish optic tectum neurons in response to looming visual stimuli. Theoretical analysis shows that the adaptive concentration threshold model is better than the derivative and fold change models in filtering stimulus noise, allowing reliable sensation in fluctuating environments. Our model unifies previous sensation models under one mechanism and demonstrates an efficient encoding sensory mechanism that reconcile apparent tradeoffs between responsiveness, noise filtering, accurate detection and fast response speed.
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[
International Worm Meeting,
2013]
Imprinting, a special form of learning during an early developmental stage, can generate a long-lasting memory and change animal behavior. We discovered a novel behavior in which early exposure of larval C. elegans to pathogen elicits a long-term aversion that is maintained for days, which we call food choice imprinting. It has been previously reported that adult C. elegans can learn to avoid pathogen Pseudomonas aeruginosa (PA14) after a single 6-hour exposure, but will lose the memory after 12 hours and return to the same preference as naive worms (Zhang et al., 2005). We modified this learning assay by performing pathogen training of newly hatched C. elegans larvae. Remarkably, larval-trained (henceforth, imprinted) animals retain this food choice memory days later, showing aversion to pathogen even as aged adults. To dissect the neural circuits of food choice imprinting, we used an inhibitory chloride channel to disrupt neuronal activity at different developmental stages, asking whether candidate neurons are required for memory formation during training, memory consolidation, or memory retrieval. In initial experiments, we have found that inhibiting the AIB interneuron during larval training disrupts performance, whereas inhibiting AIB during adult training does not affect adult learning. This result suggests that AIB is required to form a memory of the imprinted food choice, but not required for avoidance learning in adults. Through a combination of genetic and functional methods, we hope to elucidate the molecular basis of food choice imprinting in C. elegans. Reference: Zhang, Y.; Lu, H.; Bargmann, C. I., Pathogenic bacteria induce aversive olfactory learning in Caenorhabditis elegans. Nature 2005, 438 (7065), 179-84.
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[
Biotechniques,
2013]
Cori Bargmann's studies of olfaction and her work on the connections between neural circuits, genes, and behavior caught our attention. Curious to know more, BioTechniques contacted her to find out about the ambition, character, and motivation that led to her success.
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[
International Worm Meeting,
2009]
Neuronal circuits that govern goal-directed behaviors such as chemotaxis are highly interconnected, suggesting that their emergent functions may not be evident from the properties of individual neurons or connections. To study the underlying neural computation and dynamics, an engineering approach would systematically quantify output responses to many precise inputs under many circuit perturbations. While C. elegans locomotory behaviors are easily measured, and genetic tools enable precise circuit modification, the presentation of input stimuli in typical agar-plate assays is often poorly controlled. To address this limitation, we developed microfluidic liquid-filled arenas that enable the study of freely-moving animals in highly precise and dynamic microenvironments. We first optimized arena geometry to mimic C. elegans crawling motion, speed, and behavioral responses on agar surfaces. Microfluidic features create controlled liquid gradients that span several cm for population behavior or change sharply across the animal (<50 micron), and remain stable for hours or change rapidly within seconds. The transparent arenas are compatible with light-based neural control (via genetically-encoded rhodopsins) and fluorescent readouts of neural activity. We are characterizing wildtype C. elegans responses to complex spatial and temporal odorant patterns (steps and ramps) to understand how modulation of specific behaviors (e.g., speed, types of turns) influences chemotaxis strategy. Similar studies of genetic mutants with disrupted neurons or neuronal connections are revealing the role of perturbed information flow in directing these behaviors. For example, we found new behaviors (gradient-directed turning), new circuit pathways (glutamate-independent speed regulation), and strong phenotypes in subtle neuromodulatory mutants. Overall, the vast improvement in stimulus control in these microfluidic arenas enables new studies to understand the flow of information in neural circuits governing behavior.
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[
International Worm Meeting,
2013]
Sensory neurons face a dilemma: Biologically relevant changes in stimulus strength are often small compared to the possible range of stimulus intensities. One solution to this problem is sensory adaptation, in which the sensory neuron continuously adjusts its dynamic range based on stimulus history to maximize sensitivity while avoiding saturation. During chemotaxis, C. elegans relies on known chemosensory neurons to detect odors over at least five orders of magnitude in concentration, suggesting a sophisticated molecular machinery to keep ongoing sensory activity within dynamic range. To probe adaptation in C. elegans, we wanted to deliver a broad range of odor stimulus concentrations and patterns while monitoring neural responses. To this end, we developed a high throughput system for in vivo calcium imaging that allows us to record up to 20 animals simultaneously for hours, enabling quantitative mapping of sensory receptive fields and their adjustment to constant or changing stimulus levels. We observed odor-evoked calcium dynamics in AWA sensory neurons across a million-fold range of concentrations. Neurons adapted upon repeated stimulation with odor pulses on two different time scales: fast inactivation of the calcium transient during each odor pulse and slow adjustment of response magnitude and dynamics across repeated pulses. We have screened mutants and pharmacological interventions for effects on odor-evoked calcium transients and their adaptation, seeking to define mechanisms for odor sensing and fast vs. slow adaptation. Paradoxically, several chemotaxis mutants with structurally defective cilia (
che-2,
che-3,
osm-6) had stronger and more slowly adapting calcium responses to odor than wild-type animals suggesting that IFT cilia genes are more important for rapid adjustment of sensory sensitivity than for primary transduction in AWA.
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[
Nature,
1998]
Some species of the nematode worm (Caenorhabditis elegans) are sociable diners, clumping together to share a meal, yet others are more solitary. Why? According to a report by de Bono and Bargmann, these differences can be explained by a change of just one amino acid in a putative neuropeptide receptor.