Dopamine signaling regulates predator-driven changes in Caenorhabditis elegans’ egg laying behavior
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Studies of prey behavior have the potential to provide insight into the chemical encoding of stress in the brain and the mechanisms by which this generates behavioral plasticity. In this important work, the authors identify a novel predation-evoked behavior in the nematode C. elegans and implicate dopamine in its implementation. While the support for some claims in the current paper is incomplete, this work provides an exciting foundation for future studies of behavioral plasticity in this powerful system.
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Abstract
Prey respond to predators by altering their behavior to optimize their own fitness and survival. Specifically, prey are known to avoid predator-occupied territories to reduce their risk of harm or injury to themselves and their progeny. We probe the interactions between Caenorhabditis elegans and its naturally cohabiting predator Pristionchus uniformis to reveal the pathways driving changes in prey behavior. While C. elegans prefers to lay its eggs on a bacteria food lawn, the presence of a predator inside a lawn induces C. elegans to lay more eggs away from that lawn. We confirm that this change in egg laying is in response to bites from predators, rather than to predatory secretions. Moreover, predator-exposed prey continue to lay their eggs away from the dense lawn even after the predator is removed, indicating a form of learning. Next, we find that mutants in dopamine synthesis significantly reduce egg laying behavior off the lawn in both predator-free and predator-inhabited lawns, which we can rescue by transgenic complementation or supplementation with exogenous dopamine. Moreover, we find that dopamine is likely released from multiple dopaminergic neurons and requires combinations of both D1- (DOP-1) and D2-like (DOP-2 and DOP-3) dopamine receptors to alter predator-induced egg laying behavior, whereas other combinations modify baseline levels of egg laying behavior. Together, we show that dopamine signaling can alter both predator-free and predator-induced foraging strategies, suggesting a role for this pathway in defensive behaviors.
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eLife assessment
Studies of prey behavior have the potential to provide insight into the chemical encoding of stress in the brain and the mechanisms by which this generates behavioral plasticity. In this important work, the authors identify a novel predation-evoked behavior in the nematode C. elegans and implicate dopamine in its implementation. While the support for some claims in the current paper is incomplete, this work provides an exciting foundation for future studies of behavioral plasticity in this powerful system.
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Reviewer #1 (Public Review):
Understanding how predators alter the behavior of their prey, a central question in neuroethology, has the potential to provide important insight into the neurobiological basis for behavioral flexibility. In this creative and intriguing work, the authors demonstrate that the predatory nematodes Pacificus pristionchus and P. uniformus can induce long-lasting changes in the behavioral patterns of C. elegans hermaphrodites. Exposure to these predators, probably sensed by the physical damaged caused by a bite, leads C. elegans to spend more time in food-poor environments and to increase their preference for laying eggs in these regions. Interestingly, this behavioral change appears to last for at least 24 hours, indicating that predator exposure induces a longer-term modulation of neural circuit function. The …
Reviewer #1 (Public Review):
Understanding how predators alter the behavior of their prey, a central question in neuroethology, has the potential to provide important insight into the neurobiological basis for behavioral flexibility. In this creative and intriguing work, the authors demonstrate that the predatory nematodes Pacificus pristionchus and P. uniformus can induce long-lasting changes in the behavioral patterns of C. elegans hermaphrodites. Exposure to these predators, probably sensed by the physical damaged caused by a bite, leads C. elegans to spend more time in food-poor environments and to increase their preference for laying eggs in these regions. Interestingly, this behavioral change appears to last for at least 24 hours, indicating that predator exposure induces a longer-term modulation of neural circuit function. The authors convincingly demonstrate that both dopamine and serotonin are required for this behavioral change. They identify specific neurons and receptors important for the effects of dopamine in this process, though whether dopamine signaling is itself modulated by predator exposure remains unclear. Some specific conclusions are not fully supported by the results, including the proposal that the CEM neurons are the key source of dopamine and that injury, rather than chemical cues, triggers the observed behavioral changes. Nevertheless, this paper reports a fascinating and robust behavioral finding, and provides some initial progress toward understanding its underlying neurobiological basis. As such, it will be of interest to those studying neuroethology, behavioral neurogenetics, and the modulation of behavior by monoamines.
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Reviewer #2 (Public Review):
On the whole, I think this paper is a nice demonstration of how current and past aversive experiences shape an animal's behavior, and how this experience is shaped/encoded by neuromodulation. While most past work has focused on passive environmental cues such as chemical, physical, and electromagnetic perturbation, this work focuses on inter-species conflict, which is an important environmental factor that is understudied and would benefit from more research. The authors have created a nice paradigm to investigate this phenomenon further with an organism (C. elegans) that can be easily genetically modified to uncover genetic factors that influence this behavior.
The authors initially present evidence that animals avoid food patches, and egg laying on these patches, in response to predation from P. pacificus …
Reviewer #2 (Public Review):
On the whole, I think this paper is a nice demonstration of how current and past aversive experiences shape an animal's behavior, and how this experience is shaped/encoded by neuromodulation. While most past work has focused on passive environmental cues such as chemical, physical, and electromagnetic perturbation, this work focuses on inter-species conflict, which is an important environmental factor that is understudied and would benefit from more research. The authors have created a nice paradigm to investigate this phenomenon further with an organism (C. elegans) that can be easily genetically modified to uncover genetic factors that influence this behavior.
The authors initially present evidence that animals avoid food patches, and egg laying on these patches, in response to predation from P. pacificus and P. uniformis. P. pacificus is quite aggressive, and the RS5194 strain kills all prey animals after 20 hours. Even prior to death, animals exposed to this species experience significant cuticle damage that can be detected by the expression of NLP-29, a known antimicrobial peptide. After 6 hours, animals have a strong aversion to laying eggs on a bacterial lawn that is shared with this species.
However, the authors choose to not use this species, and instead use P. uniformis males which do not lay eggs, and which do not appear to damage the cuticle (or at least sufficiently to induce nlp-29 expression). Nevertheless, their presence appears to cause a slight aversion to laying eggs on food. The authors then screen for neuromodulatory mutants that may alter this behavior, and identify dopamine signaling as an important contributor to this behavior. The authors do a nice job of rescuing the mutant effect with both cell-specific rescue, and general rescue with dopamine administration.
This work is an important contribution to our understanding of predator-induced stresses on prey, and how dopamine neuromodulation alters prey behavior.
My primary criticism of this work is how the data are quantified and explained. Worms perform random walks on and off food, the statistics of which are modified based on environmental cues and internal states. This drive to perform stochastic trajectories is a fundamental feature of these organisms (Klein et al, eLife, 2017). In all assays, the worms lay eggs throughout the arena (diameter ~ 6 mm), with a higher probability of laying eggs on food (diameter ~ 3mm). However, the data are presented as median egg distances from the edge of the food, with each data point representing an assay median from a distribution that spans the entire length of the arena. The recorded effect sizes for different conditions are a fraction of a millimeter for distributions that span the entire arena. These effect sizes are smaller than the length of a worm. Also, after 20 hours of worms crawling on food, the edge of the lawn is more diffuse, with a variance that exceeds the effect size.
The authors present this as evidence of an intentional avoidance of food, but a simpler hypothesis is that the statistics of the worm's random walk have been altered as a response to predation. A larger rate of diffusion would also explain why the variance of body position and egg laying increases upon predation, and would cause the (very small) shift in median distance from the edge of the food. This is also consistent with the proposed role of dopamine, which is known to promote egg-laying during roaming (Cermak et al, 2020). The authors propose that predation increases dopamine release, which in turn leads to food avoidance, but an increased rate of egg-laying during roaming would also produce this effect.
Given the high variance and very small effect sizes observed, a simpler hypothesis of changes to random walk statistics is more parsimonious with the data, and what is already known about C. elegans random walk behavior, and how environmental cues and internal state alter the statistics of this behavior.
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