To survive, prey adjust their behavior to avoid predatory threat across a variety of situations. This repertoire of defensive behaviors includes reactions to predatory attacks, as well as proactive behaviors that promote vigilance and reduce vulnerability. Due to strong selective pressure, many prey species evolved escape responses to rapidly evade predatory attacks (Eaton, 2013; Evans et al., 2019). While instinctive and not requiring conscious thought, these responses consume significant energy and are less effective against anticipated threats. In situations that do not demand immediate action, prey can flexibly adjust their defensive strategy based on the specific threat context. These defensive strategies differ according to predatory imminence, which is the perceived spatial and temporal proximity of a predatory threat (Fanselow and Lester, 1988). In predatory imminence theory, defensive behaviors are categorized into three defense modes —pre-encounter, post-encounter, and circa-strike modes—each corresponding to increasing levels of predatory imminence—suspecting a predator, detecting a predator, and contact with a predatory attack (Fanselow and Lester, 1988). This framework has been primarily used to study rodent behaviors, such as escape actions (circa-strike), freezing (post-encounter), and altered meal patterns (pre-encounter), each linked to specific brain regions (Fanselow and Lester, 1988; Fanselow et al., 1988). Despite debates over relating animal defensive behaviors to human emotions like fear (Mobbs et al., 2019), the predatory imminence framework links circa-strike, post-encounter, and pre-encounter modes with panic, fear, and anxiety, respectively, based on threat and behavioral criteria rather than on similarity to humans in fear-related brain regions or responses to anxiolytic drugs (Perusini and Fanselow, 2015). However, this framework has predominantly been investigated with laboratory tests that use electric shocks (Fanselow and Lester, 1988; Fanselow, 1989; Helmstetter and Fanselow, 1993), rather than more naturalistic threat stimuli. Moreover, despite its species-agnostic approach, the predatory imminence framework has seldom been used to explore defensive behaviors in invertebrate models.

In naturalistic environments, prey face the dilemma of balancing the risk of predation with the need to forage, a challenge that intensifies in food-rich areas also marked by high predation risk. To navigate this balance, prey develop strategies to move between food-rich, high-risk areas and refuges, which are areas with less food but also low predation risk (Sih, 1987). Maximally safe strategies, such residing only in refuges, are often unsustainable as they result in starvation when food is scarce. Prey refuge theory, a branch of optimal foraging theory, identifies key factors influencing the use of refuges, such as predation risk, hunger level, feeding rates, and uncertainty (Sih, 1992). These factors are critical in post- and pre-encounter modes for assessing spaces for safety and adapting defensive strategies based on the particular risks and resources of the environment. Although previous studies, like those exploring the impact of electric shock on mice foraging in an operant chamber (Fanselow et al., 1988), have touched on these concepts, there has been little systematic integration of actual predators and refuges in lab studies guided by the predatory imminence framework. Recent approaches to evaluating defense modes across the predatory imminence spectrum rely on a battery of established laboratory tests (Hoffman et al., 2022), potentially complicating comparisons across defense modes due to widely varying experimental setups. Integrating predatory imminence and prey refuge theories enables us to develop behavioral tests for defense modes in a consistent and naturalistic environment, thus minimizing variables from different experimental designs.

Investigation of distinct defense modes within the same study can potentially shed light on the molecular regulation of threat behaviors and enhance the translatability of these insights. Since corticotropin-releasing factor (CRF) was identified in 1981 (Vale et al., 1981), its role in stress responses in both humans and animals has been a focus of research (Bale and Vale, 2004; Binder and Nemeroff, 2010), linking CRF system dysregulation to depression and anxiety, especially via the CRFR1 receptor (Reul and Holsboer, 2002; Arborelius et al., 1999; Heinrichs et al., 1997). However, CRFR1 antagonists, despite showing promise in animal studies, have struggled to become effective treatments in humans, partly because therapeutic indication is difficult to determine based on preclinical studies (Spierling and Zorrilla, 2017). These models often do not exhibit effects under normal conditions, requiring specific conditions to mimic stress responses, and the influence of CRF varies with the stress condition (Zorrilla and Koob, 2004). For instance, while high CRF levels correlate with PTSD in some human studies (Bremner et al., 1997; Sautter et al., 2003; Baker et al., 1999), this is not consistently seen in other anxiety disorders (Banki et al., 1992; Fossey et al., 1996; Jolkkonen et al., 1993). Additionally, research in mice shows that CRF can trigger opposite responses based on stress intensity (Lemos et al., 2012), suggesting the context of threat significantly impacts molecular mechanisms. However, variations in experimental setups and outcomes across studies complicate cross-study comparisons (Bale and Vale, 2004; Atli et al., 2016). Thus, to better understand the molecular dynamics of defensive behavior shifts, it is essential to study these behaviors through well-defined threat stages within a consistent framework in a single study.

To bridge this gap, we introduce a model system of nematode defensive behaviors with Caenorhabditis elegans as the prey and Pristionchus pacificus as the predator. Utilizing an invertebrate prey allows for investigation of interactions with life-threatening predators in a lab setting, avoiding the ethical constraints faced by rodent research. The lack of life-endangering threats in vertebrate research has been criticized as a limitation in the translatability of rodent anxiety behavior tests (Bach, 2022). While C. elegans is an obligate bacteriovore, P. pacificus is omnivorous and can choose to eat bacteria, which it prefers, or to bite and kill nematode prey for food (Serobyan et al., 2014; Wilecki et al., 2015). C. elegans has been found alongside Pristionchus sp. nematodes in samples collected from the wild (Félix et al., 2018), suggesting that C. elegans may be more likely to recognize P. pacificus as a predator than other known artificial aversive stimuli, such as blue light or electric shocks. While P. pacificus can kill larval C. elegans, adults can survive hours of repeated biting (Wilecki et al., 2015; Quach and Chalasani, 2022), enabling them to learn from these encounters and adapt their behaviors. Additionally, C. elegans has been shown to form a learned association of a bacterial patch with predation risk, as C. elegans does not innately avoid food patches occupied by Pristionchus sp. or conditioned with their secretions (Quach and Chalasani, 2022; Pribadi et al., 2023). P. pacificus tends to stay within bacterial food patches (Quach and Chalasani, 2022), creating a natural setup of risky patches and safe refuge surrounding the patch. Leveraging this setup, our model system of nematode defensive behaviors applies predatory imminence and prey refuge theories to explore C. elegans’ navigation of patch and refuge areas across defense modes.

Just as specific brain regions in rodents correlate with defense modes in predatory imminence theory, we aim to identify distinct molecular mechanisms driving defense modes in nematodes. Our focus is on SEB-3, a G protein-coupled receptor in C. elegans (Jee et al., 2013), and NLP-49, a neuropeptide locus where one of the peptides has been identified as a ligand for SEB-3 (Beets et al., 2023; Chew et al., 2018). Although SEB-3 initially appeared similar to mammalian CRF receptors, particularly CRFR1 (Cardoso et al., 2006; Jee et al., 2013; Jee et al., 2016), recent reports suggest that it is more closely related to invertebrate pigment-dispersing factor (PDF) receptors (Elphick et al., 2018; Mirabeau and Joly, 2013). Despite this, both CRF and PDF receptors are part of the secretin superfamily of receptors, with evidence suggesting that SEB-3 may influence some behaviors similarly to CRF receptors (Jee et al., 2013; Jee et al., 2016; Chew et al., 2018). Similar to the mammalian CRF signaling system, there are conflicting reports on the role SEB-3 signaling in nematode stress responses. The role SEB-3/NLP-49–3 signaling in stress response is debated, with some studies linking reduced signaling to low stress and increased signaling to high stress (Jee et al., 2013; Chew et al., 2018). One study indicating increased SEB-3 signaling reduces stress-like behaviors (Jee et al., 2016). This conflicting study differs from the others, which focus on basal stress indicators such as locomotion and arousal, by focusing on a choice between continuing to mate or escaping aversive blue light (Jee et al., 2016). Our model system of defensive behaviors also involves choosing between continuing an appealing activity and avoiding an aversive stimulus. Thus we hypothesize that decreased SEB-3/NLP-49-2 signaling will enhance defensive behaviors in our model system, while increased signaling will reduced defensive behaviors. However, we expect that the specific roles of and interactions between SEB-3 and NLP-49-2 will differ across defense modes. Overall, we demonstrate that our model system of nematode defensive behaviors can be successfully used to interrogate the specific behavioral targets of NLP-49 and SEB-3 signaling and interaction. By maintaining a consistent test environment across defense modes, we are able to attribute differences in molecular regulation to the defense mode itself, facilitating a more robust understanding of stress-related molecular signaling.

Our model system offers a comprehensive view of nematode defensive behaviors, focusing on the adaptive strategies C. elegans employs in utilizing patch and refuge spaces while foraging under predatory threat. This approach integrates principles from both prey refuge theory and predatory imminence theory. Predatory imminence theory helps us categorize defensive behaviors into distinct defense modes based on the spatiotemporal proximity of predatory attack, which dictates the urgency with which prey need to deal with predatory threat. Prey refuge theory, on the other hand, provides a framework for understanding the decision-making process of C. elegans as it navigates the trade-offs between feeding and safety when predation risk varies across space. This creates a consistent and predictable environment for examining how C. elegans should flexibly adjust its behavior in each defense mode to achieve optimal patch and refuge use. Our model delineates three defense modes that describe how C. elegans interacts with a predator-associated patch and a predator-free refuge, each representing different levels of predatory imminence, uncertainty, and experience (Figure 1A). In the circa-strike mode, C. elegans responds to a predatory bite by executing an escape response, exiting the patch, and then reentering the patch. With repeated experiences of bites and circa-strike responses, C. elegans learns to associate the patch with predation risk and develops anticipatory behaviors for future encounters in post- and pre-encounter defense modes. In the post-encounter mode, C. elegans assumes an outstretched feeding posture for feeding at the periphery of a patch that it knows to be inhabited by predators. In the pre-encounter defense mode, when approaching a new patch without specific knowledge of its safety, C. elegans is less quick to enter and explore the new patch, influenced by its accumulated experiences of predation risk associated with similar patches. These defense modes provide a narrative on how C. elegans might acquire and apply them in its natural life, shaped by experience and perceived predation risk. The consistent patch and refuge foraging environment across these modes allows for behavioral changes to be attributed to C. elegans’s changing perceptions and experiences, rather than external setup variations. This model thus bridges the behaviors observed in C. elegans with underlying theories of predator–prey interactions, offering insights into the complex decision-making processes that nematode prey may face in the wild.

Our research demonstrates that only life-threatening predators trigger all three defense modes in nematode behavioral models, highlighting how C. elegans differentiates between non-threatening, aversive but nonlethal, and life-endangering threats through a variety of responses. Consistent with the function of escape responses as innate reflexes for immediate evasion of mechanosensory stimuli (Pirri and Alkema, 2012), C. elegans executes similar numbers of escape responses for all aversive predators in our study (Figure 2B). In contrast, our study shows that more nuanced behaviors are possible when C. elegans has more time to make a behavioral choice, especially in decision-making contexts in with food access and predation risk are conflicting factors. In the circa-strike mode (exit phase) and the post-encounter mode, responses are split into three tiers of intensity: minimal response to non-aversive predators, intermediate responses to aversive but nonlethal predators (including predators that are lethal on a irrelevantly long timescale), and maximal responses to predators that are life-threatening within the timescale of the behavioral experiments (Figure 2C and E). The pre-encounter mode has the highest threshold for eliciting a defensive response, which is only observed when C. elegans is exposed to life-threatening predators (Figure 2F and G). Notably, the pre-encounter defense mode reveals C. elegans’s ability to adapt its approach to new patches based on past experiences with patches inhabited by life-threatening predators, an adjustment that is reversible with subsequent exposure to predator-free patches (Figure 1—figure supplement 3D). This underscores the importance of threat severity in behavioral studies, contributing to the debate on the adequacy of using non-life-threatening stimuli to capture a full range of animal responses to danger.

Our study reveals that the defense modes in our nematode behavior model are not merely theoretical constructs but reflect physiologically distinct states driven by specific molecular mechanisms. While previous research has found that NLP-49 peptides largely act through SEB-3 in managing a variety of basal and stimulus-evoked stress responses (Chew et al., 2018), our findings indicate a divergence in how NLP-49 peptides and SEB-3 influence defensive behaviors, with this divergence varying across different defense modes. Specifically, altered seb-3 but not nlp-49 expression modulates behavior in the defense mode/phase with the highest predatory imminence (circa-strike, exit phase) (Figure 3A and B), while altered nlp-49 but not seb-3 expression influences behavior in the defense mode with the lowest predatory imminence (pre-encounter) (Figure 3G and H, Figure 3—figure supplement 4). Interestingly, while SEB-3 and NLP-49 peptides show some interdependence in the exit phase of the circa-strike mode (Figure 4A), NLP-49 peptides operate independently of SEB-3 in the pre-encounter mode (Figure 4E and F). Between these extremes of predatory imminence, changes in the expression of both seb-3 and nlp-49 affect defensive behaviors, but in ways that are incongruous or independent. While nlp-49 and seb-3 deletion mutants have similar enhanced phenotypes in the reentry phase of the circa-strike mode (Figure 3C and D), the loss of these phenotypes in double mutants (Figure 4) suggest that this behavior is not entirely modulated by NLP-49 peptides binding to the SEB-3 receptor. Although overexpression of seb-3 and nlp-49 both suppress post-encounter responses, nlp-49 deletion enhances these responses while seb-3 deletion has no effect (Figure 3E and F). Remarkably, seb-3 overexpression animals exhibit normal behavior in the pre-encounter mode despite showing almost no response in the post-encounter mode, even though both involve extended exposure to predators (Figure 3E and G), illustrating that a deficit in one defense mode does not necessarily affect performance in another. This evidence highlights the physiological distinctiveness of the defense modes in our model system of nematode defensive behaviors. Furthermore, our results emphasize the complex interplay between SEB-3 and NLP-49 peptides, pointing to the need for further investigation into their underlying mechanisms. Moreover, our model serves as a useful instrument for an in-depth examination of the molecular signaling that drives defensive responses.

Our study extends previous findings on SEB-3’s role in how C. elegans chooses between stimuli with opposite valences. In a prior study, male C. elegans were subjected to aversive blue light while mating, while researchers measured the time it took for males to disengage from mating in order to escape the blue light (Jee et al., 2016). This behavior most closely mirrors the exit phase of the circa-strike mode in our study, where C. elegans faces a choice between continuing to feed on a bacterial patch or exiting after a predator bite. In both cases, C. elegans must decide between pursuing a desirable activity (mating or feeding) and evading an unpleasant one (blue light or a predator). Our research corroborates the other study’s finding that enhancing SEB-3 function promotes C. elegans to persist in the appetitive behavior amidst aversive factors. Building on these findings, we delve into defensive behaviors shaped by repeated encounters with acute threats, aiming to understand the broader implications of molecular regulation in these scenarios. Future research could explore the response to other known paradigms for exposing C. elegans to natural threats like predatory fungi (Maguire et al., 2011) or artificial threats such as blue light or electric shocks (Rankin et al., 1990; Tee et al., 2023), shedding light on whether C. elegans differentiates between natural and artificial threats. Investigating roles of SEB-3 and NLP-49 peptides during extended exposure to mating under aversive conditions could provide further comparative insights, particularly on the generalizability of our study’s conclusions across experimental conditions. It is important to clarify that our focus is on specific stress responses triggered by predatory threat, distinct from general stress indicators, such as hyperarousal and baseline locomotion. This distinction might explain why other studies linking SEB-3 and NLP-49 peptides to baseline stress behaviors have found contrasting results to ours regarding threat-induced responses (Jee et al., 2013; Chew et al., 2018), suggesting a need for further investigation to resolve these discrepancies.

Our study represents the continuation of ours and others’ efforts to incorporate principles from ethology, behavioral ecology, and related fields into developing naturalistic and complex laboratory models of decision-making (Krakauer et al., 2017; Mobbs et al., 2018). Previously, we leveraged concepts from intraguild predation, neuroeconomics, and foraging theory to understand the motivations behind a predator’s interactions with a prey that competes for the same bacterial food source (Quach and Chalasani, 2022). Using a similar foraging setup, the current study focuses on the prey’s perspective and completes our exploration of both sides of this particular predator–prey interaction. Our work provides intricate and specific micro-scale insights into the behavioral ecology of flexible predator–prey interactions, which complements the more complex and broad insights of meso- and macro-scale ecology of predator–prey interactions in larger and less controlled ecosystems. Specifically, we address the concept of ‘prey refuge’ within the broader, more recent framework of the ‘landscape of fear’, coined in 2001 to describe spatial variation in prey perception of predation risk (Laundré et al., 2001). Our focused study on interactions between a single prey and a few predators contrasts with broader landscape of fear research, which often examines predator–prey dynamics of free-ranging predators and prey on complex landscapes, the cascading effects of these interactions on ecosystem structure, and how spatial variation in predation risk evolves over time (Gaynor et al., 2019; Palmer et al., 2022). A common challenge in landscape of fear studies is reconciling actual predation risk with perceived predation risk. Accurately predicting the impact of prey’s anti-predator behaviors on population and ecosystem levels necessitates a deep understanding of the external and internal factors influencing prey responses at the individual level. While models of prey refuge have laid the groundwork for exploring the landscape of fear in more complex ecological systems (Sih, 1987), our work adds a new dimension by considering predator imminence as another critical factor influencing prey’s spatial behavior. This study, together with its companion study on predator decision-making (Quach and Chalasani, 2022), demonstrates that complex behavioral theories applicable to advanced nervous systems are also relevant to the simpler neural circuits of nematodes. By deconstructing complex behaviors and decision-making relevant to a nematode’s natural life, we can adapt existing theories to the unique aspects of nematode life and interactions.

All data generated or analysed during this study are included in the manuscript and supporting files.

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Author details

1. Kathleen T Quach

   Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, United States

   Contribution

   Conceptualization, Data curation, Software, Formal analysis, Funding acquisition, Investigation, Visualization, Methodology, Writing – original draft, Project administration, Writing – review and editing

   For correspondence

   kthln.t.qch@gmail.com

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-8498-1464

2. Gillian A Hughes

   Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, United States

   Contribution

   Data curation, Formal analysis, Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

3. Sreekanth H Chalasani

   Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, United States

   Contribution

   Supervision, Funding acquisition, Project administration, Writing – review and editing

   For correspondence

   schalasani@salk.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-2522-8338

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