- Email: [email protected]
Behavior: Should I Stay or Should I Go?
Current Biology
Dispatches REFERENCES 1. von Frisch, K. (1949). Die Polarisation des Himmelslichtes als orientierender Faktor bei €nzen der Bienen. Experientia 5, den Ta 142–148. 2. Wehner, R., and Mu¨ller, M. (2006). The significance of direct sunlight and polarized skylight in the ant’s celestial system of navigation. Proc. Natl. Acad. Sci. USA 103, 12575–12579. 3. Reppert, S.M., Gegear, R.J., and Merlin, C. (2010). Navigational mechanisms of migrating monarch butterflies. Trends Neurosci. 33, 399–406. 4. Homberg, U., Heinze, S., Pfeiffer, K., Kinoshita, M., and el Jundi, B. (2011). Central neural coding of sky polarization in insects. Philos. Trans. R. Soc. Lond. B 366, 680–687. 5. Hu, G., Lim, K.S., Horvitz, N., Clark, S.J., Reynolds, D.R., Sapir, N., and Chapman, J.W. (2016). Mass seasonal bioflows of high-flying insect migrants. Science 354, 1584–1587. 6. Coyne, J.A., Boussy, I.A., Prout, T., Bryant, S.H., Jones, J.S., and Moore, J.A. (1982). Long-Distance Migration of Drosophila. Am. Nat. 119, 589–595.
7. Warren, T.L., Giraldo, Y.M., and Dickinson, M.H. (2019). Celestial navigation in Drosophila. J. Exp. Biol. 222.
composition of the central complex of the monarch butterfly. J. Comp. Neurol. 521, 267–298.
8. Sancer, G., Kind, E., Plazaola-Sasieta, H., Balke, J., Pham, T., Hasan, A., Mu¨nch, L.O., Courgeon, M., Mathejczyk, T.F., and Wernet, M.F. (2019). Modality-specific circuits for skylight orientation in the fly visual system. Curr. Biol. 29, 2812–2825.
13. Labhart, T., Petzold, J., and Helbling, H. (2001). Spatial integration in polarizationsensitive interneurones of crickets: a survey of evidence, mechanisms and benefits. J. Exp. Biol. 204, 2423–2430.
9. Labhart, T., and Meyer, E.P. (1999). Detectors for polarized skylight in insects: a survey of ommatidial specializations in the dorsal rim area of the compound eye. Microsc. Res. Tech. 47, 368–379. 10. Wehner, R., and Labhart, T. (2006). Polarisation vision. In Invertebrate Vision (Cambridge, UK: Cambridge University Press), pp. 291–348. 11. Weir, P.T., Henze, M.J., Bleul, C., BaumannKlausener, F., Labhart, T., and Dickinson, M.H. (2016). Anatomical reconstruction and functional imaging reveal an ordered array of skylight polarization detectors in Drosophila. J. Neurosci. 36, 5397–5404. 12. Heinze, S., Florman, J., Asokaraj, S., El Jundi, B., and Reppert, S.M. (2013). Anatomical basis of sun compass navigation II: the neuronal
14. Homberg, U. (2004). In search of the sky compass in the insect brain. Naturwissenschaften 91, 199–208. 15. Salcedo, E., Huber, A., Henrich, S., Chadwell, L.V., Chou, W.H., Paulsen, R., and Britt, S.G. (1999). Blue- and green-absorbing visual pigments of Drosophila: ectopic expression and physiological characterization of the R8 photoreceptor cell-specific Rh5 and Rh6 rhodopsins. J. Neurosci. 19, 10716–10726. 16. Fischbach, K.-F., and Dittrich, A.P.M. (1989). The optic lobe of Drosophila melanogaster. I. A Golgi analysis of wild-type structure. Cell Tissue Res. 258, 441–475. 17. Melnattur, K.V., Pursley, R., Lin, T.-Y., Ting, C.-Y., Smith, P.D., Pohida, T., and Lee, C.-H. (2014). Multiple redundant medulla projection neurons mediate color vision in Drosophila. J. Neurogenet. 28, 374–388.
Behavior: Should I Stay or Should I Go? Brian D. Ackley Department of Molecular Biosciences, The University of Kansas, Lawrence, KS 66045, USA Correspondence: [email protected] https://doi.org/10.1016/j.cub.2019.07.057
Laboratory-conditioned ‘wild-type’ Caenorhabditis elegans are different from wild-isolated strains. Now it seems some differences lead lab-conditioned animals to act irrationally after experiencing starvation early in development. This increases the repertoire of behaviors we can study with these fascinating animals. When you get hungry on a road trip, do you stop at the first restaurant that comes along or look for options? Does it make a difference if it is the first restaurant you have seen in hours or are passing them regularly? What if it is your favorite food versus the last time you ate there you got food poisoning? When we make decisions, we integrate current data (options, risks/ rewards) and our past experiences. In an article by Pradhan et al. [1] published in this issue of Current Biology, the authors examine how Caenorhabditis elegans manage a similar situation. C. elegans are bacterivores and in their work the authors set up different opportunities for the
animals to stay in a provided lawn of bacteria or leave and forage for other, perhaps better, bacteria. Food-leaving behavior is common in the N2 strain, used by almost every C. elegans lab as the ‘wild type’. N2 worms will come and go from a bacterial lawn, independent of previous experiences of food scarcity or starvation. Conversely, strains more recently isolated from the wild make a different calculus. Without any aversive experiences they leave food as often as N2. Pradhan et al., however, show that if wild isolates experience a period of early starvation, and enter the dauer diapause, then as adults they will forage less, and stay closer
R842 Current Biology 29, R829–R850, September 9, 2019 ª 2019 Elsevier Ltd.
to the original food source [1]. This suggests their experience makes them now value available food more than the possibility of better food elsewhere. Food is, of course, a basic necessity. Scientists have used food as a reward in a multitude of behavioral paradigms, e.g., Pavlov’s proverbial bell or Skinner’s lever. Evolutionarily, food availability or preference has been a major adaptive force. Just ask Darwin’s finches or think about how stabilized food production, via agriculture, and the energetic benefits of cooking enabled increased brain size in hominids. Thus, we can understand why organisms might seek better nutrient
Current Biology
Dispatches sources. Work studying Caenorhabditis in their native environments has uncovered more about their food preferences, microbiomes and feeding behaviors. As it turns out, the commonly used food, Escherichia coli, is not preferred by C. elegans in the wild, or in the lab, if given a choice [2,3]. Also, ingesting different bacteria can help the animals manage pathogenic infections [4,5], and therefore, food variety might be protective, in addition to nutritious. Finally, differences in nutrient content, e.g. fatty acids, are critical to germline development and reproductive capacity [6]. Thus, even when E. coli are provided ad libitum, it makes sense that the animals might forage for other food. Scientists have used food as a motivator to study behavior and learning in C. elegans. The animals use oxygen, carbon dioxide and/or odors to move toward or away from bacteria, using specific neurons to sense these compounds [7,8]. They can learn to associate odors and/or temperature with food, and will exhibit chemotaxis or thermotaxis after the stimulus is associated with foods [9]. Worms can learn to avoid pathogenic bacteria after early exposure [10]. Genetic screens and cellular ablation/manipulations have allowed us to better understand the genetic and neural architecture of these abilities. Perhaps one of the more interesting findings to emerge from these studies is that transcription factors in C. elegans can act as terminal selectors for individual neuronal identity, and that mutations in those genes can completely ablate the behavior, while leaving other behaviors intact [11]. In the study by Pradhan et al., however, there is more going on than just associating a stimulus with a reward. In essence, the worms have to weigh outcomes and scale the reward of foraging with the risk of starvation. The wildisolated animals demonstrate more conservative behaviors, while the more risk-prone, laboratory-conditioned animals act as if they have an irrational belief that they will always find food when they forage. In some ways, this is similar to the construct of delay discounting, used by psychologists and behavioral economists to study human behavior. Would you prefer five dollars today or twenty next week? People can have different
Environmental cues Sensory neurons (BAG, URX, NSM, ADF)
Past experiences Sensory and interneurons (AWA, AWB, AIB, AIY, RIA)
Oxygen Carbon dioxide Bacteria (Friend or foe)
Associated odors Temperature Previous pathogen exposure Starvation
Motor and interneurons Forage? glb-5
Nutrient status Pathogen presence
Internal cues Intestine, Germline, Sensory neurons (NSM, ADF)
Current Biology
Figure 1. A potential circuit for integrating internal and external stimuli in the foraging decision. Some of the different information modalities C. elegans process during foraging behavior. Some of the sensory neurons that collect the information and interneurons that process the information are presented (C. elegans neurons are labeled with three and four letter codes, e.g. BAG, URX, etc.). Signals from the intestine and germline provide feedback to the nervous system directly or may also be released systemically in an endocrine-like fashion. Where the decision to forage or not is made remains to be determined; it is likely an interneuron(s), and likely to express the glb-5 gene.
motivations for why they would take the immediate versus delayed rewards, which enriches our understanding of decision making, but makes it more difficult (but certainly not impossible) to isolate genetic factors and/or neurological systems that regulate those decisions [12]. Investigators have previously noticed behavioral and fitness differences between N2 and wild isolates. Classically, it was noticed that N2 animals are solitary feeders, but many wild isolates feed in social clumps. The difference in this behavior can be explained by a natural allelic variant of the npr-1/Neuropeptide Y receptor gene [13]. However, other differences in their fitness have also been
noted, and variation in both npr-1 and glb5/Neuroglobin appears to explain some, but not all, of those differences [14]. In the Pradhan article, the status of npr-1 had no effect on starvation-dependent foraging, but the glb-5 variant did. To test where in the nervous system the decision to forage or not might be made the authors provided food to the animals in a microfluidic chamber, either at high or low concentration, and switched between the two to mimic leaving and reentering a bacterial lawn. Using calcium imaging the authors found that two neurons, AVA and RIM, changed how they responded to the switch in food concentration if the animals went through dauer. Next, in freely moving
Current Biology 29, R829–R850, September 9, 2019 R843
Current Biology
Dispatches animals, they inactivated neurons, using a histamine-gated chloride channel. Inactivating AVA resulted in animals with altered locomotion, specifically, movements that were confined to a smaller search area. These results begin to explain the behavioral changes, but do not yet fully elucidate the differences in starvationinduced foraging. So how are animals processing their developmental experience, storing it, then using it in their decision about whether to forage? There are advantages to having food variety, whether it be an animal’s health and well-being or the ability to generate offspring. Thus, we should probably look at the interplay between the intestine, the germline and the nervous system. Figure 1 describes the kinds of sensory (external and internal) information and past experiences that might be important in the ‘forage or not’ decision, but where those sensory inputs are being integrated, specifically for the foraging decision remains a black box for now. From a molecular perspective, there are some obvious candidates that might contribute to this behavior. For example, both insulin and TGFb signaling regulate dauer formation [15], and both pathways contribute to the innate immune responses to pathogens [16]. The daf-2 gene is the best characterized, but there are over 30 genes encoding insulin-like peptides, any one of which might be involved in resetting neuronal network activity as a consequence of starvation during development. Humoral endocrine-like feedback from the intestine to individual neurons occurs when animals experience stress, e.g. pathogenic colonization or mitochondrial impairment [17,18]. Although npr-1 was not found to be involved in this specific behavior, it represents only one of the 35 different npr/neuropeptide-like receptor genes in the genome that could be modulating neuroendocrine signaling. Alternatively, a more traditional neurotransmitter might be important in this behavior. Serotonin signaling is known to regulate both satiety and egg-laying in C. elegans [19]. Serotonin is known to be critical to behavioral responses to stress, or distress, in humans and other organisms. Serotonin can also lead to alterations in how neuronal activity is tied to different stressors, both in the short and long term, perhaps most famously shown in Aplysia habituation studies, but has been
confirmed many times since. We could hypothesize that, if the animal felt more distressed, the possibility of not finding better food elsewhere might not make it worth leaving the food provided. Serotonin defects do change locomotor behavior in response to food in C. elegans. Specifically, changes in serotonin signaling reduces the rate of forward locomotion [20], and this could clearly affect foraging behaviors. Ultimately, we will need to wait for the worm to tell us. The studies described above come from loss or gain of function mutations or cell-specific manipulations, almost exclusively in the N2 strain. Here the differences are more likely allelic variants that might alter protein function, or regulatory differences that might affect expression. Thus, the genetics of this behavior will be very interesting. Although this appears to be a binary question of ‘should I stay or should I go?’ it really is more of a ‘should I stay or should I go, now?’ question. This is a decision the animal makes over and over again, and thus the genetic differences are really shifting the distribution of the stay/go probability. This is a complex behavior, but one in a well-characterized system, with powerful genetic and cell biological tools. I for one am anxious to find out how worms make this decision, and I look forward to finding other examples of rational/irrational actions in these animals. Now, where should I go for lunch today? REFERENCES 1. Pradhan, S., Quilez, S., Homer, K., and Hendricks, M. (2019). Environmental programming of adult foraging behavior in C. elegans. Curr. Biol. 29, 2867–2879. 2. Abada, E.A., Sung, H., Dwivedi, M., Park, B.J., Lee, S.K., and Ahnn, J. (2009). C. elegans behavior of preference choice on bacterial food. Mol. Cells 28, 209–213. 3. Dirksen, P., Marsh, S.A., Braker, I., Heitland, N., Wagner, S., Nakad, R., Mader, S., Petersen, C., Kowallik, V., Rosenstiel, P., et al. (2016). The native microbiome of the nematode Caenorhabditis elegans: gateway to a new host-microbiome model. BMC Biol. 14, 38. 4. Samuel, B.S., Rowedder, H., Braendle, C., Felix, M.A., and Ruvkun, G. (2016). Caenorhabditis elegans responses to bacteria from its natural habitats. Proc. Natl. Acad. Sci. USA 113, E3941–E3949. 5. Graham, C.E., Cruz, M.R., Garsin, D.A., and Lorenz, M.C. (2017). Enterococcus faecalis bacteriocin EntV inhibits hyphal morphogenesis, biofilm formation, and
R844 Current Biology 29, R829–R850, September 9, 2019
virulence of Candida albicans. Proc. Natl. Acad. Sci. USA 114, 4507–4512. 6. Tang, H., and Han, M. (2017). Fatty acids regulate germline sex determination through ACS-4-dependent myristoylation. Cell 169, 457–469.e413. 7. Gray, J.M., Karow, D.S., Lu, H., Chang, A.J., Chang, J.S., Ellis, R.E., Marletta, M.A., and Bargmann, C.I. (2004). Oxygen sensation and social feeding mediated by a C. elegans guanylate cyclase homologue. Nature 430, 317–322. 8. Hallem, E.A., and Sternberg, P.W. (2008). Acute carbon dioxide avoidance in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 105, 8038–8043. 9. L’Etoile, N.D., and Bargmann, C.I. (2000). Olfaction and odor discrimination are mediated by the C. elegans guanylyl cyclase ODR-1. Neuron 25, 575–586. 10. Zhang, Y., Lu, H., and Bargmann, C.I. (2005). Pathogenic bacteria induce aversive olfactory learning in Caenorhabditis elegans. Nature 438, 179–184. 11. Hobert, O. (2016). Terminal selectors of neuronal identity. Curr. Top. Dev. Biol. 116, 455–475. 12. Anokhin, A.P., Grant, J.D., Mulligan, R.C., and Heath, A.C. (2015). The genetics of impulsivity: evidence for the heritability of delay discounting. Biol. Psychiatry 77, 887–894. 13. de Bono, M., and Bargmann, C.I. (1998). Natural variation in a neuropeptide Y receptor homolog modifies social behavior and food response in C. elegans. Cell 94, 679–689. 14. Zhao, Y., Long, L., Xu, W., Campbell, R.F., Large, E.E., Greene, J.S., and McGrath, P.T. (2018). Changes to social feeding behaviors are not sufficient for fitness gains of the Caenorhabditis elegans N2 reference strain. eLife 7, e38675. 15. Kimura, K.D., Tissenbaum, H.A., Liu, Y., and Ruvkun, G. (1997). daf-2, an insulin receptorlike gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277, 942–946. 16. Garsin, D.A., Villanueva, J.M., Begun, J., Kim, D.H., Sifri, C.D., Calderwood, S.B., Ruvkun, G., and Ausubel, F.M. (2003). Long-lived C. elegans daf-2 mutants are resistant to bacterial pathogens. Science 300, 1921. 17. Singh, J., and Aballay, A. (2019). Microbial colonization activates an immune fight-andflight response via neuroendocrine signaling. Dev. Cell 49, 89–99.e4. 18. Zhang, Q., Wu, X., Chen, P., Liu, L., Xin, N., Tian, Y., and Dillin, A. (2018). The mitochondrial unfolded protein response is mediated cellnon-autonomously by retromer-dependent Wnt signaling. Cell 174, 870–883.e17. 19. Segalat, L., Elkes, D.A., and Kaplan, J.M. (1995). Modulation of serotonin-controlled behaviors by Go in Caenorhabditis elegans. Science 267, 1648–1651. 20. Wakabayashi, T., Osada, T., and Shingai, R. (2005). Serotonin deficiency shortens the duration of forward movement in Caenorhabditis elegans. Biosci. Biotechnol. Biochem. 69, 1767–1770.
Dispatches REFERENCES 1. von Frisch, K. (1949). Die Polarisation des Himmelslichtes als orientierender Faktor bei €nzen der Bienen. Experientia 5, den Ta 142–148. 2. Wehner, R., and Mu¨ller, M. (2006). The significance of direct sunlight and polarized skylight in the ant’s celestial system of navigation. Proc. Natl. Acad. Sci. USA 103, 12575–12579. 3. Reppert, S.M., Gegear, R.J., and Merlin, C. (2010). Navigational mechanisms of migrating monarch butterflies. Trends Neurosci. 33, 399–406. 4. Homberg, U., Heinze, S., Pfeiffer, K., Kinoshita, M., and el Jundi, B. (2011). Central neural coding of sky polarization in insects. Philos. Trans. R. Soc. Lond. B 366, 680–687. 5. Hu, G., Lim, K.S., Horvitz, N., Clark, S.J., Reynolds, D.R., Sapir, N., and Chapman, J.W. (2016). Mass seasonal bioflows of high-flying insect migrants. Science 354, 1584–1587. 6. Coyne, J.A., Boussy, I.A., Prout, T., Bryant, S.H., Jones, J.S., and Moore, J.A. (1982). Long-Distance Migration of Drosophila. Am. Nat. 119, 589–595.
7. Warren, T.L., Giraldo, Y.M., and Dickinson, M.H. (2019). Celestial navigation in Drosophila. J. Exp. Biol. 222.
composition of the central complex of the monarch butterfly. J. Comp. Neurol. 521, 267–298.
8. Sancer, G., Kind, E., Plazaola-Sasieta, H., Balke, J., Pham, T., Hasan, A., Mu¨nch, L.O., Courgeon, M., Mathejczyk, T.F., and Wernet, M.F. (2019). Modality-specific circuits for skylight orientation in the fly visual system. Curr. Biol. 29, 2812–2825.
13. Labhart, T., Petzold, J., and Helbling, H. (2001). Spatial integration in polarizationsensitive interneurones of crickets: a survey of evidence, mechanisms and benefits. J. Exp. Biol. 204, 2423–2430.
9. Labhart, T., and Meyer, E.P. (1999). Detectors for polarized skylight in insects: a survey of ommatidial specializations in the dorsal rim area of the compound eye. Microsc. Res. Tech. 47, 368–379. 10. Wehner, R., and Labhart, T. (2006). Polarisation vision. In Invertebrate Vision (Cambridge, UK: Cambridge University Press), pp. 291–348. 11. Weir, P.T., Henze, M.J., Bleul, C., BaumannKlausener, F., Labhart, T., and Dickinson, M.H. (2016). Anatomical reconstruction and functional imaging reveal an ordered array of skylight polarization detectors in Drosophila. J. Neurosci. 36, 5397–5404. 12. Heinze, S., Florman, J., Asokaraj, S., El Jundi, B., and Reppert, S.M. (2013). Anatomical basis of sun compass navigation II: the neuronal
14. Homberg, U. (2004). In search of the sky compass in the insect brain. Naturwissenschaften 91, 199–208. 15. Salcedo, E., Huber, A., Henrich, S., Chadwell, L.V., Chou, W.H., Paulsen, R., and Britt, S.G. (1999). Blue- and green-absorbing visual pigments of Drosophila: ectopic expression and physiological characterization of the R8 photoreceptor cell-specific Rh5 and Rh6 rhodopsins. J. Neurosci. 19, 10716–10726. 16. Fischbach, K.-F., and Dittrich, A.P.M. (1989). The optic lobe of Drosophila melanogaster. I. A Golgi analysis of wild-type structure. Cell Tissue Res. 258, 441–475. 17. Melnattur, K.V., Pursley, R., Lin, T.-Y., Ting, C.-Y., Smith, P.D., Pohida, T., and Lee, C.-H. (2014). Multiple redundant medulla projection neurons mediate color vision in Drosophila. J. Neurogenet. 28, 374–388.
Behavior: Should I Stay or Should I Go? Brian D. Ackley Department of Molecular Biosciences, The University of Kansas, Lawrence, KS 66045, USA Correspondence: [email protected] https://doi.org/10.1016/j.cub.2019.07.057
Laboratory-conditioned ‘wild-type’ Caenorhabditis elegans are different from wild-isolated strains. Now it seems some differences lead lab-conditioned animals to act irrationally after experiencing starvation early in development. This increases the repertoire of behaviors we can study with these fascinating animals. When you get hungry on a road trip, do you stop at the first restaurant that comes along or look for options? Does it make a difference if it is the first restaurant you have seen in hours or are passing them regularly? What if it is your favorite food versus the last time you ate there you got food poisoning? When we make decisions, we integrate current data (options, risks/ rewards) and our past experiences. In an article by Pradhan et al. [1] published in this issue of Current Biology, the authors examine how Caenorhabditis elegans manage a similar situation. C. elegans are bacterivores and in their work the authors set up different opportunities for the
animals to stay in a provided lawn of bacteria or leave and forage for other, perhaps better, bacteria. Food-leaving behavior is common in the N2 strain, used by almost every C. elegans lab as the ‘wild type’. N2 worms will come and go from a bacterial lawn, independent of previous experiences of food scarcity or starvation. Conversely, strains more recently isolated from the wild make a different calculus. Without any aversive experiences they leave food as often as N2. Pradhan et al., however, show that if wild isolates experience a period of early starvation, and enter the dauer diapause, then as adults they will forage less, and stay closer
R842 Current Biology 29, R829–R850, September 9, 2019 ª 2019 Elsevier Ltd.
to the original food source [1]. This suggests their experience makes them now value available food more than the possibility of better food elsewhere. Food is, of course, a basic necessity. Scientists have used food as a reward in a multitude of behavioral paradigms, e.g., Pavlov’s proverbial bell or Skinner’s lever. Evolutionarily, food availability or preference has been a major adaptive force. Just ask Darwin’s finches or think about how stabilized food production, via agriculture, and the energetic benefits of cooking enabled increased brain size in hominids. Thus, we can understand why organisms might seek better nutrient
Current Biology
Dispatches sources. Work studying Caenorhabditis in their native environments has uncovered more about their food preferences, microbiomes and feeding behaviors. As it turns out, the commonly used food, Escherichia coli, is not preferred by C. elegans in the wild, or in the lab, if given a choice [2,3]. Also, ingesting different bacteria can help the animals manage pathogenic infections [4,5], and therefore, food variety might be protective, in addition to nutritious. Finally, differences in nutrient content, e.g. fatty acids, are critical to germline development and reproductive capacity [6]. Thus, even when E. coli are provided ad libitum, it makes sense that the animals might forage for other food. Scientists have used food as a motivator to study behavior and learning in C. elegans. The animals use oxygen, carbon dioxide and/or odors to move toward or away from bacteria, using specific neurons to sense these compounds [7,8]. They can learn to associate odors and/or temperature with food, and will exhibit chemotaxis or thermotaxis after the stimulus is associated with foods [9]. Worms can learn to avoid pathogenic bacteria after early exposure [10]. Genetic screens and cellular ablation/manipulations have allowed us to better understand the genetic and neural architecture of these abilities. Perhaps one of the more interesting findings to emerge from these studies is that transcription factors in C. elegans can act as terminal selectors for individual neuronal identity, and that mutations in those genes can completely ablate the behavior, while leaving other behaviors intact [11]. In the study by Pradhan et al., however, there is more going on than just associating a stimulus with a reward. In essence, the worms have to weigh outcomes and scale the reward of foraging with the risk of starvation. The wildisolated animals demonstrate more conservative behaviors, while the more risk-prone, laboratory-conditioned animals act as if they have an irrational belief that they will always find food when they forage. In some ways, this is similar to the construct of delay discounting, used by psychologists and behavioral economists to study human behavior. Would you prefer five dollars today or twenty next week? People can have different
Environmental cues Sensory neurons (BAG, URX, NSM, ADF)
Past experiences Sensory and interneurons (AWA, AWB, AIB, AIY, RIA)
Oxygen Carbon dioxide Bacteria (Friend or foe)
Associated odors Temperature Previous pathogen exposure Starvation
Motor and interneurons Forage? glb-5
Nutrient status Pathogen presence
Internal cues Intestine, Germline, Sensory neurons (NSM, ADF)
Current Biology
Figure 1. A potential circuit for integrating internal and external stimuli in the foraging decision. Some of the different information modalities C. elegans process during foraging behavior. Some of the sensory neurons that collect the information and interneurons that process the information are presented (C. elegans neurons are labeled with three and four letter codes, e.g. BAG, URX, etc.). Signals from the intestine and germline provide feedback to the nervous system directly or may also be released systemically in an endocrine-like fashion. Where the decision to forage or not is made remains to be determined; it is likely an interneuron(s), and likely to express the glb-5 gene.
motivations for why they would take the immediate versus delayed rewards, which enriches our understanding of decision making, but makes it more difficult (but certainly not impossible) to isolate genetic factors and/or neurological systems that regulate those decisions [12]. Investigators have previously noticed behavioral and fitness differences between N2 and wild isolates. Classically, it was noticed that N2 animals are solitary feeders, but many wild isolates feed in social clumps. The difference in this behavior can be explained by a natural allelic variant of the npr-1/Neuropeptide Y receptor gene [13]. However, other differences in their fitness have also been
noted, and variation in both npr-1 and glb5/Neuroglobin appears to explain some, but not all, of those differences [14]. In the Pradhan article, the status of npr-1 had no effect on starvation-dependent foraging, but the glb-5 variant did. To test where in the nervous system the decision to forage or not might be made the authors provided food to the animals in a microfluidic chamber, either at high or low concentration, and switched between the two to mimic leaving and reentering a bacterial lawn. Using calcium imaging the authors found that two neurons, AVA and RIM, changed how they responded to the switch in food concentration if the animals went through dauer. Next, in freely moving
Current Biology 29, R829–R850, September 9, 2019 R843
Current Biology
Dispatches animals, they inactivated neurons, using a histamine-gated chloride channel. Inactivating AVA resulted in animals with altered locomotion, specifically, movements that were confined to a smaller search area. These results begin to explain the behavioral changes, but do not yet fully elucidate the differences in starvationinduced foraging. So how are animals processing their developmental experience, storing it, then using it in their decision about whether to forage? There are advantages to having food variety, whether it be an animal’s health and well-being or the ability to generate offspring. Thus, we should probably look at the interplay between the intestine, the germline and the nervous system. Figure 1 describes the kinds of sensory (external and internal) information and past experiences that might be important in the ‘forage or not’ decision, but where those sensory inputs are being integrated, specifically for the foraging decision remains a black box for now. From a molecular perspective, there are some obvious candidates that might contribute to this behavior. For example, both insulin and TGFb signaling regulate dauer formation [15], and both pathways contribute to the innate immune responses to pathogens [16]. The daf-2 gene is the best characterized, but there are over 30 genes encoding insulin-like peptides, any one of which might be involved in resetting neuronal network activity as a consequence of starvation during development. Humoral endocrine-like feedback from the intestine to individual neurons occurs when animals experience stress, e.g. pathogenic colonization or mitochondrial impairment [17,18]. Although npr-1 was not found to be involved in this specific behavior, it represents only one of the 35 different npr/neuropeptide-like receptor genes in the genome that could be modulating neuroendocrine signaling. Alternatively, a more traditional neurotransmitter might be important in this behavior. Serotonin signaling is known to regulate both satiety and egg-laying in C. elegans [19]. Serotonin is known to be critical to behavioral responses to stress, or distress, in humans and other organisms. Serotonin can also lead to alterations in how neuronal activity is tied to different stressors, both in the short and long term, perhaps most famously shown in Aplysia habituation studies, but has been
confirmed many times since. We could hypothesize that, if the animal felt more distressed, the possibility of not finding better food elsewhere might not make it worth leaving the food provided. Serotonin defects do change locomotor behavior in response to food in C. elegans. Specifically, changes in serotonin signaling reduces the rate of forward locomotion [20], and this could clearly affect foraging behaviors. Ultimately, we will need to wait for the worm to tell us. The studies described above come from loss or gain of function mutations or cell-specific manipulations, almost exclusively in the N2 strain. Here the differences are more likely allelic variants that might alter protein function, or regulatory differences that might affect expression. Thus, the genetics of this behavior will be very interesting. Although this appears to be a binary question of ‘should I stay or should I go?’ it really is more of a ‘should I stay or should I go, now?’ question. This is a decision the animal makes over and over again, and thus the genetic differences are really shifting the distribution of the stay/go probability. This is a complex behavior, but one in a well-characterized system, with powerful genetic and cell biological tools. I for one am anxious to find out how worms make this decision, and I look forward to finding other examples of rational/irrational actions in these animals. Now, where should I go for lunch today? REFERENCES 1. Pradhan, S., Quilez, S., Homer, K., and Hendricks, M. (2019). Environmental programming of adult foraging behavior in C. elegans. Curr. Biol. 29, 2867–2879. 2. Abada, E.A., Sung, H., Dwivedi, M., Park, B.J., Lee, S.K., and Ahnn, J. (2009). C. elegans behavior of preference choice on bacterial food. Mol. Cells 28, 209–213. 3. Dirksen, P., Marsh, S.A., Braker, I., Heitland, N., Wagner, S., Nakad, R., Mader, S., Petersen, C., Kowallik, V., Rosenstiel, P., et al. (2016). The native microbiome of the nematode Caenorhabditis elegans: gateway to a new host-microbiome model. BMC Biol. 14, 38. 4. Samuel, B.S., Rowedder, H., Braendle, C., Felix, M.A., and Ruvkun, G. (2016). Caenorhabditis elegans responses to bacteria from its natural habitats. Proc. Natl. Acad. Sci. USA 113, E3941–E3949. 5. Graham, C.E., Cruz, M.R., Garsin, D.A., and Lorenz, M.C. (2017). Enterococcus faecalis bacteriocin EntV inhibits hyphal morphogenesis, biofilm formation, and
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