Ivermectin (IVM), a widely used anthelmintic and chemotherapeutic agent in both human and veterinary medicine, targets glutamate-gated chloride channels to induce paralysis in nematodes such as Caenorhabditis elegans. Traditionally, IVM-induced paralysis is assessed under brightfield microscopy. Here, we report that exposure to UV or blue wavelengths can induce spontaneous arousal from the IVM-paralyzed state, initiating with twitching and progressing to full swimming motion during light stimulation. This light-induced arousal response is absent in lite-1 null mutants, implicating LITE-1 photoreceptors in mediating this effect.
","acknowledgements":"The authors thank James Rand, Ph.D., for the insightful conversation and helpful review of this manuscript. ","authors":[{"affiliations":["University of Florida, Gainesville, FL, US"],"departments":[""],"credit":["conceptualization","investigation","methodology","writing_reviewEditing"],"email":"magera.shaw@ufl.edu","firstName":"Magera ","lastName":"Shaw","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Oklahoma State University Center for Health Sciences, Tulsa, OK, US"],"departments":[""],"credit":["investigation"],"email":"mylissa.stover@okstate.edu","firstName":"Mylissa","lastName":"Stover","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Oklahoma State University Center for Health Sciences, Tulsa, OK, US"],"departments":["Biochemistry and Microbiology"],"credit":["conceptualization","dataCuration","formalAnalysis","fundingAcquisition","investigation","methodology","project","resources","software","supervision","validation","visualization","writing_originalDraft","writing_reviewEditing"],"email":"jacob.manjarrez@okstate.edu","firstName":"Jacob. R","lastName":"Manjarrez","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":"0000-0002-8428-8659"}],"awards":[],"conflictsOfInterest":null,"dataTable":null,"extendedData":[],"funding":"The authors gratefully acknowledge the Oklahoma State University Center for Health Sciences Start-up funds used in the pursuit of this project.
","image":{"url":"https://portal.micropublication.org/uploads/341460d54e0cbdf1e85d4ee9e192d738.jpg"},"imageCaption":"(A–B) Ivermectin-paralyzed worms were exposed to 2 minutes of either UV (395/25 nm; Panel A) or blue (470/40 nm; Panel B) illumination. Each data point represents the latency (in seconds) to the first observed full-body wave for an individual worm. Worms that did not move during the 2-minute trial were assigned a value of 120 seconds.
(C) Summary table of arousal responses across genotypes.
","imageTitle":"Light-induced arousal from ivermectin-induced paralysis
","methods":"\n\nMethods:\nNematodes were\ncultured on OP50, E. coli, and NGM media at 20°C. One-day-old adult C.\nelegans were picked from a non-starved culture and transferred onto an\nunseeded plate or liquid buffer containing the drug compound at 20°C for the\nduration of the experiment (Brenner,\n1974).\nA 25 mg/ml Ivermectin\n(Alfa Aesar) stock solution was diluted in 100% ethanol and stored at -20°C. \n\nIVM-induced\nparalysis - One-day-old adults were individually transferred into a 96-well\nBlack-Clear Bottom Plate (ThermoScientific 265301). Each well contained 10 µM IVM\nin M9(Castro et\nal., 2020). Plates were incubated at 20˚C for 30\nminutes, which has been shown to induce paralysis, before prodding (Castro et\nal., 2020; Glendinning et al., 2011; Hernando & Bouzat, 2014), then UV and/or blue light\nstimulation. Each well contained a single worm that was stimulated with UV or blue light for 2 min, during which\nthe movement was observed using a DMi8 Leica Thunder imager with a 10x\nobjective exposed to 100% UV (395/30 nm) using a Spectra X light engine with a\noutput of 295mW (395/25) or GFP (470/40nm) with a cyan output of 196mW (470/24).\nMovements were tallied when a worm made a full wave of its body (Lumencor,\nInc., 2022). \n\n\n\n","reagents":"Strain List:
Strain | Genotype | Source |
N2 | Wild-type | Ken Miller |
KG1180 | lite-1(ce314) | Ken Miller |
TQ1101 | lite-1(xu7) | CGC |
TQ8245 | lite-1(xu492) | CGC |
RB765 | lite-1(ok530) | CGC |
RB1755 | gur-3(ok2245) | CGC |
MT21793 | lite-1(ce314); gur-3(ok2245) | CGC |
","patternDescription":"
Description:
Ivermectin (IVM) is the first semi-synthetic macrocyclic lactone approved for veterinary use as a chemotherapeutic and broad-spectrum antiparasitic agent. It is known to kill Caenorhabditis elegans (C. elegans) at therapeutic doses and has been widely used in paralytic assays at subtherapeutic concentrations. (Ardelli et al., 2009; Hibbs & Gouaux, 2011). IVM exerts its effects by binding to and activating glutamate-gated chloride channels in the muscles and nerves of nematodes and arthropods (Ardelli et al., 2009; Dent et al., 1997, 2000; Ghosh et al., 2012; Glendinning et al., 2011; Hibbs & Gouaux, 2011; Yates et al., 2003). The subtherapeutic paralytic state can be maintained over a wide range of concentrations and durations according to the previously published literature, presumably under standard brightfield imaging conditions (Ardelli et al., 2009; Castro et al., 2020; Chen & Kubo, 2018; Dent et al., 1997, 2000; Glendinning et al., 2011; Hernando & Bouzat, 2014; Le et al., 2019).
The photosensory-defective lite-1 mutant was first identified by its failure to avoid UV, violet, and blue wavelengths (Edwards et al., 2008; Liu et al., 2010). Due to its insensitivity to blue light, lite-1 is now routinely used to minimize background interference in GCaMP-based neural imaging (Ji, Madan, et al., 2021; Ji, Venkatachalam, et al., 2021; Kumar et al., 2023; Li et al., 2023; Toyoshima et al., 2020). A second light-sensitive gene, gur-3, has been associated with avoidance of extremely bright light (Bhatla & Horvitz, 2015). Although its role in light sensation is less well characterized, gur-3 was included in this study to assess its potential involvement in the reversal of IVM-induced paralysis (Bhatla & Horvitz, 2015; Fang-Yen et al., 2015; Liu et al., 2010).
UV and blue spectrum spontaneous arousal after ivermectin treatment: We initially observed that IVM-induced paralysis in wild-type animals could be reversed by exposure to UV or blue light. To determine whether this spontaneous reversal was mediated by LITE-1 photoreceptors, we compared the responses of wild-type (N2) animals, four different lite-1 mutant alleles, a gur-3(ok2245) mutant, and a lite-1(ce314); gur-3(ok2245) double mutant. Upon illumination with UV or blue light, N2, gur-3(ok2245), and lite-1(ok530) animals consistently exhibited an arousal response characterized by initial twitching followed by a return to full swimming motion during each light exposure. In contrast, lite-1(ce314), lite-1(xu7), lite-1(xu492), and the lite-1(ce314); gur-3(ok2245) double mutant displayed minimal or no arousal events (Figure 1A–C; Video S1). Green light (545/30 nm) did not trigger any movement following IVM-induced paralysis.
In contrast, the light-activated strains consistently returned to a paralyzed state once the UV or blue light stimulus was removed. However, the time required to resume paralysis varied, and we were unable to identify a consistent trend across trials.
In summary, we demonstrate that UV and blue light stimulation can induce spontaneous arousal from IVM-induced paralysis in C. elegans, characterized by initial twitching followed by a return to full swimming motion. The reversal of paralysis triggered by light is strong in wild-type animals but is almost absent in severe lite-1 photosensory mutants, suggesting that the LITE-1 protein plays a vital role in this response.
These results show the need to account for light-induced behavioral artifacts when designing experiments that use fluorophores excited by UV or blue wavelengths, especially in neuromuscular or behavioral assays, including ivermectin.
While the exact molecular mechanisms remain unclear, our findings specify that light stimulation can offset ivermectin-induced paralysis, even in strains with partially interrupted phototransduction pathways.
","references":[{"reference":"Ardelli BF, Stitt LE, Tompkins JB, Prichard RK. 2009. A comparison of the effects of ivermectin and moxidectin on the nematode. Vet. Parasitol. 165: 96-108.","pubmedId":"","doi":"10.1016/j.vetpar.2009.06.043"},{"reference":"Hibbs RE, Gouaux E. 2011. Principles of activation and permeation in an anion-selective Cys-loop. Nature. 474: 54-60.","pubmedId":"","doi":"10.1038/nature10139"},{"reference":"Dent JA, Davis MW, Avery L. 1997. avr-15 encodes a chloride channel subunit that mediates inhibitory. EMBO J. 16: 5867-5879.","pubmedId":"","doi":"10.1093/emboj/16.19.5867"},{"reference":"Dent JA, Smith MM, Vassilatis DK, Avery L. 2000. The genetics of ivermectin resistance in Caenorhabditis elegans. Proc. Natl. Acad. Sci. U. S. A. 97: 2674-2679.","pubmedId":"","doi":"10.1073/pnas.97.6.2674"},{"reference":"Ghosh R, Andersen EC, Shapiro JA, Gerke JP, Kruglyak L. 2012. Natural variation in a chloride channel subunit confers avermectin. Science. 335: 574-578.","pubmedId":"","doi":"10.1126/science.1214318"},{"reference":"Glendinning SK, Buckingham SD, Sattelle DB, Wonnacott S, Wolstenholme AJ. 2011. Glutamate-gated chloride channels of Haemonchus contortus restore drug. PLoS One. 6: e22390.","pubmedId":"","doi":"10.1371/journal.pone.0022390"},{"reference":"Yates DM, Portillo V, Wolstenholme AJ. 2003. The avermectin receptors of Haemonchus contortus and Caenorhabditis. Int. J. Parasitol. 33: 1183-1193.","pubmedId":"","doi":"10.1016/s0020-7519(03)00172-3"},{"reference":"Chen IS, Kubo Y. 2018. Ivermectin and its target molecules: shared and unique modulation. J. Physiol. 596: 1833-1845.","pubmedId":"","doi":"10.1113/JP275236"},{"reference":"Le VV, Sanchez B, Hong R. 2019. Interspecific comparison of sensitivity to paralytic compounds. MicroPubl. Biol. 2019","pubmedId":"","doi":"10.17912/micropub.biology.000185"},{"reference":"Castro MJ, Turani O, Faraoni MB, Gerbino D, Bouzat C. 2020. A new antagonist of Caenorhabditis elegans glutamate-activated chloride. Front. Neurosci. 14: 879.","pubmedId":"","doi":"10.3389/fnins.2020.00879"},{"reference":"Hernando G, Bouzat C. 2014. Caenorhabditis elegans neuromuscular junction: GABA receptors and. PLoS One. 9: e95072.","pubmedId":"","doi":"10.1371/journal.pone.0095072"},{"reference":"Edwards SL, Charlie NK, Milfort MC, Brown BS, Gravlin CN, Knecht JE, Miller KG. 2008. A novel molecular solution for ultraviolet light detection in. PLoS Biol. 6: e198.","pubmedId":"","doi":"10.1371/journal.pbio.0060198"},{"reference":"Liu J, Ward A, Gao J, Dong Y, Nishio N, Inada H, et al., Xu XZS. 2010. C. elegans phototransduction requires a G protein-dependent cGMP pathway. Nat. Neurosci. 13: 715-722.","pubmedId":"","doi":"10.1038/nn.2540"},{"reference":"Ji N, Madan GK, Fabre GI, Dayan A, Baker CM, Kramer TS, Nwabudike I, Flavell SW. 2021. A neural circuit for flexible control of persistent behavioral states. Elife. 10","pubmedId":"","doi":"10.7554/eLife.62889"},{"reference":"Ji N, Venkatachalam V, Rodgers HD, Hung W, Kawano T, Clark CM, et al., Samuel AD. 2021. Corollary discharge promotes a sustained motor state in a neural circuit. Elife. 10","pubmedId":"","doi":"10.7554/eLife.68848"},{"reference":"Kumar S, Sharma AK, Tran A, Liu M, Leifer AM. 2023. Inhibitory feedback from the motor circuit gates mechanosensory processing. PLoS Biol. 21: e3002280.","pubmedId":"","doi":"10.1371/journal.pbio.3002280"},{"reference":"Li Z, Zhou J, Wani KA, Yu T, Ronan EA, Piggott BJ, Liu J, Xu XZS. 2023. A C. elegans neuron both promotes and suppresses motor behavior to fine. Front. Mol. Neurosci. 16: 1228980.","pubmedId":"","doi":"10.3389/fnmol.2023.1228980"},{"reference":"Toyoshima Y, Wu S, Kanamori M, Sato H, Jang MS, Oe S, et al., Iino Y. 2020. Neuron ID dataset facilitates neuronal annotation for whole-brain activity. BMC Biol. 18: 30.","pubmedId":"","doi":"10.1186/s12915-020-0745-2"},{"reference":"Bhatla N, Horvitz HR. 2015. Light and hydrogen peroxide inhibit C. elegans Feeding through gustatory. Neuron. 85: 804-818.","pubmedId":"","doi":"10.1016/j.neuron.2014.12.061"},{"reference":"Fang Yen C, Alkema MJ, Samuel ADT. 2015. Illuminating neural circuits and behaviour in Caenorhabditis elegans with. Philos. Trans. R. Soc. Lond. B Biol. Sci. 370: 20140212.","pubmedId":"","doi":"10.1098/rstb.2014.0212"},{"reference":"Brenner S. 1974. The genetics of Caenorhabditis elegans. Genetics. 77: 71-94.","pubmedId":"","doi":"10.1093/genetics/77.1.71"}],"title":"LITE-1 Photoreceptor Mediates Light-Induced Reversal of Ivermectin Paralysis in Caenorhabditis elegans
","reviews":[{"reviewer":{"displayName":"Alexander Gottschalk"},"openAcknowledgement":true,"status":{"submitted":true}}],"curatorReviews":[{"curator":{"displayName":"Gary Craig Schindelman"},"openAcknowledgement":false,"submitted":null}]},{"id":"e29b7f62-b4b1-4dcd-810f-d6c805134981","decision":"edit","abstract":"Ivermectin (IVM), a widely used anthelmintic and chemotherapeutic agent in both human and veterinary medicine, targets glutamate-gated chloride channels to induce paralysis in nematodes such as Caenorhabditis elegans. Traditionally, IVM-induced paralysis is assessed under brightfield microscopy. Here, we report that exposure to UV or blue wavelengths can induce spontaneous arousal from the IVM-paralyzed state, initiating with twitching and progressing to full swimming motion during light stimulation. This light-induced arousal response is absent in lite-1 null mutants, implicating LITE-1 photoreceptors in mediating this effect.
","acknowledgements":"The authors thank James Rand, Ph.D., for the insightful conversation and helpful review of this manuscript. ","authors":[{"affiliations":["University of Florida, Gainesville, FL, US"],"departments":[""],"credit":["conceptualization","investigation","methodology","writing_reviewEditing"],"email":"magera.shaw@ufl.edu","firstName":"Magera ","lastName":"Shaw","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Oklahoma State University Center for Health Sciences, Tulsa, OK, US"],"departments":[""],"credit":["investigation"],"email":"mylissa.stover@okstate.edu","firstName":"Mylissa","lastName":"Stover","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Oklahoma State University Center for Health Sciences, Tulsa, OK, US"],"departments":["Biochemistry and Microbiology"],"credit":["validation"],"email":"crystal.a.shults@okstate.edu","firstName":"Crystal ","lastName":"Shults","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Oklahoma State University Center for Health Sciences, Tulsa, OK, US"],"departments":["Biochemistry and Microbiology"],"credit":["conceptualization","dataCuration","formalAnalysis","fundingAcquisition","investigation","methodology","project","resources","software","supervision","validation","visualization","writing_originalDraft","writing_reviewEditing"],"email":"jacob.manjarrez@okstate.edu","firstName":"Jacob. R","lastName":"Manjarrez","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":"0000-0002-8428-8659"}],"awards":[],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[{"description":"Genotyping for lite-1(ok530)
","doi":null,"resourceType":"Dataset","name":"Genotyping Figure.docx","url":"https://portal.micropublication.org/uploads/abeede9f784aae574264c689ae908b0b.docx"}],"funding":"The authors gratefully acknowledge the Oklahoma State University Center for Health Sciences Start-up funds used in the pursuit of this project.
","image":{"url":"https://portal.micropublication.org/uploads/341460d54e0cbdf1e85d4ee9e192d738.jpg"},"imageCaption":"(A–B) Ivermectin-paralyzed worms were exposed to 2 minutes of either UV (395/25 nm; Panel A) or blue (470/40 nm; Panel B) illumination. Each data point represents the latency (in seconds) to the first observed full-body wave for an individual worm. Worms that did not move during the 2-minute trial were assigned a value of 120 seconds.
(C) Summary table of arousal responses across genotypes.
","imageTitle":"Light-induced arousal from ivermectin-induced paralysis
","methods":"Methods:
Nematodes were cultured on OP50, E. coli, and NGM media at 20°C. One-day-old adult C. elegans were picked from a non-starved culture and transferred onto an unseeded plate or liquid buffer containing the drug compound at 20°C for the duration of the experiment (Brenner, 1974).
A 25 mg/ml Ivermectin (Alfa Aesar) stock solution was diluted in 100% ethanol and stored at -20°C.
IVM-induced paralysis - One-day-old adults were individually transferred into a 96-well Black-Clear Bottom Plate (ThermoScientific 265301). Each well contained 10 µM IVM in M9(Castro et al., 2020). Plates were incubated at 20˚C for 30 minutes, which has been shown to induce paralysis, before prodding (Castro et al., 2020; Glendinning et al., 2011; Hernando & Bouzat, 2014), then UV and/or blue light stimulation. Each well contained a single worm that was stimulated with UV or blue light for 2 min, during which the movement was observed using a DMi8 Leica Thunder imager with a 10x objective exposed to 100% UV (395/30 nm) using a Spectra X light engine with a output of 295mW (395/25) or GFP (470/40nm) with a cyan output of 196mW (470/24). Movements were tallied when a worm made a full wave of its body (Lumencor, Inc., 2022).
PCR genotyping was performed using worm lysis buffer, freeze-heat lysis (freezing at -80◦C then cycling at 60◦C than at 95◦C to inactivate the Proteinase K in the buffer), and using the lysate as a template for PCR with deletion-discriminating primers. PCR products were resolved on a 1.0% agarose E-Gel (Invitrogen) according to the manufacturer's instructions. Gels were imaged on an iBright Imaging Systems system, and banding patterns were scored as homozygous mutant (single ok530-sized band) or heterozygous (both WT- and ok530-sized bands).
","reagents":"Strain List:
Strain | Genotype | Source |
Wild-type | Ken Miller | |
Ken Miller | ||
CGC | ||
CGC | ||
CGC | ||
CGC | ||
CGC |
","patternDescription":"
Description:
Description:
Ivermectin (IVM) is the first semi-synthetic macrocyclic lactone approved for veterinary use as a chemotherapeutic and broad-spectrum antiparasitic agent. It is known to kill Caenorhabditis elegans (C. elegans) at therapeutic doses and has been widely used in paralytic assays at subtherapeutic concentrations. (Ardelli et al., 2009; Hibbs & Gouaux, 2011). IVM exerts its effects by binding to and activating glutamate-gated chloride channels in the muscles and nerves of nematodes and arthropods (Ardelli et al., 2009; Dent et al., 1997, 2000; Ghosh et al., 2012; Glendinning et al., 2011; Hibbs & Gouaux, 2011; Yates et al., 2003). The subtherapeutic paralytic state can be maintained over a wide range of concentrations and durations according to the previously published literature, presumably under standard brightfield imaging conditions (Ardelli et al., 2009; Castro et al., 2020; Chen & Kubo, 2018; Dent et al., 1997, 2000; Glendinning et al., 2011; Hernando & Bouzat, 2014; Le et al., 2019).
The photosensory-defective lite-1 mutant has been described in several studies based on its failure to avoid UV, violet, and blue wavelengths (Edwards et al., 2008; Liu et al., 2010). However, this phenotype was initially identified by its ability to induce movement in otherwise paralyzed unc-31 mutants upon light stimulation (Ward et al., 2008). The nature of the underlying signal remains unidentified; however, multiple studies are beginning to implicate neuropeptides in modulating this response, including NLP-10 and FLP-1 (Aoki et al., 2024; Dunkel et al., 2025).
Due to its insensitivity to blue light, lite-1 is now routinely used to minimize background interference in GCaMP-based neural imaging (Ji, Madan, et al., 2021; Ji, Venkatachalam, et al., 2021; Kumar et al., 2023; Li et al., 2023; Toyoshima et al., 2020). A second light-sensitive gene, gur-3, has been associated with avoidance of extremely bright light (Bhatla & Horvitz, 2015). Although its role in light sensation is less well characterized, gur-3 was included in this study to assess its potential involvement in the reversal of IVM-induced paralysis (Bhatla & Horvitz, 2015; Fang-Yen et al., 2015; Liu et al., 2010).
UV and blue spectrum spontaneous arousal after ivermectin treatment: We initially observed that IVM-induced paralysis in wild-type animals could be reversed by exposure to UV or blue light. To determine whether this spontaneous reversal was mediated by LITE-1 photoreceptors, we compared the responses of wild-type (N2) animals, four different lite-1 mutant alleles, a gur-3(ok2245) mutant, and a lite-1(ce314); gur-3(ok2245) double mutant. Upon illumination with UV or blue light, N2, gur-3(ok2245), and lite-1(ok530) animals consistently exhibited an arousal response characterized by initial twitching followed by a return to full swimming motion during each light exposure. In contrast, lite-1(ce314), lite-1(xu7), lite-1(xu492), and the lite-1(ce314); gur-3(ok2245) double mutant displayed minimal or no arousal events (Figure 1A–C; Video S1). Green light (545/30 nm) did not trigger any movement following IVM-induced paralysis.
In contrast, the light-activated strains consistently returned to a paralyzed state once the UV or blue light stimulus was removed. However, the time required to resume paralysis varied, and we were unable to identify a consistent trend across trials.
The reduced penetrance shown for lite-1(ok530) was confirmed not to be due to heterozygosity (Figure S1). However, because this strain was used without outcrossing, it remains possible that an additional mutation could compensate for the continued light-sensing function. Nonetheless, this study indicates that such a compensatory component is not associated with gur-3 (Figure 1).
Conclusion:
In summary, we demonstrate that UV and blue light stimulation can induce spontaneous arousal from IVM-induced paralysis in C. elegans, characterized by initial twitching followed by a return to full swimming motion. The reversal of paralysis triggered by light is strong in wild-type animals but is almost absent in severe lite-1 photosensory mutants, suggesting that the LITE-1 protein plays a vital role in this response. This response may be mediated by neuropeptide signaling, which has been recently implicated in light-induced arousal pathways.
However, these results show the need to account for light-induced behavioral artifacts when designing experiments that use fluorophores excited by UV or blue wavelengths, especially in neuromuscular or behavioral assays, including ivermectin.
While the exact molecular mechanisms remain unclear, our findings demonstrate that light stimulation can alleviate ivermectin-induced paralysis, even in strains with partially disrupted phototransduction pathways.ays.
","references":[{"reference":"Ardelli BF, Stitt LE, Tompkins JB, Prichard RK. 2009. A comparison of the effects of ivermectin and moxidectin on the nematode. Vet. Parasitol. 165: 96-108.","pubmedId":"","doi":"10.1016/j.vetpar.2009.06.043"},{"reference":"Hibbs RE, Gouaux E. 2011. Principles of activation and permeation in an anion-selective Cys-loop. Nature. 474: 54-60.","pubmedId":"","doi":"10.1038/nature10139"},{"reference":"Dent JA, Davis MW, Avery L. 1997. avr-15 encodes a chloride channel subunit that mediates inhibitory. EMBO J. 16: 5867-5879.","pubmedId":"","doi":"10.1093/emboj/16.19.5867"},{"reference":"Dent JA, Smith MM, Vassilatis DK, Avery L. 2000. The genetics of ivermectin resistance in Caenorhabditis elegans. Proc. Natl. Acad. Sci. U. S. A. 97: 2674-2679.","pubmedId":"","doi":"10.1073/pnas.97.6.2674"},{"reference":"Ghosh R, Andersen EC, Shapiro JA, Gerke JP, Kruglyak L. 2012. Natural variation in a chloride channel subunit confers avermectin. Science. 335: 574-578.","pubmedId":"","doi":"10.1126/science.1214318"},{"reference":"Glendinning SK, Buckingham SD, Sattelle DB, Wonnacott S, Wolstenholme AJ. 2011. Glutamate-gated chloride channels of Haemonchus contortus restore drug. PLoS One. 6: e22390.","pubmedId":"","doi":"10.1371/journal.pone.0022390"},{"reference":"Yates DM, Portillo V, Wolstenholme AJ. 2003. The avermectin receptors of Haemonchus contortus and Caenorhabditis. Int. J. Parasitol. 33: 1183-1193.","pubmedId":"","doi":"10.1016/s0020-7519(03)00172-3"},{"reference":"Chen IS, Kubo Y. 2018. Ivermectin and its target molecules: shared and unique modulation. J. Physiol. 596: 1833-1845.","pubmedId":"","doi":"10.1113/JP275236"},{"reference":"Le VV, Sanchez B, Hong R. 2019. Interspecific comparison of sensitivity to paralytic compounds. MicroPubl. Biol. 2019","pubmedId":"","doi":"10.17912/micropub.biology.000185"},{"reference":"Castro MJ, Turani O, Faraoni MB, Gerbino D, Bouzat C. 2020. A new antagonist of Caenorhabditis elegans glutamate-activated chloride. Front. Neurosci. 14: 879.","pubmedId":"","doi":"10.3389/fnins.2020.00879"},{"reference":"Hernando G, Bouzat C. 2014. Caenorhabditis elegans neuromuscular junction: GABA receptors and. PLoS One. 9: e95072.","pubmedId":"","doi":"10.1371/journal.pone.0095072"},{"reference":"Edwards SL, Charlie NK, Milfort MC, Brown BS, Gravlin CN, Knecht JE, Miller KG. 2008. A novel molecular solution for ultraviolet light detection in. PLoS Biol. 6: e198.","pubmedId":"","doi":"10.1371/journal.pbio.0060198"},{"reference":"Liu J, Ward A, Gao J, Dong Y, Nishio N, Inada H, et al., Xu XZS. 2010. C. elegans phototransduction requires a G protein-dependent cGMP pathway. Nat. Neurosci. 13: 715-722.","pubmedId":"","doi":"10.1038/nn.2540"},{"reference":"Ji N, Madan GK, Fabre GI, Dayan A, Baker CM, Kramer TS, Nwabudike I, Flavell SW. 2021. A neural circuit for flexible control of persistent behavioral states. Elife. 10","pubmedId":"","doi":"10.7554/eLife.62889"},{"reference":"Ji N, Venkatachalam V, Rodgers HD, Hung W, Kawano T, Clark CM, et al., Samuel AD. 2021. Corollary discharge promotes a sustained motor state in a neural circuit. Elife. 10","pubmedId":"","doi":"10.7554/eLife.68848"},{"reference":"Kumar S, Sharma AK, Tran A, Liu M, Leifer AM. 2023. Inhibitory feedback from the motor circuit gates mechanosensory processing. PLoS Biol. 21: e3002280.","pubmedId":"","doi":"10.1371/journal.pbio.3002280"},{"reference":"Li Z, Zhou J, Wani KA, Yu T, Ronan EA, Piggott BJ, Liu J, Xu XZS. 2023. A C. elegans neuron both promotes and suppresses motor behavior to fine. Front. Mol. Neurosci. 16: 1228980.","pubmedId":"","doi":"10.3389/fnmol.2023.1228980"},{"reference":"Toyoshima Y, Wu S, Kanamori M, Sato H, Jang MS, Oe S, et al., Iino Y. 2020. Neuron ID dataset facilitates neuronal annotation for whole-brain activity. BMC Biol. 18: 30.","pubmedId":"","doi":"10.1186/s12915-020-0745-2"},{"reference":"Bhatla N, Horvitz HR. 2015. Light and hydrogen peroxide inhibit C. elegans Feeding through gustatory. Neuron. 85: 804-818.","pubmedId":"","doi":"10.1016/j.neuron.2014.12.061"},{"reference":"Fang Yen C, Alkema MJ, Samuel ADT. 2015. Illuminating neural circuits and behaviour in Caenorhabditis elegans with. Philos. Trans. R. Soc. Lond. B Biol. Sci. 370: 20140212.","pubmedId":"","doi":"10.1098/rstb.2014.0212"},{"reference":"Brenner S. 1974. The genetics of Caenorhabditis elegans. Genetics. 77: 71-94.","pubmedId":"","doi":"10.1093/genetics/77.1.71"},{"reference":"Aoki, I., Golinelli, L., Dunkel, E. et al. Hierarchical regulation of functionally antagonistic neuropeptides expressed in a single neuron pair. Nat Commun 15, 9504 (2024). https://doi.org/10.1038/s41467-024-53899-7
","pubmedId":"","doi":""},{"reference":"Dunkel, D., Aoki, I., Bergs, A., & Gottschalk, A. Neurons and molecules involved in noxious light sensation in Caenorhabditis elegans, G3 Genes|Genomes|Genetics, Volume 15, Issue 6, June 2025, jkaf086, https://doi.org/10.1093/g3journal/jkaf086
","pubmedId":"","doi":""},{"reference":"Hanson, S. M. et al. Structure-function analysis suggests that the photoreceptor LITE-1 is a light-activated ion channel. Curr. Biol. 33, 3423–3435.e5 (2023).
","pubmedId":"","doi":""},{"reference":"Ward, A., Liu, J., Feng, Z. & Xu, X. Z. S. Light-sensitive neurons and channels mediate phototaxis in C. elegans. Nat. Neurosci. 11, 916–922 (2008).
","pubmedId":"","doi":""}],"title":"LITE-1 Photoreceptor Mediates Light-Induced Reversal of Ivermectin Paralysis in Caenorhabditis elegans
","reviews":[],"curatorReviews":[{"curator":{"displayName":"Gary Craig Schindelman"},"openAcknowledgement":false,"submitted":"1775852128704"}]},{"id":"0898de9b-9468-4f75-b63b-3f1fc68113b5","decision":"edit","abstract":"Ivermectin (IVM), a widely used anthelmintic and chemotherapeutic agent in both human and veterinary medicine, targets glutamate-gated chloride channels to induce paralysis in nematodes such as Caenorhabditis elegans. Traditionally, IVM-induced paralysis is assessed under brightfield microscopy. Here, we report that exposure to UV or blue wavelengths can induce spontaneous arousal from the IVM-paralyzed state, initiating with twitching and progressing to full swimming motion during light stimulation. This light-induced arousal response is absent in lite-1 null mutants, implicating LITE-1 photoreceptors in mediating this effect.
","acknowledgements":"The authors thank James Rand, Ph.D., for the insightful conversation and helpful review of this manuscript. ","authors":[{"affiliations":["University of Florida, Gainesville, FL, US"],"departments":[""],"credit":["conceptualization","investigation","methodology","writing_reviewEditing"],"email":"magera.shaw@ufl.edu","firstName":"Magera ","lastName":"Shaw","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Oklahoma State University Center for Health Sciences, Tulsa, OK, US"],"departments":[""],"credit":["investigation"],"email":"mylissa.stover@okstate.edu","firstName":"Mylissa","lastName":"Stover","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Oklahoma State University Center for Health Sciences, Tulsa, OK, US"],"departments":["Biochemistry and Microbiology"],"credit":["validation"],"email":"crystal.a.shults@okstate.edu","firstName":"Crystal ","lastName":"Shults","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Oklahoma State University Center for Health Sciences, Tulsa, OK, US"],"departments":["Biochemistry and Microbiology"],"credit":["conceptualization","dataCuration","formalAnalysis","fundingAcquisition","investigation","methodology","project","resources","software","supervision","validation","visualization","writing_originalDraft","writing_reviewEditing"],"email":"jacob.manjarrez@okstate.edu","firstName":"Jacob. R","lastName":"Manjarrez","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":"0000-0002-8428-8659"}],"awards":[],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[{"description":"Genotyping for lite-1(ok530)
","doi":null,"resourceType":"Dataset","name":"Genotyping Figure.docx","url":"https://portal.micropublication.org/uploads/abeede9f784aae574264c689ae908b0b.docx"}],"funding":"The authors gratefully acknowledge the Oklahoma State University Center for Health Sciences Start-up funds used in the pursuit of this project.
","image":{"url":"https://portal.micropublication.org/uploads/341460d54e0cbdf1e85d4ee9e192d738.jpg"},"imageCaption":"(A–B) Ivermectin-paralyzed worms were exposed to 2 minutes of either UV (395/25 nm; Panel A) or blue (470/40 nm; Panel B) illumination. Each data point represents the latency (in seconds) to the first observed full-body wave for an individual worm. Worms that did not move during the 2-minute trial were assigned a value of 120 seconds.
(C) Summary table of arousal responses across genotypes.
","imageTitle":"Light-induced arousal from ivermectin-induced paralysis
","methods":"Methods:
Nematodes were cultured on OP50, E. coli, and NGM media at 20°C. One-day-old adult C. elegans were picked from a non-starved culture and transferred onto an unseeded plate or liquid buffer containing the drug compound at 20°C for the duration of the experiment (Brenner, 1974).
A 25 mg/ml Ivermectin (Alfa Aesar) stock solution was diluted in 100% ethanol and stored at -20°C.
IVM-induced paralysis - One-day-old adults were individually transferred into a 96-well Black-Clear Bottom Plate (ThermoScientific 265301). Each well contained 10 µM IVM in M9(Castro et al., 2020). Plates were incubated at 20˚C for 30 minutes, which has been shown to induce paralysis, before prodding (Castro et al., 2020; Glendinning et al., 2011; Hernando & Bouzat, 2014), then UV and/or blue light stimulation. Each well contained a single worm that was stimulated with UV or blue light for 2 min, during which the movement was observed using a DMi8 Leica Thunder imager with a 10x objective exposed to 100% UV (395/30 nm) using a Spectra X light engine with a output of 295mW (395/25) or GFP (470/40nm) with a cyan output of 196mW (470/24). Movements were tallied when a worm made a full wave of its body (Lumencor, Inc., 2022).
PCR genotyping was performed using worm lysis buffer, freeze-heat lysis (freezing at -80◦C then cycling at 60◦C than at 95◦C to inactivate the Proteinase K in the buffer), and using the lysate as a template for PCR with deletion-discriminating primers. PCR products were resolved on a 1.0% agarose E-Gel (Invitrogen) according to the manufacturer's instructions. Gels were imaged on an iBright Imaging Systems system, and banding patterns were scored as homozygous mutant (single ok530-sized band) or heterozygous (both WT- and ok530-sized bands).
","reagents":"Strain List:
Strain | Genotype | Source |
Wild-type | Ken Miller | |
Ken Miller | ||
CGC | ||
CGC | ||
CGC | ||
CGC | ||
CGC |
","patternDescription":"
Description:
Ivermectin (IVM) is the first semi-synthetic macrocyclic lactone approved for veterinary use as a chemotherapeutic and broad-spectrum antiparasitic agent. It is known to kill Caenorhabditis elegans (C. elegans) at therapeutic doses and has been widely used in paralytic assays at subtherapeutic concentrations. (Ardelli et al., 2009; Hibbs & Gouaux, 2011). IVM exerts its effects by binding to and activating glutamate-gated chloride channels in the muscles and nerves of nematodes and arthropods (Ardelli et al., 2009; Dent et al., 1997, 2000; Ghosh et al., 2012; Glendinning et al., 2011; Hibbs & Gouaux, 2011; Yates et al., 2003). The subtherapeutic paralytic state can be maintained over a wide range of concentrations and durations according to the previously published literature, presumably under standard brightfield imaging conditions (Ardelli et al., 2009; Castro et al., 2020; Chen & Kubo, 2018; Dent et al., 1997, 2000; Glendinning et al., 2011; Hernando & Bouzat, 2014; Le et al., 2019).
The photosensory-defective lite-1 mutant has been described in several studies based on its failure to avoid UV, violet, and blue wavelengths (Edwards et al., 2008; Liu et al., 2010). However, this phenotype was initially identified by its ability to induce movement in otherwise paralyzed unc-31 mutants upon light stimulation (Ward et al., 2008). The nature of the underlying signal remains unidentified; however, multiple studies are beginning to implicate neuropeptides in modulating this response, including NLP-10 and FLP-1 (Aoki et al., 2024; Dunkel et al., 2025).
Due to its insensitivity to blue light, lite-1 is now routinely used to minimize background interference in GCaMP-based neural imaging (Ji, Madan, et al., 2021; Ji, Venkatachalam, et al., 2021; Kumar et al., 2023; Li et al., 2023; Toyoshima et al., 2020). A second light-sensitive gene, gur-3, has been associated with avoidance of extremely bright light (Bhatla & Horvitz, 2015). Although its role in light sensation is less well characterized, gur-3 was included in this study to assess its potential involvement in the reversal of IVM-induced paralysis (Bhatla & Horvitz, 2015; Fang-Yen et al., 2015; Liu et al., 2010).
UV and blue spectrum spontaneous arousal after ivermectin treatment: We initially observed that IVM-induced paralysis in wild-type animals could be reversed by exposure to UV or blue light. To determine whether this spontaneous reversal was mediated by LITE-1 photoreceptors, we compared the responses of wild-type (N2) animals, four different lite-1 mutant alleles, a gur-3(ok2245) mutant, and a lite-1(ce314); gur-3(ok2245) double mutant. Upon illumination with UV or blue light, N2, gur-3(ok2245), and lite-1(ok530) animals consistently exhibited an arousal response characterized by initial twitching followed by a return to full swimming motion during each light exposure. In contrast, lite-1(ce314), lite-1(xu7), lite-1(xu492), and the lite-1(ce314); gur-3(ok2245) double mutant displayed minimal or no arousal events (Figure 1A–C; Video S1). Green light (545/30 nm) did not trigger any movement following IVM-induced paralysis.
In contrast, the light-activated strains consistently returned to a paralyzed state once the UV or blue light stimulus was removed. However, the time required to resume paralysis varied, and we were unable to identify a consistent trend across trials.
The reduced penetrance shown for lite-1(ok530) was confirmed not to be due to heterozygosity (Figure S1). However, because this strain was used without outcrossing, it remains possible that an additional mutation could compensate for the continued light-sensing function. Nonetheless, this study indicates that such a compensatory component is not associated with gur-3 (Figure 1).
Conclusion:
In summary, we demonstrate that UV and blue light stimulation can induce spontaneous arousal from IVM-induced paralysis in C. elegans, characterized by initial twitching followed by a return to full swimming motion. The reversal of paralysis triggered by light is strong in wild-type animals but is almost absent in severe lite-1 photosensory mutants, suggesting that the LITE-1 protein plays a vital role in this response. This response may be mediated by neuropeptide signaling, which has been recently implicated in light-induced arousal pathways.
However, these results show the need to account for light-induced behavioral artifacts when designing experiments that use fluorophores excited by UV or blue wavelengths, especially in neuromuscular or behavioral assays, including ivermectin.
While the exact molecular mechanisms remain unclear, our findings demonstrate that light stimulation can alleviate ivermectin-induced paralysis, even in strains with partially disrupted phototransduction pathways.ays.
","references":[{"reference":"Ardelli BF, Stitt LE, Tompkins JB, Prichard RK. 2009. A comparison of the effects of ivermectin and moxidectin on the nematode. Vet. Parasitol. 165: 96-108.","pubmedId":"","doi":"10.1016/j.vetpar.2009.06.043"},{"reference":"Hibbs RE, Gouaux E. 2011. Principles of activation and permeation in an anion-selective Cys-loop. Nature. 474: 54-60.","pubmedId":"","doi":"10.1038/nature10139"},{"reference":"Dent JA, Davis MW, Avery L. 1997. avr-15 encodes a chloride channel subunit that mediates inhibitory. EMBO J. 16: 5867-5879.","pubmedId":"","doi":"10.1093/emboj/16.19.5867"},{"reference":"Dent JA, Smith MM, Vassilatis DK, Avery L. 2000. The genetics of ivermectin resistance in Caenorhabditis elegans. Proc. Natl. Acad. Sci. U. S. A. 97: 2674-2679.","pubmedId":"","doi":"10.1073/pnas.97.6.2674"},{"reference":"Ghosh R, Andersen EC, Shapiro JA, Gerke JP, Kruglyak L. 2012. Natural variation in a chloride channel subunit confers avermectin. Science. 335: 574-578.","pubmedId":"","doi":"10.1126/science.1214318"},{"reference":"Glendinning SK, Buckingham SD, Sattelle DB, Wonnacott S, Wolstenholme AJ. 2011. Glutamate-gated chloride channels of Haemonchus contortus restore drug. PLoS One. 6: e22390.","pubmedId":"","doi":"10.1371/journal.pone.0022390"},{"reference":"Yates DM, Portillo V, Wolstenholme AJ. 2003. The avermectin receptors of Haemonchus contortus and Caenorhabditis. Int. J. Parasitol. 33: 1183-1193.","pubmedId":"","doi":"10.1016/s0020-7519(03)00172-3"},{"reference":"Chen IS, Kubo Y. 2018. Ivermectin and its target molecules: shared and unique modulation. J. Physiol. 596: 1833-1845.","pubmedId":"","doi":"10.1113/JP275236"},{"reference":"Le VV, Sanchez B, Hong R. 2019. Interspecific comparison of sensitivity to paralytic compounds. MicroPubl. Biol. 2019","pubmedId":"","doi":"10.17912/micropub.biology.000185"},{"reference":"Castro MJ, Turani O, Faraoni MB, Gerbino D, Bouzat C. 2020. A new antagonist of Caenorhabditis elegans glutamate-activated chloride. Front. Neurosci. 14: 879.","pubmedId":"","doi":"10.3389/fnins.2020.00879"},{"reference":"Hernando G, Bouzat C. 2014. Caenorhabditis elegans neuromuscular junction: GABA receptors and. PLoS One. 9: e95072.","pubmedId":"","doi":"10.1371/journal.pone.0095072"},{"reference":"Edwards SL, Charlie NK, Milfort MC, Brown BS, Gravlin CN, Knecht JE, Miller KG. 2008. A novel molecular solution for ultraviolet light detection in. PLoS Biol. 6: e198.","pubmedId":"","doi":"10.1371/journal.pbio.0060198"},{"reference":"Liu J, Ward A, Gao J, Dong Y, Nishio N, Inada H, et al., Xu XZS. 2010. C. elegans phototransduction requires a G protein-dependent cGMP pathway. Nat. Neurosci. 13: 715-722.","pubmedId":"","doi":"10.1038/nn.2540"},{"reference":"Ji N, Madan GK, Fabre GI, Dayan A, Baker CM, Kramer TS, Nwabudike I, Flavell SW. 2021. A neural circuit for flexible control of persistent behavioral states. Elife. 10","pubmedId":"","doi":"10.7554/eLife.62889"},{"reference":"Ji N, Venkatachalam V, Rodgers HD, Hung W, Kawano T, Clark CM, et al., Samuel AD. 2021. Corollary discharge promotes a sustained motor state in a neural circuit. Elife. 10","pubmedId":"","doi":"10.7554/eLife.68848"},{"reference":"Kumar S, Sharma AK, Tran A, Liu M, Leifer AM. 2023. Inhibitory feedback from the motor circuit gates mechanosensory processing. PLoS Biol. 21: e3002280.","pubmedId":"","doi":"10.1371/journal.pbio.3002280"},{"reference":"Li Z, Zhou J, Wani KA, Yu T, Ronan EA, Piggott BJ, Liu J, Xu XZS. 2023. A C. elegans neuron both promotes and suppresses motor behavior to fine. Front. Mol. Neurosci. 16: 1228980.","pubmedId":"","doi":"10.3389/fnmol.2023.1228980"},{"reference":"Toyoshima Y, Wu S, Kanamori M, Sato H, Jang MS, Oe S, et al., Iino Y. 2020. Neuron ID dataset facilitates neuronal annotation for whole-brain activity. BMC Biol. 18: 30.","pubmedId":"","doi":"10.1186/s12915-020-0745-2"},{"reference":"Bhatla N, Horvitz HR. 2015. Light and hydrogen peroxide inhibit C. elegans Feeding through gustatory. Neuron. 85: 804-818.","pubmedId":"","doi":"10.1016/j.neuron.2014.12.061"},{"reference":"Fang Yen C, Alkema MJ, Samuel ADT. 2015. Illuminating neural circuits and behaviour in Caenorhabditis elegans with. Philos. Trans. R. Soc. Lond. B Biol. Sci. 370: 20140212.","pubmedId":"","doi":"10.1098/rstb.2014.0212"},{"reference":"Brenner S. 1974. The genetics of Caenorhabditis elegans. Genetics. 77: 71-94.","pubmedId":"","doi":"10.1093/genetics/77.1.71"},{"reference":"Aoki, I., Golinelli, L., Dunkel, E. et al. Hierarchical regulation of functionally antagonistic neuropeptides expressed in a single neuron pair. Nat Commun 15, 9504 (2024). https://doi.org/10.1038/s41467-024-53899-7
","pubmedId":"","doi":""},{"reference":"Dunkel, D., Aoki, I., Bergs, A., & Gottschalk, A. Neurons and molecules involved in noxious light sensation in Caenorhabditis elegans, G3 Genes|Genomes|Genetics, Volume 15, Issue 6, June 2025, jkaf086, https://doi.org/10.1093/g3journal/jkaf086
","pubmedId":"","doi":""},{"reference":"Hanson, S. M. et al. Structure-function analysis suggests that the photoreceptor LITE-1 is a light-activated ion channel. Curr. Biol. 33, 3423–3435.e5 (2023).
","pubmedId":"","doi":""},{"reference":"Ward, A., Liu, J., Feng, Z. & Xu, X. Z. S. Light-sensitive neurons and channels mediate phototaxis in C. elegans. Nat. Neurosci. 11, 916–922 (2008).
","pubmedId":"","doi":""}],"title":"LITE-1 Photoreceptor Mediates Light-Induced Reversal of Ivermectin Paralysis in Caenorhabditis elegans
","reviews":[],"curatorReviews":[{"curator":{"displayName":"Gary Craig Schindelman"},"openAcknowledgement":false,"submitted":null}]},{"id":"2a0f8773-c179-4805-a9e1-eb9eb7002ec3","decision":"accept","abstract":"Ivermectin (IVM), a widely used anthelmintic and chemotherapeutic agent in both human and veterinary medicine, targets glutamate-gated chloride channels to induce paralysis in nematodes such as Caenorhabditis elegans. Traditionally, IVM-induced paralysis is assessed under brightfield microscopy. Here, we report that exposure to UV or blue wavelengths can induce spontaneous arousal from the IVM-paralyzed state, initiating with twitching and progressing to full swimming motion during light stimulation. This light-induced arousal response is absent in lite-1 null mutants, implicating LITE-1 photoreceptors in mediating this effect.
","acknowledgements":"The authors thank James Rand, Ph.D., for the insightful conversation and helpful review of this manuscript. ","authors":[{"affiliations":["University of Florida, Gainesville, FL, US"],"departments":[""],"credit":["conceptualization","investigation","methodology","writing_reviewEditing"],"email":"magera.shaw@ufl.edu","firstName":"Magera ","lastName":"Shaw","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Oklahoma State University Center for Health Sciences, Tulsa, OK, US"],"departments":[""],"credit":["investigation"],"email":"mylissa.stover@okstate.edu","firstName":"Mylissa","lastName":"Stover","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Oklahoma State University Center for Health Sciences, Tulsa, OK, US"],"departments":["Biochemistry and Microbiology"],"credit":["validation"],"email":"crystal.a.shults@okstate.edu","firstName":"Crystal ","lastName":"Shults","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Oklahoma State University Center for Health Sciences, Tulsa, OK, US"],"departments":["Biochemistry and Microbiology"],"credit":["conceptualization","dataCuration","formalAnalysis","fundingAcquisition","investigation","methodology","project","resources","software","supervision","validation","visualization","writing_originalDraft","writing_reviewEditing"],"email":"jacob.manjarrez@okstate.edu","firstName":"Jacob. R","lastName":"Manjarrez","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":"0000-0002-8428-8659"}],"awards":[],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[{"description":"Genotyping for lite-1(ok530)
","doi":null,"resourceType":"Dataset","name":"Genotyping Figure.docx","url":"https://portal.micropublication.org/uploads/abeede9f784aae574264c689ae908b0b.docx"}],"funding":"The authors gratefully acknowledge the Oklahoma State University Center for Health Sciences Start-up funds used in the pursuit of this project.
","image":{"url":"https://portal.micropublication.org/uploads/341460d54e0cbdf1e85d4ee9e192d738.jpg"},"imageCaption":"(A–B) Ivermectin-paralyzed worms were exposed to 2 minutes of either UV (395/25 nm; Panel A) or blue (470/40 nm; Panel B) illumination. Each data point represents the latency (in seconds) to the first observed full-body wave for an individual worm. Worms that did not move during the 2-minute trial were assigned a value of 120 seconds.
(C) Summary table of arousal responses across genotypes.
","imageTitle":"Light-induced arousal from ivermectin-induced paralysis
","methods":"Nematodes were cultured on OP50, E. coli, and NGM media at 20°C. One-day-old adult C. elegans were picked from a non-starved culture and transferred onto an unseeded plate or liquid buffer containing the drug compound at 20°C for the duration of the experiment (Brenner, 1974).
A 25 mg/ml Ivermectin (Alfa Aesar) stock solution was diluted in 100% ethanol and stored at -20°C.
IVM-induced paralysis - One-day-old adults were individually transferred into a 96-well Black-Clear Bottom Plate (ThermoScientific 265301). Each well contained 10 µM IVM in M9(Castro et al., 2020). Plates were incubated at 20˚C for 30 minutes, which has been shown to induce paralysis, before prodding (Castro et al., 2020; Glendinning et al., 2011; Hernando & Bouzat, 2014), then UV and/or blue light stimulation. Each well contained a single worm that was stimulated with UV or blue light for 2 min, during which the movement was observed using a DMi8 Leica Thunder imager with a 10x objective exposed to 100% UV (395/30 nm) using a Spectra X light engine with a output of 295mW (395/25) or GFP (470/40nm) with a cyan output of 196mW (470/24). Movements were tallied when a worm made a full wave of its body (Lumencor, Inc., 2022).
PCR genotyping was performed using worm lysis buffer, freeze-heat lysis (freezing at -80◦C then cycling at 60◦C than at 95◦C to inactivate the Proteinase K in the buffer), and using the lysate as a template for PCR with deletion-discriminating primers. PCR products were resolved on a 1.0% agarose E-Gel (Invitrogen) according to the manufacturer's instructions. Gels were imaged on an iBright Imaging Systems system, and banding patterns were scored as homozygous mutant (single ok530-sized band) or heterozygous (both WT- and ok530-sized bands).
","reagents":"Strain List:
Strain | Genotype | Source |
Wild-type | Ken Miller | |
Ken Miller | ||
CGC | ||
CGC | ||
CGC | ||
CGC | ||
CGC |
","patternDescription":"
Ivermectin (IVM) is the first semi-synthetic macrocyclic lactone approved for veterinary use as a chemotherapeutic and broad-spectrum antiparasitic agent. It is known to kill Caenorhabditis elegans (C. elegans) at therapeutic doses and has been widely used in paralytic assays at subtherapeutic concentrations. (Ardelli et al., 2009; Hibbs & Gouaux, 2011). IVM exerts its effects by binding to and activating glutamate-gated chloride channels in the muscles and nerves of nematodes and arthropods (Ardelli et al., 2009; Dent et al., 1997, 2000; Ghosh et al., 2012; Glendinning et al., 2011; Hibbs & Gouaux, 2011; Yates et al., 2003). The subtherapeutic paralytic state can be maintained over a wide range of concentrations and durations according to the previously published literature, presumably under standard brightfield imaging conditions (Ardelli et al., 2009; Castro et al., 2020; Chen & Kubo, 2018; Dent et al., 1997, 2000; Glendinning et al., 2011; Hernando & Bouzat, 2014; Le et al., 2019).
The photosensory-defective lite-1 mutant has been described in several studies based on its failure to avoid UV, violet, and blue wavelengths (Edwards et al., 2008; Liu et al., 2010). However, this phenotype was initially identified by its ability to induce movement in otherwise paralyzed unc-31 mutants upon light stimulation (Ward et al., 2008). The nature of the underlying signal remains unidentified; however, multiple studies are beginning to implicate neuropeptides in modulating this response, including NLP-10 and FLP-1 (Aoki et al., 2024; Dunkel et al., 2025).
Due to its insensitivity to blue light, lite-1 is now routinely used to minimize background interference in GCaMP-based neural imaging (Ji, Madan, et al., 2021; Ji, Venkatachalam, et al., 2021; Kumar et al., 2023; Li et al., 2023; Toyoshima et al., 2020). A second light-sensitive gene, gur-3, has been associated with avoidance of extremely bright light (Bhatla & Horvitz, 2015). Although its role in light sensation is less well characterized, gur-3 was included in this study to assess its potential involvement in the reversal of IVM-induced paralysis (Bhatla & Horvitz, 2015; Fang-Yen et al., 2015; Liu et al., 2010).
UV and blue spectrum spontaneous arousal after ivermectin treatment: We initially observed that IVM-induced paralysis in wild-type animals could be reversed by exposure to UV or blue light. To determine whether this spontaneous reversal was mediated by LITE-1 photoreceptors, we compared the responses of wild-type (N2) animals, four different lite-1 mutant alleles, a gur-3(ok2245) mutant, and a lite-1(ce314); gur-3(ok2245) double mutant. Upon illumination with UV or blue light, N2, gur-3(ok2245), and lite-1(ok530) animals consistently exhibited an arousal response characterized by initial twitching followed by a return to full swimming motion during each light exposure. In contrast, lite-1(ce314), lite-1(xu7), lite-1(xu492), and the lite-1(ce314); gur-3(ok2245) double mutant displayed minimal or no arousal events (Figure 1A–C; Video S1). Green light (545/30 nm) did not trigger any movement following IVM-induced paralysis.
In contrast, the light-activated strains consistently returned to a paralyzed state once the UV or blue light stimulus was removed. However, the time required to resume paralysis varied, and we were unable to identify a consistent trend across trials.
The reduced penetrance shown for lite-1(ok530) was confirmed not to be due to heterozygosity (Figure S1). However, because this strain was used without outcrossing, it remains possible that an additional mutation could compensate for the continued light-sensing function. Nonetheless, this study indicates that such a compensatory component is not associated with gur-3 (Figure 1).
Conclusion:
In summary, we demonstrate that UV and blue light stimulation can induce spontaneous arousal from IVM-induced paralysis in C. elegans, characterized by initial twitching followed by a return to full swimming motion. The reversal of paralysis triggered by light is strong in wild-type animals but is almost absent in severe lite-1 photosensory mutants, suggesting that the LITE-1 protein plays a vital role in this response. This response may be mediated by neuropeptide signaling, which has been recently implicated in light-induced arousal pathways.
However, these results show the need to account for light-induced behavioral artifacts when designing experiments that use fluorophores excited by UV or blue wavelengths, especially in neuromuscular or behavioral assays, including ivermectin.
While the exact molecular mechanisms remain unclear, our findings demonstrate that light stimulation can alleviate ivermectin-induced paralysis, even in strains with partially disrupted phototransduction pathways.ays.
","references":[{"reference":"Ardelli BF, Stitt LE, Tompkins JB, Prichard RK. 2009. A comparison of the effects of ivermectin and moxidectin on the nematode. Vet. Parasitol. 165: 96-108.","pubmedId":"","doi":"10.1016/j.vetpar.2009.06.043"},{"reference":"Hibbs RE, Gouaux E. 2011. Principles of activation and permeation in an anion-selective Cys-loop. Nature. 474: 54-60.","pubmedId":"","doi":"10.1038/nature10139"},{"reference":"Dent JA, Davis MW, Avery L. 1997. avr-15 encodes a chloride channel subunit that mediates inhibitory. EMBO J. 16: 5867-5879.","pubmedId":"","doi":"10.1093/emboj/16.19.5867"},{"reference":"Dent JA, Smith MM, Vassilatis DK, Avery L. 2000. The genetics of ivermectin resistance in Caenorhabditis elegans. Proc. Natl. Acad. Sci. U. S. A. 97: 2674-2679.","pubmedId":"","doi":"10.1073/pnas.97.6.2674"},{"reference":"Ghosh R, Andersen EC, Shapiro JA, Gerke JP, Kruglyak L. 2012. Natural variation in a chloride channel subunit confers avermectin. Science. 335: 574-578.","pubmedId":"","doi":"10.1126/science.1214318"},{"reference":"Glendinning SK, Buckingham SD, Sattelle DB, Wonnacott S, Wolstenholme AJ. 2011. Glutamate-gated chloride channels of Haemonchus contortus restore drug. PLoS One. 6: e22390.","pubmedId":"","doi":"10.1371/journal.pone.0022390"},{"reference":"Yates DM, Portillo V, Wolstenholme AJ. 2003. The avermectin receptors of Haemonchus contortus and Caenorhabditis. Int. J. Parasitol. 33: 1183-1193.","pubmedId":"","doi":"10.1016/s0020-7519(03)00172-3"},{"reference":"Chen IS, Kubo Y. 2018. Ivermectin and its target molecules: shared and unique modulation. J. Physiol. 596: 1833-1845.","pubmedId":"","doi":"10.1113/JP275236"},{"reference":"Le VV, Sanchez B, Hong R. 2019. Interspecific comparison of sensitivity to paralytic compounds. MicroPubl. Biol. 2019","pubmedId":"","doi":"10.17912/micropub.biology.000185"},{"reference":"Castro MJ, Turani O, Faraoni MB, Gerbino D, Bouzat C. 2020. A new antagonist of Caenorhabditis elegans glutamate-activated chloride. Front. Neurosci. 14: 879.","pubmedId":"","doi":"10.3389/fnins.2020.00879"},{"reference":"Hernando G, Bouzat C. 2014. Caenorhabditis elegans neuromuscular junction: GABA receptors and. PLoS One. 9: e95072.","pubmedId":"","doi":"10.1371/journal.pone.0095072"},{"reference":"Edwards SL, Charlie NK, Milfort MC, Brown BS, Gravlin CN, Knecht JE, Miller KG. 2008. A novel molecular solution for ultraviolet light detection in. PLoS Biol. 6: e198.","pubmedId":"","doi":"10.1371/journal.pbio.0060198"},{"reference":"Liu J, Ward A, Gao J, Dong Y, Nishio N, Inada H, et al., Xu XZS. 2010. C. elegans phototransduction requires a G protein-dependent cGMP pathway. Nat. Neurosci. 13: 715-722.","pubmedId":"","doi":"10.1038/nn.2540"},{"reference":"Ji N, Madan GK, Fabre GI, Dayan A, Baker CM, Kramer TS, Nwabudike I, Flavell SW. 2021. A neural circuit for flexible control of persistent behavioral states. Elife. 10","pubmedId":"","doi":"10.7554/eLife.62889"},{"reference":"Ji N, Venkatachalam V, Rodgers HD, Hung W, Kawano T, Clark CM, et al., Samuel AD. 2021. Corollary discharge promotes a sustained motor state in a neural circuit. Elife. 10","pubmedId":"","doi":"10.7554/eLife.68848"},{"reference":"Kumar S, Sharma AK, Tran A, Liu M, Leifer AM. 2023. Inhibitory feedback from the motor circuit gates mechanosensory processing. PLoS Biol. 21: e3002280.","pubmedId":"","doi":"10.1371/journal.pbio.3002280"},{"reference":"Li Z, Zhou J, Wani KA, Yu T, Ronan EA, Piggott BJ, Liu J, Xu XZS. 2023. A C. elegans neuron both promotes and suppresses motor behavior to fine. Front. Mol. Neurosci. 16: 1228980.","pubmedId":"","doi":"10.3389/fnmol.2023.1228980"},{"reference":"Toyoshima Y, Wu S, Kanamori M, Sato H, Jang MS, Oe S, et al., Iino Y. 2020. Neuron ID dataset facilitates neuronal annotation for whole-brain activity. BMC Biol. 18: 30.","pubmedId":"","doi":"10.1186/s12915-020-0745-2"},{"reference":"Bhatla N, Horvitz HR. 2015. Light and hydrogen peroxide inhibit C. elegans Feeding through gustatory. Neuron. 85: 804-818.","pubmedId":"","doi":"10.1016/j.neuron.2014.12.061"},{"reference":"Fang Yen C, Alkema MJ, Samuel ADT. 2015. Illuminating neural circuits and behaviour in Caenorhabditis elegans with. Philos. Trans. R. Soc. Lond. B Biol. Sci. 370: 20140212.","pubmedId":"","doi":"10.1098/rstb.2014.0212"},{"reference":"Brenner S. 1974. The genetics of Caenorhabditis elegans. Genetics. 77: 71-94.","pubmedId":"","doi":"10.1093/genetics/77.1.71"},{"reference":"Aoki, I., Golinelli, L., Dunkel, E. et al. Hierarchical regulation of functionally antagonistic neuropeptides expressed in a single neuron pair. Nat Commun 15, 9504 (2024). https://doi.org/10.1038/s41467-024-53899-7
","pubmedId":"","doi":""},{"reference":"Dunkel, D., Aoki, I., Bergs, A., & Gottschalk, A. Neurons and molecules involved in noxious light sensation in Caenorhabditis elegans, G3 Genes|Genomes|Genetics, Volume 15, Issue 6, June 2025, jkaf086, https://doi.org/10.1093/g3journal/jkaf086
","pubmedId":"","doi":""},{"reference":"Hanson, S. M. et al. Structure-function analysis suggests that the photoreceptor LITE-1 is a light-activated ion channel. Curr. Biol. 33, 3423–3435.e5 (2023).
","pubmedId":"","doi":""},{"reference":"Ward, A., Liu, J., Feng, Z. & Xu, X. Z. S. Light-sensitive neurons and channels mediate phototaxis in C. elegans. Nat. Neurosci. 11, 916–922 (2008).
","pubmedId":"","doi":""}],"title":"LITE-1 Photoreceptor Mediates Light-Induced Reversal of Ivermectin Paralysis in Caenorhabditis elegans
","reviews":[],"curatorReviews":[{"curator":{"displayName":"Gary Craig Schindelman"},"openAcknowledgement":false,"submitted":null}]},{"id":"b77551c8-8a22-4da2-95d4-4ebd3965f45a","decision":"edit","abstract":"Ivermectin (IVM), a widely used anthelmintic and chemotherapeutic agent in both human and veterinary medicine, targets glutamate-gated chloride channels to induce paralysis in nematodes such as Caenorhabditis elegans. Traditionally, IVM-induced paralysis is assessed under brightfield microscopy. Here, we report that exposure to UV or blue wavelengths can induce spontaneous arousal from the IVM-paralyzed state, initiating with twitching and progressing to full swimming motion during light stimulation. This light-induced arousal response is absent in lite-1 null mutants, implicating LITE-1 photoreceptors in mediating this effect.
","acknowledgements":"The authors thank James Rand, Ph.D., for the insightful conversation and helpful review of this manuscript. ","authors":[{"affiliations":["University of Florida, Gainesville, FL, US"],"departments":[""],"credit":["conceptualization","investigation","methodology","writing_reviewEditing"],"email":"magera.shaw@ufl.edu","firstName":"Magera ","lastName":"Shaw","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Oklahoma State University Center for Health Sciences, Tulsa, OK, US"],"departments":[""],"credit":["investigation"],"email":"mylissa.stover@okstate.edu","firstName":"Mylissa","lastName":"Stover","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Oklahoma State University Center for Health Sciences, Tulsa, OK, US"],"departments":["Biochemistry and Microbiology"],"credit":["validation"],"email":"crystal.a.shults@okstate.edu","firstName":"Crystal ","lastName":"Shults","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Oklahoma State University Center for Health Sciences, Tulsa, OK, US"],"departments":["Biochemistry and Microbiology"],"credit":["conceptualization","dataCuration","formalAnalysis","fundingAcquisition","investigation","methodology","project","resources","software","supervision","validation","visualization","writing_originalDraft","writing_reviewEditing"],"email":"jacob.manjarrez@okstate.edu","firstName":"Jacob. R","lastName":"Manjarrez","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":"0000-0002-8428-8659"}],"awards":[],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[{"description":"Genotyping for lite-1(ok530)
","doi":null,"resourceType":"Dataset","name":"Genotyping Figure.docx","url":"https://portal.micropublication.org/uploads/abeede9f784aae574264c689ae908b0b.docx"}],"funding":"The authors gratefully acknowledge the Oklahoma State University Center for Health Sciences Start-up funds used in the pursuit of this project.
","image":{"url":"https://portal.micropublication.org/uploads/341460d54e0cbdf1e85d4ee9e192d738.jpg"},"imageCaption":"(A–B) Ivermectin-paralyzed worms were exposed to 2 minutes of either UV (395/25 nm; Panel A) or blue (470/40 nm; Panel B) illumination. Each data point represents the latency (in seconds) to the first observed full-body wave for an individual worm. Worms that did not move during the 2-minute trial were assigned a value of 120 seconds. (C) Summary table of arousal responses across genotypes.
","imageTitle":"Light-induced arousal from ivermectin-induced paralysis
","methods":"Nematodes were cultured on OP50, E. coli, and NGM media at 20°C. One-day-old adult C. elegans were picked from a non-starved culture and transferred onto an unseeded plate or liquid buffer containing the drug compound at 20°C for the duration of the experiment (Brenner, 1974).
A 25 mg/ml Ivermectin (Alfa Aesar) stock solution was diluted in 100% ethanol and stored at -20°C.
IVM-induced paralysis - One-day-old adults were individually transferred into a 96-well Black-Clear Bottom Plate (ThermoScientific 265301). Each well contained 10 µM IVM in M9(Castro et al., 2020). Plates were incubated at 20˚C for 30 minutes, which has been shown to induce paralysis, before prodding (Castro et al., 2020; Glendinning et al., 2011; Hernando & Bouzat, 2014), then UV and/or blue light stimulation. Each well contained a single worm that was stimulated with UV or blue light for 2 min, during which the movement was observed using a DMi8 Leica Thunder imager with a 10x objective exposed to 100% UV (395/30 nm) using a Spectra X light engine with a output of 295mW (395/25) or GFP (470/40nm) with a cyan output of 196mW (470/24). Movements were tallied when a worm made a full wave of its body (Lumencor, Inc., 2022).
PCR genotyping was performed using worm lysis buffer, freeze-heat lysis (freezing at -80◦C then cycling at 60◦C than at 95◦C to inactivate the Proteinase K in the buffer), and using the lysate as a template for PCR with deletion-discriminating primers. PCR products were resolved on a 1.0% agarose E-Gel (Invitrogen) according to the manufacturer's instructions. Gels were imaged on an iBright Imaging Systems system, and banding patterns were scored as homozygous mutant (single ok530-sized band) or heterozygous (both WT- and ok530-sized bands).
","reagents":"Strain List:
Strain | Genotype | Source |
Wild-type | Ken Miller | |
Ken Miller | ||
CGC | ||
CGC | ||
CGC | ||
CGC | ||
CGC |
","patternDescription":"
Ivermectin (IVM) is the first semi-synthetic macrocyclic lactone approved for veterinary use as a chemotherapeutic and broad-spectrum antiparasitic agent. It is known to kill Caenorhabditis elegans (C. elegans) at therapeutic doses and has been widely used in paralytic assays at subtherapeutic concentrations. (Ardelli et al., 2009; Hibbs & Gouaux, 2011). IVM exerts its effects by binding to and activating glutamate-gated chloride channels in the muscles and nerves of nematodes and arthropods (Ardelli et al., 2009; Dent et al., 1997, 2000; Ghosh et al., 2012; Glendinning et al., 2011; Hibbs & Gouaux, 2011; Yates et al., 2003). The subtherapeutic paralytic state can be maintained over a wide range of concentrations and durations according to the previously published literature, presumably under standard brightfield imaging conditions (Ardelli et al., 2009; Castro et al., 2020; Chen & Kubo, 2018; Dent et al., 1997, 2000; Glendinning et al., 2011; Hernando & Bouzat, 2014; Le et al., 2019).
The photosensory-defective lite-1 mutant has been described in several studies based on its failure to avoid UV, violet, and blue wavelengths (Edwards et al., 2008; Liu et al., 2010). However, this phenotype was initially identified by its ability to induce movement in otherwise paralyzed unc-31 mutants upon light stimulation (Ward et al., 2008). The nature of the underlying signal remains unidentified; however, multiple studies are beginning to implicate neuropeptides in modulating this response, including NLP-10 and FLP-1 (Aoki et al., 2024; Dunkel et al., 2025).
Due to its insensitivity to blue light, lite-1 is now routinely used to minimize background interference in GCaMP-based neural imaging (Ji, Madan, et al., 2021; Ji, Venkatachalam, et al., 2021; Kumar et al., 2023; Li et al., 2023; Toyoshima et al., 2020). A second light-sensitive gene, gur-3, has been associated with avoidance of extremely bright light (Bhatla & Horvitz, 2015). Although its role in light sensation is less well characterized, gur-3 was included in this study to assess its potential involvement in the reversal of IVM-induced paralysis (Bhatla & Horvitz, 2015; Fang-Yen et al., 2015; Liu et al., 2010).
UV and blue spectrum spontaneous arousal after ivermectin treatment: We initially observed that IVM-induced paralysis in wild-type animals could be reversed by exposure to UV or blue light. To determine whether this spontaneous reversal was mediated by LITE-1 photoreceptors, we compared the responses of wild-type (N2) animals, four different lite-1 mutant alleles, a gur-3(ok2245) mutant, and a lite-1(ce314); gur-3(ok2245) double mutant. Upon illumination with UV or blue light, N2, gur-3(ok2245), and lite-1(ok530) animals consistently exhibited an arousal response characterized by initial twitching followed by a return to full swimming motion during each light exposure. In contrast, lite-1(ce314), lite-1(xu7), lite-1(xu492), and the lite-1(ce314); gur-3(ok2245) double mutant displayed minimal or no arousal events (Figure 1A–C; Video S1). Green light (545/30 nm) did not trigger any movement following IVM-induced paralysis.
In contrast, the light-activated strains consistently returned to a paralyzed state once the UV or blue light stimulus was removed. However, the time required to resume paralysis varied, and we were unable to identify a consistent trend across trials.
The reduced penetrance shown for lite-1(ok530) was confirmed not to be due to heterozygosity (Figure S1). However, because this strain was used without outcrossing, it remains possible that an additional mutation could compensate for the continued light-sensing function. Nonetheless, this study indicates that such a compensatory component is not associated with gur-3 (Figure 1).
In summary, we demonstrate that UV and blue light stimulation can induce spontaneous arousal from IVM-induced paralysis in C. elegans, characterized by initial twitching followed by a return to full swimming motion. The reversal of paralysis triggered by light is strong in wild-type animals but is almost absent in severe lite-1 photosensory mutants, suggesting that the LITE-1 protein plays a vital role in this response. This response may be mediated by neuropeptide signaling, which has been recently implicated in light-induced arousal pathways.
However, these results show the need to account for light-induced behavioral artifacts when designing experiments that use fluorophores excited by UV or blue wavelengths, especially in neuromuscular or behavioral assays, including ivermectin. While the exact molecular mechanisms remain unclear, our findings demonstrate that light stimulation can alleviate ivermectin-induced paralysis, even in strains with partially disrupted phototransduction pathways.
","references":[{"reference":"Ardelli BF, Stitt LE, Tompkins JB, Prichard RK. 2009. A comparison of the effects of ivermectin and moxidectin on the nematode. Vet. Parasitol. 165: 96-108.","pubmedId":"","doi":"10.1016/j.vetpar.2009.06.043"},{"reference":"Hibbs RE, Gouaux E. 2011. Principles of activation and permeation in an anion-selective Cys-loop. Nature. 474: 54-60.","pubmedId":"","doi":"10.1038/nature10139"},{"reference":"Dent JA, Davis MW, Avery L. 1997. avr-15 encodes a chloride channel subunit that mediates inhibitory. EMBO J. 16: 5867-5879.","pubmedId":"","doi":"10.1093/emboj/16.19.5867"},{"reference":"Dent JA, Smith MM, Vassilatis DK, Avery L. 2000. The genetics of ivermectin resistance in Caenorhabditis elegans. Proc. Natl. Acad. Sci. U. S. A. 97: 2674-2679.","pubmedId":"","doi":"10.1073/pnas.97.6.2674"},{"reference":"Ghosh R, Andersen EC, Shapiro JA, Gerke JP, Kruglyak L. 2012. Natural variation in a chloride channel subunit confers avermectin. Science. 335: 574-578.","pubmedId":"","doi":"10.1126/science.1214318"},{"reference":"Glendinning SK, Buckingham SD, Sattelle DB, Wonnacott S, Wolstenholme AJ. 2011. Glutamate-gated chloride channels of Haemonchus contortus restore drug. PLoS One. 6: e22390.","pubmedId":"","doi":"10.1371/journal.pone.0022390"},{"reference":"Yates DM, Portillo V, Wolstenholme AJ. 2003. The avermectin receptors of Haemonchus contortus and Caenorhabditis. Int. J. Parasitol. 33: 1183-1193.","pubmedId":"","doi":"10.1016/s0020-7519(03)00172-3"},{"reference":"Chen IS, Kubo Y. 2018. Ivermectin and its target molecules: shared and unique modulation. J. Physiol. 596: 1833-1845.","pubmedId":"","doi":"10.1113/JP275236"},{"reference":"Le VV, Sanchez B, Hong R. 2019. Interspecific comparison of sensitivity to paralytic compounds. MicroPubl. Biol. 2019","pubmedId":"","doi":"10.17912/micropub.biology.000185"},{"reference":"Castro MJ, Turani O, Faraoni MB, Gerbino D, Bouzat C. 2020. A new antagonist of Caenorhabditis elegans glutamate-activated chloride. Front. Neurosci. 14: 879.","pubmedId":"","doi":"10.3389/fnins.2020.00879"},{"reference":"Hernando G, Bouzat C. 2014. Caenorhabditis elegans neuromuscular junction: GABA receptors and. PLoS One. 9: e95072.","pubmedId":"","doi":"10.1371/journal.pone.0095072"},{"reference":"Edwards SL, Charlie NK, Milfort MC, Brown BS, Gravlin CN, Knecht JE, Miller KG. 2008. A novel molecular solution for ultraviolet light detection in. PLoS Biol. 6: e198.","pubmedId":"","doi":"10.1371/journal.pbio.0060198"},{"reference":"Liu J, Ward A, Gao J, Dong Y, Nishio N, Inada H, et al., Xu XZS. 2010. C. elegans phototransduction requires a G protein-dependent cGMP pathway. Nat. Neurosci. 13: 715-722.","pubmedId":"","doi":"10.1038/nn.2540"},{"reference":"Ji N, Madan GK, Fabre GI, Dayan A, Baker CM, Kramer TS, Nwabudike I, Flavell SW. 2021. A neural circuit for flexible control of persistent behavioral states. Elife. 10","pubmedId":"","doi":"10.7554/eLife.62889"},{"reference":"Ji N, Venkatachalam V, Rodgers HD, Hung W, Kawano T, Clark CM, et al., Samuel AD. 2021. Corollary discharge promotes a sustained motor state in a neural circuit. Elife. 10","pubmedId":"","doi":"10.7554/eLife.68848"},{"reference":"Kumar S, Sharma AK, Tran A, Liu M, Leifer AM. 2023. Inhibitory feedback from the motor circuit gates mechanosensory processing. PLoS Biol. 21: e3002280.","pubmedId":"","doi":"10.1371/journal.pbio.3002280"},{"reference":"Li Z, Zhou J, Wani KA, Yu T, Ronan EA, Piggott BJ, Liu J, Xu XZS. 2023. A C. elegans neuron both promotes and suppresses motor behavior to fine. Front. Mol. Neurosci. 16: 1228980.","pubmedId":"","doi":"10.3389/fnmol.2023.1228980"},{"reference":"Toyoshima Y, Wu S, Kanamori M, Sato H, Jang MS, Oe S, et al., Iino Y. 2020. Neuron ID dataset facilitates neuronal annotation for whole-brain activity. BMC Biol. 18: 30.","pubmedId":"","doi":"10.1186/s12915-020-0745-2"},{"reference":"Bhatla N, Horvitz HR. 2015. Light and hydrogen peroxide inhibit C. elegans Feeding through gustatory. Neuron. 85: 804-818.","pubmedId":"","doi":"10.1016/j.neuron.2014.12.061"},{"reference":"Fang Yen C, Alkema MJ, Samuel ADT. 2015. Illuminating neural circuits and behaviour in Caenorhabditis elegans with. Philos. Trans. R. Soc. Lond. B Biol. Sci. 370: 20140212.","pubmedId":"","doi":"10.1098/rstb.2014.0212"},{"reference":"Brenner S. 1974. The genetics of Caenorhabditis elegans. Genetics. 77: 71-94.","pubmedId":"","doi":"10.1093/genetics/77.1.71"},{"reference":"Aoki, I., Golinelli, L., Dunkel, E. et al. Hierarchical regulation of functionally antagonistic neuropeptides expressed in a single neuron pair. Nat Commun 15, 9504 (2024). https://doi.org/10.1038/s41467-024-53899-7
","pubmedId":"","doi":""},{"reference":"Dunkel, D., Aoki, I., Bergs, A., & Gottschalk, A. Neurons and molecules involved in noxious light sensation in Caenorhabditis elegans, G3 Genes|Genomes|Genetics, Volume 15, Issue 6, June 2025, jkaf086, https://doi.org/10.1093/g3journal/jkaf086
","pubmedId":"","doi":""},{"reference":"Hanson, S. M. et al. Structure-function analysis suggests that the photoreceptor LITE-1 is a light-activated ion channel. Curr. Biol. 33, 3423–3435.e5 (2023).
","pubmedId":"","doi":""},{"reference":"Ward, A., Liu, J., Feng, Z. & Xu, X. Z. S. Light-sensitive neurons and channels mediate phototaxis in C. elegans. Nat. Neurosci. 11, 916–922 (2008).
","pubmedId":"","doi":""}],"title":"LITE-1 Photoreceptor Mediates Light-Induced Reversal of Ivermectin Paralysis in Caenorhabditis elegans
","reviews":[],"curatorReviews":[{"curator":{"displayName":"Gary Craig Schindelman"},"openAcknowledgement":false,"submitted":null}]},{"id":"c9913a61-b9b9-426b-8382-e85c5beb0006","decision":"publish","abstract":"Ivermectin (IVM), a widely used anthelmintic and chemotherapeutic agent in both human and veterinary medicine, targets glutamate-gated chloride channels to induce paralysis in nematodes such as Caenorhabditis elegans. Traditionally, IVM-induced paralysis is assessed under brightfield microscopy. Here, we report that exposure to UV or blue wavelengths can induce spontaneous arousal from the IVM-paralyzed state, initiating with twitching and progressing to full swimming motion during light stimulation. This light-induced arousal response is absent in lite-1 null mutants, implicating LITE-1 photoreceptors in mediating this effect.
","acknowledgements":"The authors thank James Rand, Ph.D., for the insightful conversation and helpful review of this manuscript. ","authors":[{"affiliations":["University of Florida, Gainesville, FL, US"],"departments":[""],"credit":["conceptualization","investigation","methodology","writing_reviewEditing"],"email":"magera.shaw@ufl.edu","firstName":"Magera ","lastName":"Shaw","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Oklahoma State University Center for Health Sciences, Tulsa, OK, US"],"departments":[""],"credit":["investigation"],"email":"mylissa.stover@okstate.edu","firstName":"Mylissa","lastName":"Stover","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Oklahoma State University Center for Health Sciences, Tulsa, OK, US"],"departments":["Biochemistry and Microbiology"],"credit":["validation"],"email":"crystal.a.shults@okstate.edu","firstName":"Crystal ","lastName":"Shults","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Oklahoma State University Center for Health Sciences, Tulsa, OK, US"],"departments":["Biochemistry and Microbiology"],"credit":["conceptualization","dataCuration","formalAnalysis","fundingAcquisition","investigation","methodology","project","resources","software","supervision","validation","visualization","writing_originalDraft","writing_reviewEditing"],"email":"jacob.manjarrez@okstate.edu","firstName":"Jacob. R","lastName":"Manjarrez","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":"0000-0002-8428-8659"}],"awards":[],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[{"description":"Genotyping for lite-1(ok530)
","doi":"10.22002/daj1g-d5k79","resourceType":"Dataset","name":"Genotyping Figure.docx","url":"https://portal.micropublication.org/uploads/abeede9f784aae574264c689ae908b0b.docx"}],"funding":"The authors gratefully acknowledge the Oklahoma State University Center for Health Sciences Start-up funds used in the pursuit of this project.
","image":{"url":"https://portal.micropublication.org/uploads/341460d54e0cbdf1e85d4ee9e192d738.jpg"},"imageCaption":"(A–B) Ivermectin-paralyzed worms were exposed to 2 minutes of either UV (395/25 nm; Panel A) or blue (470/40 nm; Panel B) illumination. Each data point represents the latency (in seconds) to the first observed full-body wave for an individual worm. Worms that did not move during the 2-minute trial were assigned a value of 120 seconds. (C) Summary table of arousal responses across genotypes.
","imageTitle":"Light-induced arousal from ivermectin-induced paralysis
","methods":"Nematodes were cultured on OP50, E. coli, and NGM media at 20°C. One-day-old adult C. elegans were picked from a non-starved culture and transferred onto an unseeded plate or liquid buffer containing the drug compound at 20°C for the duration of the experiment (Brenner, 1974).
A 25 mg/ml Ivermectin (Alfa Aesar) stock solution was diluted in 100% ethanol and stored at -20°C.
IVM-induced paralysis - One-day-old adults were individually transferred into a 96-well Black-Clear Bottom Plate (ThermoScientific 265301). Each well contained 10 µM IVM in M9(Castro et al., 2020). Plates were incubated at 20˚C for 30 minutes, which has been shown to induce paralysis, before prodding (Castro et al., 2020; Glendinning et al., 2011; Hernando & Bouzat, 2014), then UV and/or blue light stimulation. Each well contained a single worm that was stimulated with UV or blue light for 2 min, during which the movement was observed using a DMi8 Leica Thunder imager with a 10x objective exposed to 100% UV (395/30 nm) using a Spectra X light engine with a output of 295mW (395/25) or GFP (470/40nm) with a cyan output of 196mW (470/24). Movements were tallied when a worm made a full wave of its body (Lumencor, Inc., 2022).
PCR genotyping was performed using worm lysis buffer, freeze-heat lysis (freezing at -80◦C then cycling at 60◦C than at 95◦C to inactivate the Proteinase K in the buffer), and using the lysate as a template for PCR with deletion-discriminating primers. PCR products were resolved on a 1.0% agarose E-Gel (Invitrogen) according to the manufacturer's instructions. Gels were imaged on an iBright Imaging Systems system, and banding patterns were scored as homozygous mutant (single ok530-sized band) or heterozygous (both WT- and ok530-sized bands).
","reagents":"Strain List:
Strain | Genotype | Source |
Wild-type | Ken Miller | |
Ken Miller | ||
CGC | ||
CGC | ||
CGC | ||
CGC | ||
CGC |
","patternDescription":"
Ivermectin (IVM) is the first semi-synthetic macrocyclic lactone approved for veterinary use as a chemotherapeutic and broad-spectrum antiparasitic agent. It is known to kill Caenorhabditis elegans (C. elegans) at therapeutic doses and has been widely used in paralytic assays at subtherapeutic concentrations. (Ardelli et al., 2009; Hibbs & Gouaux, 2011). IVM exerts its effects by binding to and activating glutamate-gated chloride channels in the muscles and nerves of nematodes and arthropods (Ardelli et al., 2009; Dent et al., 1997, 2000; Ghosh et al., 2012; Glendinning et al., 2011; Hibbs & Gouaux, 2011; Yates et al., 2003). The subtherapeutic paralytic state can be maintained over a wide range of concentrations and durations according to the previously published literature, presumably under standard brightfield imaging conditions (Ardelli et al., 2009; Castro et al., 2020; Chen & Kubo, 2018; Dent et al., 1997, 2000; Glendinning et al., 2011; Hernando & Bouzat, 2014; Le et al., 2019).
The photosensory-defective lite-1 mutant has been described in several studies based on its failure to avoid UV, violet, and blue wavelengths (Edwards et al., 2008; Liu et al., 2010). However, this phenotype was initially identified by its ability to induce movement in otherwise paralyzed unc-31 mutants upon light stimulation (Ward et al., 2008). The nature of the underlying signal remains unidentified; however, multiple studies are beginning to implicate neuropeptides in modulating this response, including NLP-10 and FLP-1 (Aoki et al., 2024; Dunkel et al., 2025).
Due to its insensitivity to blue light, lite-1 is now routinely used to minimize background interference in GCaMP-based neural imaging (Ji, Madan, et al., 2021; Ji, Venkatachalam, et al., 2021; Kumar et al., 2023; Li et al., 2023; Toyoshima et al., 2020). A second light-sensitive gene, gur-3, has been associated with avoidance of extremely bright light (Bhatla & Horvitz, 2015). Although its role in light sensation is less well characterized, gur-3 was included in this study to assess its potential involvement in the reversal of IVM-induced paralysis (Bhatla & Horvitz, 2015; Fang-Yen et al., 2015; Liu et al., 2010).
UV and blue spectrum spontaneous arousal after ivermectin treatment: We initially observed that IVM-induced paralysis in wild-type animals could be reversed by exposure to UV or blue light. To determine whether this spontaneous reversal was mediated by LITE-1 photoreceptors, we compared the responses of wild-type (N2) animals, four different lite-1 mutant alleles, a gur-3(ok2245) mutant, and a lite-1(ce314); gur-3(ok2245) double mutant. Upon illumination with UV or blue light, N2, gur-3(ok2245), and lite-1(ok530) animals consistently exhibited an arousal response characterized by initial twitching followed by a return to full swimming motion during each light exposure. In contrast, lite-1(ce314), lite-1(xu7), lite-1(xu492), and the lite-1(ce314); gur-3(ok2245) double mutant displayed minimal or no arousal events (Figure 1A–C; Video S1). Green light (545/30 nm) did not trigger any movement following IVM-induced paralysis.
In contrast, the light-activated strains consistently returned to a paralyzed state once the UV or blue light stimulus was removed. However, the time required to resume paralysis varied, and we were unable to identify a consistent trend across trials.
The reduced penetrance shown for lite-1(ok530) was confirmed not to be due to heterozygosity (Figure S1). However, because this strain was used without outcrossing, it remains possible that an additional mutation could compensate for the continued light-sensing function. Nonetheless, this study indicates that such a compensatory component is not associated with gur-3 (Figure 1).
In summary, we demonstrate that UV and blue light stimulation can induce spontaneous arousal from IVM-induced paralysis in C. elegans, characterized by initial twitching followed by a return to full swimming motion. The reversal of paralysis triggered by light is strong in wild-type animals but is almost absent in severe lite-1 photosensory mutants, suggesting that the LITE-1 protein plays a vital role in this response. This response may be mediated by neuropeptide signaling, which has been recently implicated in light-induced arousal pathways.
However, these results show the need to account for light-induced behavioral artifacts when designing experiments that use fluorophores excited by UV or blue wavelengths, especially in neuromuscular or behavioral assays, including ivermectin. While the exact molecular mechanisms remain unclear, our findings demonstrate that light stimulation can alleviate ivermectin-induced paralysis, even in strains with partially disrupted phototransduction pathways.
","references":[{"reference":"Aoki, I., Golinelli, L., Dunkel, E. et al. Hierarchical regulation of functionally antagonistic neuropeptides expressed in a single neuron pair. Nat Commun 15, 9504 (2024). https://doi.org/10.1038/s41467-024-53899-7
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","pubmedId":"","doi":""},{"reference":"Yates DM, Portillo V, Wolstenholme AJ. 2003. The avermectin receptors of Haemonchus contortus and Caenorhabditis. Int. J. Parasitol. 33: 1183-1193.","pubmedId":"","doi":"10.1016/s0020-7519(03)00172-3"}],"title":"LITE-1 Photoreceptor Mediates Light-Induced Reversal of Ivermectin Paralysis in Caenorhabditis elegans
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