Stage-specific heat shock effects on learning and memory in kynurenine-deficient Drosophila
DOI:
https://doi.org/10.33910/2687-1270-2025-6-1-85-96Keywords:
Drosophila, kynurenine tryptophan pathway, learning, memory, heat shock, conditioned courtship suppression, mushroom bodies, central complexAbstract
In the 1960s–1970s, I. P. Lapin first demonstrated that kynurenine and its metabolites modulate brain function, proposing their involvement in depression pathogenesis and antidepressant mechanisms. Subsequent research revealed the conserved action of these compounds across vertebrates and invertebrates, enabling the widespread use of Drosophila models, particularly mutants of the kynurenine pathway of tryptophan metabolism (KPTM). Kynurenines have since been implicated in various human neuropathologies, aging-related disorders, and chronic inflammatory conditions. Drosophila KPTM mutants provide an established model for investigating how these metabolites influence behavioral processes. Given contemporary neuroscience’s focus on identifying shared mechanisms linking cognitive function and stress response, this study examines the stage-specific effects of heat shock on learning and memory formation under kynurenine deficiency in Drosophila. The preserved learning and memory observed in mutant v1 suggests these processes depend critically on altered ratios of KPTM metabolites rather than absolute kynurenine deficiency.
References
Badawy, A. A.-B. (2017) Kynurenine pathway of tryptophan metabolism: Regulatory and functional aspects. International Journal of Tryptophan Research, vol. 10, article 1178646917691938. https://doi.org/10.1177/1178646917691938 (In English)
Bang, S., Hyun, S., Hong, S.-T. et al. (2011) Dopamine signalling in mushroom bodies regulates temperature-preference behaviour in Drosophila. PLoS Genetics, vol. 7, no. 3, article e1001346. https://doi.org/10.1371/journal.pgen.1001346 (In English)
Bässler, U. (1983) Neural basis of elementary behavior in stick insects. Berlin: Springer-Verlag, 169 р. (In English)
Bryleva, E. Y., Brundin, L. (2017) Kynurenine pathway metabolites and suicidality. Neuropharmacology, vol. 112 (B), pp. 324–330. https://doi.org/10.1016/j.neuropharm.2016.01.034 (In English)
Buhl, E., Kottler, B., Hodge, J. J. L., Hirth, F. (2021) Thermoresponsive motor behavior is mediated by ring neuron circuits in the central complex of Drosophila. Scientific Reports, vol. 11, no. 1, article 155. https://doi.org/10.1038/s41598-020-80103-9 (In English)
Campesan, S., Green, E. W., Breda, C. et al. (2011) The kynurenine pathway modulates neurodegeneration in a Drosophila model of Huntington’s disease. Current Biology, vol. 21, no. 11, pp. 961–966. https://doi.org/10.1016/j.cub.2011.04.028 (In English)
Davis, R. L. (2023) Learning and memory using Drosophila melanogaster: A focus on advances made in the fifth decade of research. Genetics, vol. 224, no. 4, article iyad085. https://doi.org/10.1093/genetics/iyad085 (In English)
El-Defrawy, S. R., Boegman, R. J., Jhamandas, K., Beninger, R. J. (1986) The neurotoxic actions of quinolinic acid in the central nervous system. Canadian Journal of Physiology and Pharmacology, vol. 64, no. 3, pp. 369–375. https://doi.org/10.1139/y86-060 (In English)
Erhardt, S., Schwieler, L., Imbeault, S., Engberg, G. (2017) The kynurenine pathway in schizophrenia and bipolar disorder. Neuropharmacology, vol. 112 (B), pp. 297–306. https://doi.org/10.1016/j.neuropharm.2016.05.020 (In English)
Fathi, M., Vakili, K., Yaghoobpoor, S. et al. (2022) Dynamic changes in metabolites of the kynurenine pathway in Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease: A systematic review and meta-analysis. Frontiers in Immunology, vol. 13, article 997240. https://doi.org/10.3389/fimmu.2022.997240 (In English)
Ferré, J. (1983) Accumulation of kynurenic acid in the “cinnabar” mutant of Drosophila melanogaster as revealed by thin-layer chromatography. Insect Biochemistry, vol. 13, no. 3, pp. 289–294. https://doi.org/10.1016/0020-1790(83)90051-3 (In English)
Fiala, A., Kaun, K. R. (2024) What do the mushroom bodies do for the insect brain? Twenty-five years of progress. Learning & Memory, vol. 31, no. 5, article a053827. https://doi.org/10.1101/lm.053827.123 (In English)
Flores-Valle, A., Gonçalves, P. J., Seelig, J. D. (2021) Integration of sleep homeostasis and navigation in Drosophila. PLOS Computational Biology, vol. 17, no. 7, article e1009088. https://doi.org/10.1371/journal.pcbi.1009088 (In English)
Foster, A. C., Vezzani, A., French, E. D., Schwarcz, R. (1984) Kynurenic acid blocks neurotoxicity and seizures induced in rats by the related brain metabolite quinolinic acid. Neuroscience Letters, vol. 48, no. 3, pp. 273–278. https://doi.org/10.1016/0304-3940(84)90050-8 (In English)
Green, E. W., Campesan, S., Breda, C. et al. (2012) Drosophila eye color mutants as therapeutic tools for Huntington disease. Fly, vol. 6, no. 2, pp. 117–120. https://doi.org/10.4161/fly.19999 (In English)
Hanesch, U., Fischbach, K.-F., Heisenberg, M. (1989) Neuronal architecture of the central complex in Drosophila melanogaster. Cell and Tissue Research, vol. 257, no. 2, pp. 343–366. https://doi.org/10.1007/BF00261838 (In English)
Heisenberg, M., Borst, A., Wagner, S., Byers, D. (1985) Drosophila mushroom body mutants are deficient in olfactory learning. Journal of Neurogenetics, vol. 2, no. 1, pp. 1–30. https://doi.org/10.3109/01677068509100140 (In English)
Hilmas, C., Pereira, E. F., Alkondon, M. et al. (2001) The brain metabolite kynurenic acid inhibits α7 nicotinic receptor activity and increases non-α7 nicotinic receptor expression: Physiopathological implications. Journal of Neuroscience, vol. 21, no. 19, pp. 7463–7473. https://doi.org/10.1523/JNEUROSCI.21-19-07463.2001 (In English)
Honkanen, A., Adden, A., da Silva Freitas, J., Heinze, S. (2019) The insect central complex and the neural basis of navigational strategies. Journal of Experimental Biology, vol. 222, suppl. 1, article jeb188854. https://doi.org/10.1242/jeb.188854 (In English)
Ichinose, T., Kanno, M., Wu, H. et al. (2021) Mushroom body output differentiates memory processes and distinct memory-guided behaviors. Current Biology, vol. 31, no. 6, pp. 1294–1302. https://doi.org/10.1016/j.cub.2020.12.032 (In English)
Kamyshev, N. G. (1980) Lifetime and its relationship to motor activity in Drosophila mutants of the tryptophan-xanthommatin metabolic pathway. Doklady Akademii nauk SSSR, vol. 253, no. 6, pp. 355–357. (In English)
Kamyshev, N. G., Iliadi, K. G., Bragina, J. V. (1999) Drosophila conditioned courtship: Two ways of testing memory. Learning & Memory, vol. 6, no. 1, pp. 1–20. https://pubmed.ncbi.nlm.nih.gov/10355520 (In English)
Kessler, M., Terramani, T., Lynch, G., Baudry, M. (1989) A glycine site associated with N-methyl-D-aspartic acid receptors: Characterization and identification of a new class of antagonists. Journal of Neurochemistry, vol. 52, no. 4, pp. 1319–1328. https://doi.org/10.1111/j.1471-4159.1989.tb01881.x (In English)
Lapin, I. P. (1973) Kynurenines as probable participants of depression. Pharmakopsychiatrie — Neuro-Psychopharmacologie, vol. 6, no. 6, pp. 273–279. https://doi.org/10.1055/s-0028-1094391 (In English)
Lee, T., Lee, A., Luo, L. (1999) Development of the Drosophila mushroom bodies: Sequential generation of three distinct types of neurons from a neuroblast. Development, vol. 126, no. 18, pp. 4065–4076. https://doi.org/10.1242/dev.126.18.4065 (In English)
Linzen, B. (1974) The tryptophan → ommochrome pathway in insects. Advances in Insect Physiology, vol. 10, pp. 117–246. https://doi.org/10.1016/S0065-2806(08)60130-7 (In English)
Lopatina, N. G., Chesnokova, E. G., Smirnov, V. B. et al. (2004) Kinureninovyj put’ obmena triptofana i ego znachenie v nejrofiziologii nasekomykh [Kynurenine pathway of tryptophan metabolism and its significance in neurophysiology of insects]. Entomologicheskoe obozrenie — Entomological Review, vol. 83, no. 1, pp. 3–22. (In Russian)
Lopatina, N. G., Zachepilo, T. G., Chesnokova, E. G., Savvateeva-Popova, E. V. (2011) Behavioral and molecular consequences of deficiency of endogenous kynurenines in honeybees (Apis mellifera L.). Neuroscience and Behavioral Physiology, vol. 41, no. 6, pp. 626–631. https://doi.org/10.1007/s11055-011-9465-y (In English)
Masek, P., Keene, A. C. (2016) Gustatory processing and taste memory in Drosophila. Journal of Neurogenetics, vol. 30, no. 2, pp. 112–121. https://doi.org/10.1080/01677063.2016.1185104 (In English)
Navrotskaya, V., Wnorowski, A., Turski, W., Oxenkrug, G. (2018) Effect of kynurenic acid on pupae viability of Drosophila melanogaster cinnabar and cardinal eye color mutants with altered tryptophan-kynurenine metabolism. Neurotoxicity Research, vol. 34, no. 2, pp. 324–331. https://doi.org/10.1007/s12640-018-9891-5 (In English)
Nikitina, E. A. (2024) O vliyanii mutatsii white na obuchenie i pamyat’ u drozofily pri dejstvii teplovogo shoka [The effect of the white mutation on learning and memory in Drosophila under heat shock]. Integrativnaya fiziologiya — Integrative Physiology, vol. 5, no. 1, pp. 72–82. https://doi.org/10.33910/2687-1270-2024-5-1-72-82 (In Russian)
Nikitina, E. A., Kaminskaya, A. N., Molotkov, D. A. et al. (2014) Effect of heat shock on courtship behavior, sound production, and learning in comparison with the brain content of LIMK1 in Drosophila melanogaster males with altered structure of the limk1 gene. Journal of Evolutionary Biochemistry and Physiology, vol. 50, no. 2, pp. 154–166. https://doi.org/10.1134/S0022093014020082 (In English)
Nikitina, E. A., Komarova, A. V., Golubkova, E. V. et al. (2003a) Dominant effects of l(1)ts403 (sbr10) mutation at the disjunction of sex chromosomes in meiosis of Drosophila melanogaster female after heat shock. Russian Journal of Genetics, vol. 39, no. 3, pp. 269–276. https://doi.org/10.1023/A:1023208725228 (In English)
Nikitina, E. A., Medvedeva, A. V., Dolgaya, Yu. F. et al. (2012) Involvement of GDNF and LIMK1 and heat shock proteins in Drosophila learning and memory formation. Journal of Evolutionary Biochemistry and Physiology, vol. 48, no. 5–6, pp. 529–539. https://doi.org/10.1134/S0022093012050076 (In English)
Nikitina, E. A., Tokmatcheva, E. V., Savvateeva-Popova, E. V. (2003a) Heat shock during the development of central structures of the Drosophila brain: Memory formation in the l(1)ts403 mutant of Drosophila melanogaster. Russian Journal of Genetics, vol. 39, no. 1, pp. 25–31. https://doi.org/10.1023/A:1022062609102 (In English)
Nikitina, E. A., Zhuravlev, A. V., Savvateeva-Popova, E. V. (2021) Vliyanie narusheniya sinteza kinureninov na pamyat’ u drozofily [Effect of impaired kynurenine synthesis on memory in Drosophila]. Integrativnaya fiziologiya — Integrative Physiology, vol. 2, no. 1, pp. 49–60. https://doi.org/10.33910/2687-1270-2021-2-1-49-60 (In Russian)
Phillips, J. P., Forrest, H. S., Kulkarni, A. D. (1973) Terminal synthesis of xanthommatin in Drosophila melanogaster. III. Mutational pleiotropy and pigment granule association of phenoxazinone synthetase. Genetics, vol. 73, no. 1, pp. 46–56. https://doi.org/10.1093/genetics/73.1.45 (In English)
Sakai, T., Kitamoto, T. (2006) Differential roles of two major brain structures, mushroom bodies and central complex, for Drosophila male courtship behavior. Journal of Neurobiology, vol. 66, no. 8, pp. 821–834. https://doi.org/10.1002/neu.20262 (In English)
Savvateeva, E. V., Popov, A. V., Kamyshev, N. G. et al. (2000) Age-dependent memory loss, synaptic pathology and altered brain plasticity in the Drosophila mutant cardinal accumulating 3-hydroxykynurenine. Journal of Neural Transmission, vol. 107, no. 5, pp. 581–601. https://doi.org/10.1007/s007020070080 (In English)
Savvateeva-Popova, E. V., Popov, A. V., Grossman, A. I. et al. (2007) Pathogenic chaperone-like RNA induces congophilic aggregates and facilitates neurodegeneration in Drosophila. Cell Stress & Chaperones, vol. 12, no. 1, pp. 9–19. https://pubmed.ncbi.nlm.nih.gov/17441503 (In English)
Savvateeva-Popova, E. V., Popov, A. V., Grossman, A. I. et al. (2008) Non-coding RNA as a trigger of neuropathologic disorder phenotypes in transgenic Drosophila. Journal of Neuronal Transmission, vol. 115, no. 12, pp. 1629–1642. https://doi.org/10.1007/s00702-008-0078-8 (In English)
Schwarcz, R., Bruno, J. P., Muchowski, P. J., Wu, H.-Q. (2012) Kynurenines in the mammalian brain: When physiology meets pathology. Nature Review Neuroscience, vol. 13, no. 7, pp. 465–477. https://doi.org/10.1038/nrn3257 (In English)
Solanki, N., Wolf, R., Heisenberg, M. (2015) Central complex and mushroom bodies mediate novelty choice behavior in Drosophila. Journal of Neurogenetics, vol. 29, no. 1, pp. 30–37. https://doi.org/10.3109/01677063.2014.1002661 (In English)
Stone, T. W. (1991) Kynurenine and glycine enhance neuronal sensitivity to N-methyl-D-aspartate. Life Sciences, vol. 48, no. 8, pp. 765–772. https://doi.org/10.1016/0024-3205(91)90091-o (In English)
Strauss, R., Heisenberg, M. (1993) A higher control center of locomotor behavior in the Drosophila brain. The Journal of Neuroscience, vol. 13, no. 5, pp. 1852–1861. https://doi.org/10.1523/JNEUROSCI.13-05-01852.1993 (In English)
Sun, Y., Qiu, R., Li, X. et al. (2020) Social attraction in Drosophila is regulated by the mushroom body and serotonergic system. Nature Communications, vol. 11, no. 1, article 5350. https://doi.org/10.1038/s41467-020-19102-3 (In English)
Tsao, C.-H., Chen, C.-C., Lin, C.-H. et al. (2018) Drosophila mushroom bodies integrate hunger and satiety signals to control innate food-seeking behavior. Elife, vol. 7, article e35264. https://doi.org/10.7554/eLife.35264 (In English)
Venkatesan, D., Iyer, M., Narayanasamy, A. et al. (2020) Kynurenine pathway in Parkinson’s disease — An update. eNeurologicalSci, vol. 21, article 100270. https://doi.org/10.1016/j.ensci.2020.100270 (In English)
Warren, T. L., Giraldo, Y. M., Dickinson, M. H. (2019) Celestial navigation in Drosophila. Journal of Experimental Biology, vol. 222, suppl. 1, article jeb186148. https://doi.org/10.1242/jeb.186148 (In English)
Weiss, J. T., Donlea, J. M. (2021) Sleep deprivation results in diverse patterns of synaptic scaling across the Drosophila mushroom bodies. Current Biology, vol. 31, no. 15, pp. 3248–3261. https://doi.org/10.1016/j.cub.2021.05.018 (In English)
Zakharov, G. A., Zhuravlev, A. V., Payalina, T. L. et al. (2012) The effect of mutations of the kynurenine pathway of tryptophan metabolism on locomotor behavior and gene expression in glutamatergic and cholinergic systems of D. melanogaster. Russian Journal of Genetics: Applied Research, vol. 2, no. 2, pp. 197–204. https://doi.org/10.1134/S2079059712020141 (In English)
Zhuravlev, A. V., Nikitina, E. A., Savvateeva-Popova, E. V. (2015) Obuchenie i pamyat’ u drozofily: fiziologo-geneticheskie osnovy [Learning and memory in Drosophila: Physiologic and genetic bases]. Uspekhi fiziologicheskikh nauk — Progress in Physiological Science, vol. 46, no. 1, pp. 76–92. (In Russian)
Zhuravlev, A. V., Nikitina, E. A., Savvateeva-Popova, E. V. (2020a) Rol’ kinureninov v regulyatsii povedeniya i protsessov pamyati u drozofily [The role of kynurenines in regulation of behavior and memory processes in Drosophila]. Integrativnaya fiziologiya — Integrative Physiology, vol. 1, no. 1, pp. 40–50. https://doi.org/10.33910/2687-1270-2020-1-1-40-50 (In Russian)
Zhuravlev, A. V., Vetrovoy, O. V., Ivanova, P. N., Savvateeva-Popova, E. V. (2020b) 3-hydroxykynurenine in regulation of Drosophila behavior: The novel mechanisms for cardinal phenotype manifestations. Frontiers in Physiology, vol. 11, article 971. https://doi.org/10.3389/fphys.2020.00971 (In English)
Zhuravlev, A. V., Zakharov, G. A., Shchegolev, B. F., Savvateeva-Popova, E. V. (2012) Stacking interaction and its role in kynurenic acid binding to glutamate ionotropic receptors. Journal of Molecular Modeling, vol. 18, no. 5, pp. 1755–1766. https://doi.org/10.1007/s00894-011-1206-1 (In English)
Zhuravlev, A. V., Shchegolev, B. F., Zakharov, G. A. et al. (2022) 3-hydroxykynurenine as a potential ligand for Hsp70 proteins and its effects on Drosophila memory after heat shock. Molecular Neurobiology, vol. 59, no. 3, pp. 1862–1871. https://doi.org/10.1007/s12035-021-02704-3 (In English)
Downloads
Published
Issue
Section
License
Copyright (c) 2025 Ekaterina A. Nikitina
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
The work is provided under the terms of the Public Offer and of Creative Commons public license Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). This license allows an unlimited number of persons to reproduce and share the Licensed Material in all media and formats. Any use of the Licensed Material shall contain an identification of its Creator(s) and must be for non-commercial purposes only.
