Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

An Endogenous Ligand of Aryl Hydrocarbon Receptor 6-Formylindolo[3,2-b]Carbazole (FICZ) Is a Signaling Molecule in Neurogenesis of Adult Hippocampal Neurons


Neurogenesis is a dynamic and physiologic developmental process that affects learning and hippocampal dependent memory. It is regulated by multi-cellular micro-environment and different types of transcription factors. The neurogenesis effects of endogenously activated aryl hydrocarbon receptor (AHR) by its endogenous ligand, 6-formylindolo[3,2-b] carbazole (FICZ), and its interactions with the Wnt/β-catenin signaling pathway were the main purpose of this study. In accordance, learning and hippocampus-dependent memory were examined. Male BALB/C mice received FICZ, CH223191, and XAV-939 in a single dose of 100 μg/kg, 1 mg/kg, and 5 mg/kg of body weight respectively via intraperitoneal (IP) injection. qRT-PCR for gene analyses and protein assay on the 7th and 28th days were performed. To assess the hippocampal dependent memory, they also underwent contextual fear conditioning on the 28th day after treatment. Our results showed that FICZ treatment led to elevation of the proneural transcription factors ASCL1 and Ngn2, immature neural marker DCX, differentiation neurons marker, NeuN, as well as β-catenin at mRNA and protein levels. We also indicated that hippocampal dependent memory and learning task were improved by FICZ treatment and impaired by the AHR and Wnt/ß-catenin inhibition. In this study for the first time, we demonstrated that the endogenous ligand of AHR, FICZ, has a positive effect on short- and long-term memory as well as learning skills. This ability is possibly mediated by the AHR-Wnt/ß-catenin cross-talk.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7


  1. Aberle H, Bauer A, Stappert J, Kispert A, Kemler R (1997) β-Catenin is a target for the ubiquitin–proteasome pathway. EMBO J 16:3797–3804

  2. Aimone JB, Deng W, Gage FH (2011) Resolving new memories: a critical look at the dentate gyrus, adult neurogenesis, and pattern separation. Neuron 70:589–596

  3. Alam MJ, Kitamura T, Saitoh Y, Ohkawa N, Kondo T, Inokuchi K (2018) Adult neurogenesis conserves hippocampal memory capacity. J Neurosci 38:6854–6863. https://doi.org/10.1523/JNEUROSCI.2976-17.2018

  4. Bergander L, Wincent E, Rannug A, Foroozesh M, Alworth W, Rannug U (2004) Metabolic fate of the ah receptor ligand 6-formylindolo [3, 2-b] carbazole. Chem Biol Interact 149:151–164

  5. Berninger B, Guillemot F, Götz M (2007) Directing neurotransmitter identity of neurones derived from expanded adult neural stem cells. Eur J Neurosci 25:2581–2590

  6. Bonaguidi MA, Song J, Ming G-L, Song H (2012) A unifying hypothesis on mammalian neural stem cell properties in the adult hippocampus. Curr Opin Neurobiol 22:754–761

  7. Bracko O, Singer T, Aigner S, Knobloch M, Winner B, Ray J, Clemenson GD Jr, Suh H, Couillard-Despres S, Aigner L, Gage FH, Jessberger S (2012) Gene expression profiling of neural stem cells and their neuronal progeny reveals IGF2 as a regulator of adult hippocampal neurogenesis. J Neurosci 32:3376–3387

  8. Collins LL, Williamson MA, Thompson BD, Dever DP, Gasiewicz TA, Opanashuk LA (2008) 2,3,7,8-Tetracholorodibenzo-p-dioxin exposure disrupts granule neuron precursor maturation in the developing mouse cerebellum. Toxicol Sci 103:125–136

  9. Couillard-Despres S et al (2006) Targeted transgene expression in neuronal precursors: watching young neurons in the old brain. Eur J Neurosci 24:1535–1545

  10. Deng W, Aimone JB, Gage FH (2010) New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat Rev Neurosci 11:339

  11. Ehninger D, Kempermann G (2008) Neurogenesis in the adult hippocampus. Cell Tissue Res 331:243–250

  12. Encinas JM, Vaahtokari A, Enikolopov G (2006) Fluoxetine targets early progenitor cells in the adult brain. Proc Natl Acad Sci 103:8233–8238

  13. Encinas JM, Sierra A, Valcárcel-Martín R, Martín-Suárez S (2013) A developmental perspective on adult hippocampal neurogenesis. Int J Dev Neurosci 31:640–645

  14. Espósito MS, Piatti VC, Laplagne DA, Morgenstern NA, Ferrari CC, Pitossi FJ, Schinder AF (2005) Neuronal differentiation in the adult hippocampus recapitulates embryonic development. J Neurosci 25:10074–10086

  15. Filippov V, Kronenberg G, Pivneva T, Reuter K, Steiner B, Wang LP, Yamaguchi M, Kettenmann H, Kempermann G (2003) Subpopulation of nestin-expressing progenitor cells in the adult murine hippocampus shows electrophysiological and morphological characteristics of astrocytes. Mol Cell Neurosci 23:373–382

  16. Geoffroy CG, Critchley JA, Castro DS, Ramelli S, Barraclough C, Descombes P, Guillemot F, Raineteau O (2009) Engineering of dominant active basic helix-loop-helix proteins that are resistant to negative regulation by postnatal central nervous system antineurogenic cues. Stem Cells 27:847–856

  17. Gerbal-Chaloin S, Dumé AS, Briolotti P, Klieber S, Raulet E, Duret C, Fabre JM, Ramos J, Maurel P, Daujat-Chavanieu M (2014) The WNT/β-catenin pathway is a transcriptional regulator of CYP2E1, CYP1A2, and aryl hydrocarbon receptor gene expression in primary human hepatocytes. Mol Pharmacol 86:624–634

  18. Gerlach JP, Emmink BL, Nojima H, Kranenburg O, Maurice MM (2014) Wnt signalling induces accumulation of phosphorylated β-catenin in two distinct cytosolic complexes. Open Biol 4:140120

  19. Hevner RF, Hodge RD, Daza RA, Englund C (2006) Transcription factors in glutamatergic neurogenesis: conserved programs in neocortex, cerebellum, and adult hippocampus. Neurosci Res 55:223–233

  20. Hsieh J (2012) Orchestrating transcriptional control of adult neurogenesis. Genes Dev 26:1010–1021

  21. Huang X, Powell-Coffman JA, Jin Y (2004) The AHR-1 aryl hydrocarbon receptor and its co-factor the AHA-1 aryl hydrocarbon receptor nuclear translocator specify GABAergic neuron cell fate in C. elegans. Development 131:819–828

  22. Inestrosa NC, Arenas E (2010) Emerging roles of Wnts in the adult nervous system. Nat Rev Neurosci 11:77

  23. Juricek L, Coumoul X (2018) The aryl hydrocarbon receptor and the nervous system. Int J Mol Sci 19:2504

  24. Kameyama T, Nabeshima T, Kozawa T (1986) Step-down-type passive avoidance-and escape-learning method: Suitability for experimental amnesia models. J Pharmacol Methods 16:39–52

  25. Kee N, Teixeira CM, Wang AH, Frankland PW (2007) Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus. Nat Neurosci 10:355

  26. Kempermann G, Jessberger S, Steiner B, Kronenberg G (2004) Milestones of neuronal development in the adult hippocampus. Trends Neurosci 27:447–452

  27. Kempermann G, Song H, Gage FH (2015) Neurogenesis in the adult hippocampus. Cold Spring Harb Perspect Biol 7:a018812

  28. Kim EJ, Leung CT, Reed RR, Johnson JE (2007) In vivo analysis of Ascl1 defined progenitors reveals distinct developmental dynamics during adult neurogenesis and gliogenesis. J Neurosci 27:12764–12774

  29. Kim ME, Park HR, Gong EJ, Choi SY, Kim HS, Lee J (2011) Exposure to bisphenol A appears to impair hippocampal neurogenesis and spatial learning and memory. Food Chem Toxicol 49:3383–3389

  30. Kim WR, Christian K, Ming G-L, Song H (2012) Time-dependent involvement of adult-born dentate granule cells in behavior. Behav Brain Res 227:470–479

  31. Kimura E, Tohyama C (2017) Embryonic and postnatal expression of aryl hydrocarbon receptor mRNA in mouse brain Front Neuroanat 11:4

  32. Kobayashi Y, Hirano T, Omotehara T, Hashimoto R, Umemura Y, Yuasa H, Ishihara-Sugano M (2015). Immunohistochemical analysis of 2, 3, 7, 8- tetrachlorodibenzo-p-dioxin (TCDD) toxicity on the developmental dentate gyrus and hippocampal fimbria in fetal mice. J Vet Med Sci: 77(11):1355–61. https://doi.org/10.1292/jvms.15-0238

  33. Kronenberg G, Reuter K, Steiner B, Brandt MD, Jessberger S, Yamaguchi M, Kempermann G (2003) Subpopulations of proliferating cells of the adult hippocampus respond differently to physiologic neurogenic stimuli. J Comp Neurol 467:455–463

  34. Kronenberg G, Bick-Sander A, Bunk E, Wolf C, Ehninger D, Kempermann G (2006) Physical exercise prevents age-related decline in precursor cell activity in the mouse dentate gyrus. Neurobiol Aging 27:1505–1513. https://doi.org/10.1016/j.neurobiolaging.2005.09.016

  35. Latchney SE, Lioy DT, Henry EC, Gasiewicz TA, Strathmann FG, Mayer-Pröschel M, Opanashuk LA (2010) Neural precursor cell proliferation is disrupted through activation of the aryl hydrocarbon receptor by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Stem Cells Dev 20:313–326

  36. Latchney SE, Hein AM, O'Banion MK, DiCicco-Bloom E, Opanashuk LA (2013) Deletion or activation of the aryl hydrocarbon receptor alters adult hippocampal neurogenesis and contextual fear memory. J Neurochem 125:430–445

  37. Lie D-C et al (2005) Wnt signalling regulates adult hippocampal neurogenesis. Nature 437:1370

  38. Lugert S, Basak O, Knuckles P, Haussler U, Fabel K, Götz M, Haas CA, Kempermann G, Taylor V, Giachino C (2010) Quiescent and active hippocampal neural stem cells with distinct morphologies respond selectively to physiological and pathological stimuli and aging. Cell Stem Cell 6:445–456

  39. Luo Z, Qian W, Han X (2014) Inhibition of Wnt/-catenin signaling promotes epithelial differentiation of mesenchymal stem cells and repairs bleomycin-induced lung injury Am J Phys Cell Physiol 307:C234-C244

  40. Machon O, Backman M, Machonova O, Kozmik Z, Vacik T, Andersen L, Krauss S (2007) A dynamic gradient of Wnt signaling controls initiation of neurogenesis in the mammalian cortex and cellular specification in the hippocampus. Dev Biol 311:223–237

  41. Maretto S et al (2003) Mapping Wnt/β-catenin signaling during mouse development and in colorectal tumors. Proc Natl Acad Sci 100:3299–3304

  42. Marlatt MW, Potter MC, Lucassen PJ, van Praag H (2012) Running throughout middle-age improves memory function, hippocampal neurogenesis, and BDNF levels in female C57BL/6J mice. Dev Neurobiol 72:943–952. https://doi.org/10.1002/dneu.22009

  43. Marlowe JL, Puga A (2005) Aryl hydrocarbon receptor, cell cycle regulation, toxicity, and tumorigenesis. J Cell Biochem 96:1174–1184

  44. Mohamed HT et al (2019) Inflammatory breast cancer: activation of the aryl hydrocarbon receptor and its target CYP1B1 correlates closely with Wnt5a/b-β-catenin signalling, the stem cell phenotype and disease progression. J Adv Res 16:75–86

  45. Mohammadi-Bardbori A, Akbarizadeh AR, Delju F, Rannug A (2016) Chromatin remodeling by curcumin alters endogenous aryl hydrocarbon receptor signaling. Chem Biol Interact 25;252:19–27. https://doi.org/10.1016/j.cbi.2016.03.037

  46. Mohammadi-Bardbor, A, Bengtsson J, Rannug U, Rannug A, Wincent E (2012) Quercetin, resveratrol, and curcumin are indirect activators of the aryl hydrocarbon receptor (AHR). Chem Res Toxicol 17;25(9):1878–84. https://doi.org/10.1021/tx300169e

  47. Mohammadi-Bardbori A, Omidi M, Arabnezhad M R (2019) Impact of CH223191-induced mitochondrial dysfunction on its aryl hydrocarbon receptor agonistic and antagonistic activities. Chem Res Toxicol 15;32(4):691–697. https://doi.org/10.1021/acs.chemrestox.8b

  48. Mohammadi-Bardbori A, Vikström Bergander L, Rannug U, Rannug A (2015) NADPH oxidase-dependent mechanism explains how arsenic and other oxidants can activate aryl hydrocarbon receptor signaling. Chem Res Toxicol 21;28(12):2278–2286. https://doi.org/10.1021/acs.chemrestox.5b00415

  49. Montaron MF et al (2006) Lifelong corticosterone level determines age-related decline in neurogenesis and memory. Neurobiol Aging 27:645–654. https://doi.org/10.1016/j.neurobiolaging.2005.02.014

  50. Mullen RJ, Buck CR, Smith AM (1992) NeuN, a neuronal specific nuclear protein in vertebrates. Development 116:201–211

  51. Nacher J, Varea E, Blasco-Ibañez JM, Castillo-Gomez E, Crespo C, Martinez-Guijarro FJ, McEwen BS (2005) Expression of the transcription factor Pax6 in the adult rat dentate gyrus. J Neurosci Res 81:753–761

  52. Nguyen L, Besson A, Roberts JM, Guillemot F (2006) Coupling cell cycle exit, neuronal differentiation and migration in cortical neurogenesis. Cell Cycle 5:2314–2318

  53. Nikkhah A, Ghahremanitamadon F, Zargooshnia S, Shahidi S, Asl SS (2014) Effect of amyloid β-peptide on passive avoidance learning in rats: a behavioral study. Avicenna J Neuro Psych Physiol 1:e18664

  54. Noonan MA, Bulin SE, Fuller DC, Eisch AJ (2010) Reduction of adult hippocampal neurogenesis confers vulnerability in an animal model of cocaine addiction. J Neurosci 30:304–315

  55. Nusse R, Varmus H (2012) Three decades of Wnts: a personal perspective on how a scientific field developed. EMBO J 31:2670–2684

  56. Okamoto M, Inoue K, Iwamura H, Terashima K, Soya H, Asashima M, Kuwabara T (2011) Reduction in paracrine Wnt3 factors during aging causes impaired adult neurogenesis. FASEB J 25:3570–3582

  57. Omidi M, Niknahad H, Noorafshan A, Fardid R, Nadimi E, Naderi S, Bakhtari A, Mohammadi-Bardbori A (2019) Co-exposure to an aryl hydrocarbon receptor endogenous ligand, 6-formylindolo [3, 2-b] carbazole (FICZ), and cadmium induces cardiovascular developmental abnormalities in mice. Biol Trace Elem Res 187:442–451

  58. Petersen SL, Curran MA, Marconi SA, Carpenter CD, Lubbers LS, McAbee MD (2000) Distribution of mRNAs encoding the arylhydrocarbon receptor, arylhydrocarbon receptor nuclear translocator, and arylhydrocarbon receptor nuclear translocator-2 in the rat brain and brainstem. J Comp Neurol 427:428–439

  59. Petrik D, Lagace DC, Eisch AJ (2012) The neurogenesis hypothesis of affective and anxiety disorders: are we mistaking the scaffolding for the building? Neuropharmacology 62:21–34

  60. Pleasure SJ, Collins AE, Lowenstein DH (2000) Unique expression patterns of cell fate molecules delineate sequential stages of dentate gyrus development. J Neurosci 20:6095–6105

  61. Pozniak CD, Pleasure SJ (2006) A tale of two signals: Wnt and Hedgehog in dentate neurogenesis. Sci STKE 24;2006(319):pe5

  62. Puga A, Tomlinson CR, Xia Y (2005) Ah receptor signals cross-talk with multiple developmental pathways. Biochem Pharmacol 69:199–207

  63. Qin H, Powell-Coffman JA (2004) The Caenorhabditis elegans aryl hydrocarbon receptor, AHR-1, regulates neuronal development. Dev Biol 270:64–75

  64. Rannug A, Rannug U (2018) The tryptophan derivative 6-formylindolo [3, 2-b] carbazole, FICZ, a dynamic mediator of endogenous aryl hydrocarbon receptor signaling, balances cell growth and differentiation. Crit Rev Toxicol 48:555–574

  65. Roybon L, Hjalt T, Stott S, Guillemot F, Li J-Y, Brundin P (2009) Neurogenin2 directs granule neuroblast production and amplification while NeuroD1 specifies neuronal fate during hippocampal neurogenesis. PLoS One 4:e4779

  66. Sahay A, Wilson DA, Hen R (2011) Pattern separation: a common function for new neurons in hippocampus and olfactory bulb. Neuron 70:582–588

  67. Suh H, Consiglio A, Ray J, Sawai T, D'Amour KA, Gage FH (2007) In vivo fate analysis reveals the multipotent and self-renewal capacities of Sox2+ neural stem cells in the adult hippocampus. Cell Stem Cell 1:515–528

  68. Touyarot K, Bonhomme D, Roux P, Alfos S, Lafenêtre P, Richard E, Higueret P, Pallet V (2013) A mid-life vitamin A supplementation prevents age-related spatial memory deficits and hippocampal neurogenesis alterations through CRABP-I. PLoS One 8:e72101 https://doi.org/10.1371/journal.pone.0072101

  69. Urbán N, Guillemot F (2014) Neurogenesis in the embryonic and adult brain: same regulators, different roles. Front Cell Neurosci 8:396

  70. Vadodaria KC, Jessberger S (2014) Functional neurogenesis in the adult hippocampus: then and now. Front Neurosci 8:55

  71. van Praag H, Christie BR, Sejnowski TJ, Gage FH (1999) Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci U S A 96:13427–13431. https://doi.org/10.1073/pnas.96.23.13427

  72. Varela-Nallar L, Inestrosa NC (2013) Wnt signaling in the regulation of adult hippocampal neurogenesis. Front Cell Neurosci 7:100

  73. Williamson MA, Gasiewicz TA, Opanashuk LA (2004) Aryl hydrocarbon receptor expression and activity in cerebellar granule neuroblasts: implications for development and dioxin neurotoxicity. Toxicol Sci 83:340–348

  74. Wincent E, Bengtsson J, Bardbori AM, Alsberg T, Luecke S, Rannug U, Rannug A (2012) Inhibition of cytochrome P4501-dependent clearance of the endogenous agonist FICZ as a mechanism for activation of the aryl hydrocarbon receptor. Proc Natl Acad Sci 109:4479–4484

  75. Wincent E, Kubota A, Timme-Laragy A, Jönsson ME, Hahn ME, Stegeman JJ (2016) Biological effects of 6-formylindolo[3,2-b]carbazole (FICZ) in vivo are enhanced by loss of CYP1A function in an Ahr2-dependent manner. Biochem Pharmacol 110:117–129

  76. Wu D et al (2011) Activation of aryl hydrocarbon receptor induces vascular inflammation and promotes atherosclerosis in apolipoprotein E−/− mice. Arterioscler Thromb Vasc Biol 31:1260–1267

  77. Zhao C, Deng W, Gage FH (2008) Mechanisms and functional implications of adult neurogenesis. Cell 132:645–660

Download references


The authors of this manuscript wish to express their appreciation to Shiraz University of Medical Sciences, Shiraz, Iran.


This work was supported by the Shiraz University of Medical Sciences grant for the accomplishment of the PhD thesis of Majid Keshavarzi (Grant number: 15168).

Author information

MK, MJK, AGB, and AMB participated in study design, data collection and evaluation, drafting, and statistical analysis. MK AGB and AMB conducted molecular experiments and RT qPCR analysis. All authors performed editing and approving the final version of this paper for submission.

Correspondence to Afshin Mohammadi-Bardbori.

Ethics declarations

This article does not contain any studies with human participants performed by any of the authors. All experimental protocols were performed in accordance with the ethics committee guideline of the Shiraz University of Medical Sciences.

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Keshavarzi, M., Khoshnoud, M.J., Ghaffarian Bahraman, A. et al. An Endogenous Ligand of Aryl Hydrocarbon Receptor 6-Formylindolo[3,2-b]Carbazole (FICZ) Is a Signaling Molecule in Neurogenesis of Adult Hippocampal Neurons. J Mol Neurosci (2020). https://doi.org/10.1007/s12031-020-01506-x

Download citation


  • Neurogenesis
  • AHR
  • Wnt/ß-catenin
  • FICZ
  • Learning and memory