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Hippocampal neural stem cells and microglia response to experimental inflammatory bowel disease (IBD)

A Correction to this article was published on 01 September 2020

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Abstract

Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is a disease associated with dysbiosis, resulting in compromised intestinal epithelial barrier and chronic mucosal inflammation. Patients with IBD present with increased incidence of psychiatric disorders and cognitive impairment. Hippocampus is a brain region where adult neurogenesis occurs with functional implications in mood control and cognition. Using a well-established model of experimental colitis based on the administration of dextran sodium sulfate (DSS) in the drinking water, we sought to characterize the short and long-term effects of colitis on neurogenesis and glia responses in the hippocampus. We show that acute DSS colitis enhanced neurogenesis but with deficits in cell cycle kinetics of proliferating progenitors in the hippocampus. Chronic DSS colitis was characterized by normal levels of neurogenesis but with deficits in the migration and integration of newborn neurons in the functional circuitry of the DG. Notably, we found that acute DSS colitis-induced enhanced infiltration of the hippocampus with macrophages and inflammatory myeloid cells from the periphery, along with elevated frequencies of inflammatory M1-like microglia and increased release of pro-inflammatory cytokines. In contrast, increased percentages of tissue-repairing M2-like microglia, along with elevated levels of the anti-inflammatory cytokine, IL-10 were observed in the hippocampus during chronic DSS colitis. These findings uncover key effects of acute and chronic experimental colitis on adult hippocampal neurogenesis and innate immune cell responses, highlighting the potential mechanisms underlying cognitive and mood dysfunction in patients with IBD.

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Fig. 1: Acute DSS colitis induces hippocampal neurogenesis.
Fig. 2: Acute DSS colitis induces deficits in cell cycle kinetics of proliferating hippocampal progenitors.
Fig. 3: Chronic DSS colitis affects the migration of newborn neurons in the DG.
Fig. 4: Chronic DSS colitis affects the integration of newborn and mature dentate granule neurons in the functional circuitry of the DG.
Fig. 5: Innate immune cells in the hippocampus exhibit distinct phenotypes during acute and chronic DSS colitis.
Fig. 6: Cytokine profile in the brain and the periphery during acute and chronic DSS colitis.

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References

  1. Danese S, Fiocchi C. Ulcerative colitis. N Engl J Med. 2011;365:1713–25.

    Article  CAS  PubMed  Google Scholar 

  2. Addolorato G, Capristo E, Stefanini GF, Gasbarrini G. Inflammatory bowel disease: a study of the association between anxiety and depression, physical morbidity, and nutritional status. Scand J Gastroenterol. 1997;32:1013–21.

    Article  CAS  PubMed  Google Scholar 

  3. Bhamre R, Sawrav S, Adarkar S, Sakaria R, J Bhatia S. Psychiatric comorbidities in patients with inflammatory bowel disease. Indian J Gastroenterol. 2018;37:307.

    Article  PubMed  Google Scholar 

  4. Bonaz BL, Bernstein CN. Brain-gut interactions in inflammatory bowel disease. Gastroenterology. 2013;144:36–49.

    Article  PubMed  Google Scholar 

  5. MacQueen G, Frodl T. The hippocampus in major depression: evidence for the convergence of the bench and bedside in psychiatric research? Mol Psychiatry. 2011;16:252–64.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  7. Anacker C, Hen R. Adult hippocampal neurogenesis and cognitive flexibility—linking memory and mood. Nat Rev Neurosci. 2017;18:335–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hayashi Y, Jinnou H, Sawamoto K, Hitoshi S. Adult neurogenesis and its role in brain injury and psychiatric diseases. J Neurochem. 2018;147:584–94.

    Article  CAS  PubMed  Google Scholar 

  9. Rosi S. Neuroinflammation and the plasticity-related immediate-early gene Arc. Brain Behav Immun. 2011;25:S39–S49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Monje ML, Toda H, Palmer TD. Inflammatory blockade restores adult hippocampal neurogenesis. Science. 2003;302:1760–5.

    Article  CAS  PubMed  Google Scholar 

  11. Jakubs K, Bonde S, Iosif RE, Ekdahl CT, Kokaia Z, Kokaia M, et al. Inflammation regulates functional integration of neurons born in adult brain. J Neurosci. 2008;28:12477–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ekdahl CT, Claasen J-H, Bonde S, Kokaia Z, Lindvall O. Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci USA. 2003;100:13632–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Belarbi K, Arellano C, Ferguson R, Jopson T, Rosi S. Chronic neuroinflammation impacts the recruitment of adult-born neurons into behaviorally relevant hippocampal networks. Brain Behav Immun. 2012;26:18–23.

    Article  CAS  PubMed  Google Scholar 

  14. Rosi S, Belarbi K, Ferguson RA, Fishman K, Obenaus A, Raber J, et al. Trauma-induced alterations in cognition and Arc expression are reduced by previous exposure to 56Fe irradiation. Hippocampus. 2012;22:544–54.

    Article  CAS  PubMed  Google Scholar 

  15. Rosi S. Neuroinflammation alters the hippocampal pattern of behaviorally induced arc expression. J Neurosci. 2005;25:723–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. van Langenberg DR, Yelland GW, Robinson SR, Gibson PR. Cognitive impairment in Crohn’s disease is associated with systemic inflammation, symptom burden and sleep disturbance. United Eur Gastroenterol J. 2017;5:579–87.

    Article  Google Scholar 

  17. Petruo VA, Zeißig S, Schmelz R, Hampe J, Beste C. Specific neurophysiological mechanisms underlie cognitive inflexibility in inflammatory bowel disease. Sci Rep. 2017;7:13943.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Lv K, Fan Y-H, Xu L, Xu M-S. Brain changes detected by functional magnetic resonance imaging and spectroscopy in patients with Crohn’s disease. World J Gastroenterol. 2017;23:3607–14.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Bao CH, Liu P, Liu HR, Wu LY, Shi Y, Chen WF, et al. Alterations in brain grey matter structures in patients with crohn’s disease and their correlation with psychological distress. J Crohns Colitis. 2015;9:532–40.

    Article  PubMed  Google Scholar 

  20. Pickering M, O’Connor JJ. Pro-inflammatory cytokines and their effects in the dentate gyrus. Prog Brain Res. 2007;163:339–54.

    Article  CAS  PubMed  Google Scholar 

  21. Misiak B, Beszłej JA, Kotowicz K, Szewczuk-Bogusławska M, Samochowiec J, Kucharska-Mazur J, et al. Cytokine alterations and cognitive impairment in major depressive disorder: From putative mechanisms to novel treatment targets. Prog Neuropsychopharmacol Biol Psychiatry. 2018;80:177–88.

    Article  CAS  PubMed  Google Scholar 

  22. Wilson CJ, Finch CE, Cohen HJ. Cytokines and cognition-the case for a head-to-toe inflammatory paradigm. J Am Geriatr Soc. 2002;50:2041–56.

    Article  PubMed  Google Scholar 

  23. Riazi K, Galic MA, Kuzmiski JB, Ho W, Sharkey KA, Pittman QJ. Microglial activation and TNFalpha production mediate altered CNS excitability following peripheral inflammation. Proc Natl Acad Sci USA. 2008;105:17151–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Nyuyki KD, Cluny NL, Swain MG, Sharkey KA, Pittman QJ. Altered brain excitability and increased anxiety in mice with experimental colitis: consideration of hyperalgesia and sex differences. Front Behav Neurosci. 2018;12:58.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Wirtz S, Popp V, Kindermann M, Gerlach K, Weigmann B, Fichtner-Feigl S, et al. Chemically induced mouse models of acute and chronic intestinal inflammation. Nat Protoc. 2017;12:1295–309.

    Article  CAS  PubMed  Google Scholar 

  26. Kim JJ, Shajib MS, Manocha MM, Khan WI. Investigating intestinal inflammation in DSS-induced model of IBD. J Vis Exp. 2012. https://doi.org/10.3791/3678.

  27. Ramírez-Amaya V, Vazdarjanova A, Mikhael D, Rosi S, Worley PF, Barnes CA. Spatial exploration-induced Arc mRNA and protein expression: evidence for selective, network-specific reactivation. J Neurosci. 2005;25:1761–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Wojtowicz JM, Kee N. BrdU assay for neurogenesis in rodents. Nat Protoc. 2006;1:1399–405.

    Article  CAS  PubMed  Google Scholar 

  29. Farioli-Vecchioli S, Saraulli D, Costanzi M, Pacioni S, Cinà I, Aceti M, et al. The timing of differentiation of adult hippocampal neurons is crucial for spatial memory. PLoS Biol. 2008;6:e246.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Klempin F, Beis D, Mosienko V, Kempermann G, Bader M, Alenina N. Serotonin is required for exercise-induced adult hippocampal neurogenesis. J Neurosci. 2013;33:8270–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kee N, Teixeira CM, Wang AH, Frankland PW. Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus. Nat Neurosci. 2007;10:355–62.

    Article  CAS  PubMed  Google Scholar 

  32. Andersson KME, Wasén C, Juzokaite L, Leifsdottir L, Erlandsson MC, Silfverswärd ST, et al. Inflammation in the hippocampus affects IGF1 receptor signaling and contributes to neurological sequelae in rheumatoid arthritis. Proc Natl Acad Sci USA. 2018;115:E12063–E12072.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ferreira AC, Santos T, Sampaio-Marques B, Novais A, Mesquita SD, Ludovico P, et al. Lipocalin-2 regulates adult neurogenesis and contextual discriminative behaviours. Mol Psychiatry. 2018;23:1031–9.

    Article  CAS  PubMed  Google Scholar 

  34. Belarbi K, Jopson T, Arellano C, Fike JR, Rosi S. CCR2 deficiency prevents neuronal dysfunction and cognitive impairments induced by cranial irradiation. Cancer Res. 2013;73:1201–10.

    Article  CAS  PubMed  Google Scholar 

  35. Belarbi K, Rosi S. Modulation of adult-born neurons in the inflamed hippocampus. Front Cell Neurosci. 2013;7:145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ramirez-Amaya V, Marrone DF, Gage FH, Worley PF, Barnes CA. Integration of new neurons into functional neural networks. J Neurosci. 2006;26:12237–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Szepesi Z, Manouchehrian O, Bachiller S, Deierborg T. Bidirectional microglia–neuron communication in health and disease. Front Cell Neurosci. 2018;12:323.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Vezzani A, Viviani B. Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability. Neuropharmacology. 2015;96:70–82.

    Article  CAS  PubMed  Google Scholar 

  39. Borsini A, Zunszain PA, Thuret S, Pariante CM. The role of inflammatory cytokines as key modulators of neurogenesis. Trends Neurosci. 2015;38:145–57.

    Article  CAS  PubMed  Google Scholar 

  40. Besedovsky HO, del Rey A. Central and peripheral cytokines mediate immune-brain connectivity. Neurochem Res. 2011;36:1–6.

    Article  CAS  PubMed  Google Scholar 

  41. Klein B, Mrowetz H, Thalhamer J, Scheiblhofer S, Weiss R, Aigner L. Allergy enhances neurogenesis and modulates microglial activation in the hippocampus. Front Cell Neurosci. 2016;10:169.

    PubMed  PubMed Central  Google Scholar 

  42. Wolf SA, Steiner B, Wengner A, Lipp M, Kammertoens T, Kempermann G. Adaptive peripheral immune response increases proliferation of neural precursor cells in the adult hippocampus. FASEB J. 2009;23:3121–8.

    Article  CAS  PubMed  Google Scholar 

  43. Parihar VK, Hattiangady B, Kuruba R, Shuai B, AshokK Shetty. Predictable chronic mild stress improves mood, hippocampal neurogenesis and memory. Mol Psychiatry. 2011;16:171–83.

    Article  CAS  PubMed  Google Scholar 

  44. Hassan AM, Jain P, Reichmann F, Mayerhofer R, Farzi A, Schuligoi R, et al. Repeated predictable stress causes resilience against colitis-induced behavioral changes in mice. Front Behav Neurosci. 2014;8:386.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Reichmann F, Hassan AM, Farzi A, Jain P, Schuligoi R, Holzer P. Dextran sulfate sodium-induced colitis alters stress-associated behaviour and neuropeptide gene expression in the amygdala-hippocampus network of mice. Sci Rep. 2015;5:9970.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Bethin KE, Vogt SK, Muglia LJ. Interleukin-6 is an essential, corticotropin-releasing hormone-independent stimulator of the adrenal axis during immune system activation. Proc Natl Acad Sci. 2000;97:9317–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lehmann ML, Brachman RA, Martinowich K, Schloesser RJ, Herkenham M. Glucocorticoids orchestrate divergent effects on mood through adult neurogenesis. J Neurosci. 2013;33:2961–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Straub RH, Cutolo M. Glucocorticoids and chronic inflammation. Rheumatology. 2016;55:ii6–ii14.

    Article  PubMed  Google Scholar 

  49. Ikrar T, Guo N, He K, Besnard A, Levinson S, Hill A, et al. Adult neurogenesis modifies excitability of the dentate gyrus. Front Neural Circuits. 2013;7:204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. David DJ, Wang J, Samuels BA, Rainer Q, David I, Gardier AM, et al. Implications of the functional integration of adult-born hippocampal neurons in anxiety-depression disorders. Neuroscientist. 2010;16:578–91.

    Article  PubMed  Google Scholar 

  51. Sahay A, Hen R. Adult hippocampal neurogenesis in depression. Nat Neurosci. 2007;10:1110–5.

    Article  CAS  PubMed  Google Scholar 

  52. Gonçalves JT, Schafer ST, Gage FH. Adult neurogenesis in the hippocampus: from stem cells to behavior. Cell. 2016;167:897–914.

    Article  PubMed  CAS  Google Scholar 

  53. Fan W, Zhang S, Hu J, Liu B, Wen L, Gong M, et al. Aberrant brain function in active-stage ulcerative colitis patients: a resting-state functional MRI study. Front Hum Neurosci. 2019;13:107.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Castaneda AE, Tuulio-Henriksson A, Aronen ET, Marttunen M, Kolho K-L. Cognitive functioning and depressive symptoms in adolescents with inflammatory bowel disease. World J Gastroenterol. 2013;19:1611–7.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Garthe A, Roeder I, Kempermann G. Mice in an enriched environment learn more flexibly because of adult hippocampal neurogenesis. Hippocampus. 2016;26:261–71.

    Article  PubMed  Google Scholar 

  56. D’Mello C, Le T, Swain MG. Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factoralpha signaling during peripheral organ inflammation. J Neurosci. 2009;29:2089–102.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Yuan J, Ge H, Liu W, Zhu H, Chen Y, Zhang X, et al. M2 microglia promotes neurogenesis and oligodendrogenesis from neural stem/progenitor cells via the PPARγ signaling pathway. Oncotarget. 2017;8:19855–65.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Kreisel T, Wolf B, Keshet E, Licht T. Unique role for dentate gyrus microglia in neuroblast survival and in VEGF-induced activation. Glia. 2019;67:594–618.

    Article  PubMed  Google Scholar 

  59. Mitroulis I, Ruppova K, Wang B, Chen L-S, Grzybek M, Grinenko T, et al. Modulation of myelopoiesis progenitors is an integral component of trained immunity. Cell. 2018;172:147–.e12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wendeln A-C, Degenhardt K, Kaurani L, Gertig M, Ulas T, Jain G, et al. Innate immune memory in the brain shapes neurological disease hallmarks. Nature. 2018;556:332–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Shin J, Berg DA, Zhu Y, Shin JY, Song J, Bonaguidi MA, et al. Single-cell RNA-seq with waterfall reveals molecular cascades underlying adult neurogenesis. Cell Stem Cell. 2015;17:360–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Panos Sarantis, and Marianna Orfanou at the Center for Experimental Surgery, Clinical and Translational Research, BRFAA, for their valuable technical assistance in the experiments performed. The study was partially supported by Bodossakis Foundation, Athens, Greece, Captain Fanourakis Foundation, Kos island, Greece, the General Secretariat for Research and Technology (GSRT), and the Hellenic Foundation for Research and Innovation (HFRI) (Code: 1030). KK was supported by Excellence II and the General Secretariat for Research and Technology (GSRT). GX was supported by a ‘Research Excellence’ Grant (# 5035) funded by the General Secretariat for Research and Technology (GSRT) and by a ‘Fondation Santé’ Research Grant in the Biomedical Sciences. AG and IC were supported by DINNESMIN (Τ1Ε∆Κ - 03186) co-financed by Greece and EU in the context of Operational Program “Competitiveness, Entrepreneurship and Innovation” (ΕΠΑΝΕΚ) of the NSRF 2014–2020.

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Correspondence to Katia P. Karalis.

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Gampierakis, IA., Koutmani, Y., Semitekolou, M. et al. Hippocampal neural stem cells and microglia response to experimental inflammatory bowel disease (IBD). Mol Psychiatry 26, 1248–1263 (2021). https://doi.org/10.1038/s41380-020-0651-6

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