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Repeated restraint stress promotes hippocampal neuronal cell ciliogenesis and proliferation in mice

Laboratory Animal Research volume 34, pages 203–210 (2018)Cite this article

Abstract

Stress severely disturbs physiological and mental homeostasis which includes adult neurogenesis in hippocampus. Neurogenesis in hippocampus is a key feature to adapt to environmental changes and highly regulated by multiple cellular signaling pathways. The primary cilium is a cellular organelle, which acts as a signaling center during development and neurogenesis in adult mice. However, it is not clear how the primary cilia are involved in the process of restraint (RST) stress response. Using a mouse model, we examined the role of primary cilia in repeated and acute RST stress response. Interestingly, RST stress increased the number of ciliated cells in the adult hippocampal dentate gyrus (DG). In our RST model, cell proliferation in the DG also increased in a time-dependent manner. Moreover, the analysis of ciliated cells in the hippocampal DG with cell type markers indicated that cells that were ciliated in response to acute RST stress are neurons. Taken together, these findings suggest that RST stress response is closely associated with an increase in the number of ciliated neurons and leads to an increase in cell proliferation.

References

  1. Rodgers RJ, Dalvi A. Anxiety, defence and the elevated plus-maze. Neurosci Biobehav Rev 1997; 21(6): 801–810.

    Article  CAS  PubMed  Google Scholar 

  2. Aimone JB, Li Y, Lee SW, Clemenson GD, Deng W, Gage FH. Regulation and function of adult neurogenesis: from genes to cognition. Physiol Rev 2014; 94(4): 991–1026.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lai K, Kaspar BK, Gage FH, Schaffer DV. Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nat Neurosci 2003; 6(1): 21–27.

    Article  CAS  PubMed  Google Scholar 

  4. Kim JJ, Diamond DM. The stressed hippocampus, synaptic plasticity and lost memories. Nat Rev Neurosci 2002; 3(6): 453–462.

    Article  CAS  PubMed  Google Scholar 

  5. Smith SM, Vale WW. The role of the hypothalamic-pituitaryadrenal axis in neuroendocrine responses to stress. Dialogues Clin Neurosci 2006; 8(4): 383–395.

    PubMed  PubMed Central  Google Scholar 

  6. Gunnar M, Quevedo K. The neurobiology of stress and development. Annu Rev Psychol 2007; 58: 145–173.

    Article  PubMed  Google Scholar 

  7. Bartolomucci A, Leopardi R. Stress and depression: preclinical research and clinical implications. PLoS One 2009; 4(1): e4265.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Pham K, Nacher J, Hof PR, McEwen BS. Repeated restraint stress suppresses neurogenesis and induces biphasic PSA-NCAM expression in the adult rat dentate gyrus. Eur J Neurosci 2003; 17(4): 879–886.

    Article  PubMed  Google Scholar 

  9. Cameron HA, Gould E. Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus. Neuroscience 1994; 61(2): 203–209.

    Article  CAS  PubMed  Google Scholar 

  10. Leuner B, Glasper ER, Gould E. Sexual experience promotes adult neurogenesis in the hippocampus despite an initial elevation in stress hormones. PLoS One 2010; 5(7): e11597.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Ko HW. The primary cilium as a multiple cellular signaling scaffold in development and disease. BMB Rep 2012; 45(8): 427–432.

    Article  CAS  PubMed  Google Scholar 

  12. Buynitsky T, Mostofsky DI. Restraint stress in biobehavioral research: Recent developments. Neurosci Biobehav Rev 2009; 33(7): 1089–1098.

    Article  PubMed  Google Scholar 

  13. Han YG, Kim HJ, Dlugosz AA, Ellison DW, Gilbertson RJ, Alvarez-Buylla A. Dual and opposing roles of primary cilia in medulloblastoma development. Nat Med 2009; 15(9): 1062–1065.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Porsolt RD, Bertin A, Jalfre M. Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 1977; 229(2): 327–336.

    CAS  PubMed  Google Scholar 

  15. Chiba S, Numakawa T, Ninomiya M, Richards MC, Wakabayashi C, Kunugi H. Chronic restraint stress causes anxiety- and depression-like behaviors, downregulates glucocorticoid receptor expression, and attenuates glutamate release induced by brainderived neurotrophic factor in the prefrontal cortex. Prog Neuropsychopharmacol Biol Psychiatry 2012; 39(1): 112–119.

    Article  CAS  PubMed  Google Scholar 

  16. Mirescu C, Gould E. Stress and adult neurogenesis. Hippocampus 2006; 16(3): 233–238.

    Article  CAS  PubMed  Google Scholar 

  17. Han YG, Spassky N, Romaguera-Ros M, Garcia-Verdugo JM, Aguilar A, Schneider-Maunoury S, Alvarez-Buylla A. Hedgehog signaling and primary cilia are required for the formation of adult neural stem cells. Nat Neurosci 2008; 11(3): 277–284.

    Article  CAS  PubMed  Google Scholar 

  18. Han YM, Kang GM, Byun K, Ko HW, Kim J, Shin MS, Kim HK, Gil SY, Yu JH, Lee B, Kim MS. Leptin-promoted cilia assembly is critical for normal energy balance. J Clin Invest 2014; 124(5): 2193–2197.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bain MJ, Dwyer SM, Rusak B. Restraint stress affects hippocampal cell proliferation differently in rats and mice. Neurosci Lett 2004; 368(1): 7–10.

    Article  CAS  PubMed  Google Scholar 

  20. Doetsch F. A niche for adult neural stem cells. Curr Opin Genet Dev 2003; 13(5): 543–550.

    Article  CAS  PubMed  Google Scholar 

  21. Seri B, García-Verdugo JM, Collado-Morente L, McEwen BS, Alvarez-Buylla A. Cell types, lineage, and architecture of the germinal zone in the adult dentate gyrus. J Comp Neurol 2004; 478(4): 359–378.

    Article  PubMed  Google Scholar 

  22. Goetz SC, Anderson KV. The primary cilium: a signalling centre during vertebrate development. Nat Rev Genet 2010; 11(5): 331–344.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wong SY, Reiter JF. The primary cilium at the crossroads of mammalian hedgehog signaling. Curr Top Dev Biol 2008; 85: 225–260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Eichers ER, Abd-El-Barr MM, Paylor R, Lewis RA, Bi W, Lin X, Meehan TP, Stockton DW, Wu SM, Lindsay E, Justice MJ, Beales PL, Katsanis N, Lupski JR. Phenotypic characterization of Bbs4 null mice reveals age-dependent penetrance and variable expressivity. Hum Genet 2006; 120(2): 211–226.

    Article  CAS  PubMed  Google Scholar 

  25. Wang Z, Phan T, Storm DR. The type 3 adenylyl cyclase is required for novel object learning and extinction of contextual memory: role of cAMP signaling in primary cilia. J Neurosci 2011; 31(15): 5557–5561.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Veena J, Srikumar BN, Mahati K, Bhagya V, Raju TR, Shankaranarayana Rao BS. Enriched environment restores hippocampal cell proliferation and ameliorates cognitive deficits in chronically stressed rats. J Neurosci Res 2009; 87(4): 831–843.

    Article  CAS  PubMed  Google Scholar 

  27. Nagata K, Nakashima-Kamimura N, Mikami T, Ohsawa I, Ohta S. Consumption of molecular hydrogen prevents the stressinduced impairments in hippocampus-dependent learning tasks during chronic physical restraint in mice. Neuropsychopharmacology 2009; 34(2): 501–508.

    Article  CAS  PubMed  Google Scholar 

  28. Kirby ED, Muroy SE, Sun WG, Covarrubias D, Leong MJ, Barchas LA, Kaufer D. Acute stress enhances adult rat hippocampal neurogenesis and activation of newborn neurons via secreted astrocytic FGF2. Elife 2013; 2: e00362.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Machold R, Hayashi S, Rutlin M, Muzumdar MD, Nery S, Corbin JG, Gritli-Linde A, Dellovade T, Porter JA, Rubin LL, Dudek H, McMahon AP, Fishell G. Sonic hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches. Neuron 2003; 39(6): 937–950.

    Article  CAS  PubMed  Google Scholar 

  30. Amador-Arjona A, Elliott J, Miller A, Ginbey A, Pazour GJ, Enikolopov G, Roberts AJ, Terskikh AV. Primary cilia regulate proliferation of amplifying progenitors in adult hippocampus: implications for learning and memory. J Neurosci 2011; 31(27): 9933–9944.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sannino G, Pasqualini L, Ricciardelli E, Montilla P, Soverchia L, Ruggeri B, Falcinelli S, Renzi A, Ludka C, Kirchner T, Grünewald TG, Ciccocioppo R, Ubaldi M, Hardiman G. Acute stress enhances the expression of neuroprotection- and neurogenesis-associated genes in the hippocampus of a mouse restraint model. Oncotarget 2016; 7(8): 8455–8465.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. College of Pharmacy, Dongguk University, Goyang, Korea

    Kyounghye Lee

  2. Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 50 Yonseiro, Seodaemun-gu, Seoul, 03722, Korea

    Kyounghye Lee & Hyuk Wan Ko

Authors
  1. Kyounghye Lee
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  2. Hyuk Wan Ko
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Correspondence to Hyuk Wan Ko.

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Lee, K., Ko, H.W. Repeated restraint stress promotes hippocampal neuronal cell ciliogenesis and proliferation in mice. Lab Anim Res 34, 203–210 (2018). https://doi.org/10.5625/lar.2018.34.4.203

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  • DOI: https://doi.org/10.5625/lar.2018.34.4.203

Keywords

  • Restraint stress
  • primary cilia
  • adult neurogenesis
  • hippocampus

Laboratory Animal Research

ISSN: 2233-7660