Brain Structure and Function

, Volume 223, Issue 2, pp 749–767 | Cite as

Voluntary running-enhanced synaptic plasticity, learning and memory are mediated by Notch1 signal pathway in C57BL mice

  • Xiaochen Zhang
  • Chunxiao Yang
  • Jing Gao
  • Hongqiang Yin
  • Hui Zhang
  • Tao Zhang
  • Zhuo YangEmail author
Original Article


It is well known that voluntary running can enhance synaptic plasticity and improve learning and memory abilities. The Notch1 receptor is also reported to be associated with these processes, but its role in running-induced alterations is unclear. In this study, we aimed to investigate whether the Notch1 signalling pathway was involved in voluntary running-induced enhancement of synaptic plasticity, learning and memory. Notch1 heterozygous deficient (Notch1+/−) mice and wildtype (WT) C57BL littermates were randomly divided into runner group and non-runner group. Mice were given free access to running wheels for 14 days in both the Notch1+/− runner group and the WT runner group. Our results demonstrate that Notch1 knockdown impairs the performance in the novel object recognition (NOR) test and Morris water maze test and decreases the synaptic plasticity. Voluntary running improves spatial learning and memory abilities, promotes synaptic plasticity and increases expressions of postsynaptic proteins in WT mice but not in Notch1+/− mice. Our results suggest that Notch1 plays a vital role in spatial learning and memory, synaptic plasticity under normal physiological conditions and voluntary running conditions. These findings will set the groundwork and fill in some gaps for understanding the role of Notch1 signalling in voluntary running-induced phenomena.


Voluntary running Synaptic plasticity Learning and memory Notch1 receptor 



This work was supported by the National Natural Science Foundation of China (81571804, 11232005) and Tianjin Research Program of Application Foundation and Advanced Technology (14JCZDJC35000).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All animal experiments were approved by the Animal Research Ethics Committee, School of Medicine, Nankai University, and were performed in accordance with the Animal Management Rules of the Ministry of Health of the People’s Republic of China.


  1. Ables JL et al (2010) Notch1 is required for maintenance of the reservoir of adult hippocampal stem cells. J Neurosci 30:10484–10492CrossRefPubMedPubMedCentralGoogle Scholar
  2. Alberi L et al (2011) Activity-induced notch signaling in neurons requires Arc/Arg3.1 and is essential for synaptic plasticity in hippocampal networks. Neuron 69:437–444CrossRefPubMedPubMedCentralGoogle Scholar
  3. Andreas AT et al (2006) Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 442:823–826CrossRefGoogle Scholar
  4. Behl C, Skutella T, Lezoualc’H F, Post A, Widmann M, Newton CJ, Holsboer F (1997) Neuroprotection against oxidative stress by estrogens: structure-activity relationship. Mol Pharmacol 51:535–541CrossRefPubMedGoogle Scholar
  5. Bevins RA, Joyce B (2006) Object recognition in rats and mice: a one-trial non-matching-to-sample learning task to study ‘recognition memory’. Nat Protoc 1:1306–1311CrossRefPubMedGoogle Scholar
  6. Bliss TV, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Mol Cancer Res 13:575–583Google Scholar
  7. Brai E et al (2015) Notch1 regulates hippocampal plasticity through interaction with the Reelin pathway, glutamatergic transmission and CREB signaling. Front Cell Neurosci 9:447CrossRefPubMedPubMedCentralGoogle Scholar
  8. Brandt MD, Maass A, Kempermann G, Storch A (2010) Physical exercise increases Notch activity, proliferation and cell cycle exit of type-3 progenitor cells in adult hippocampal neurogenesis. Eur J Neurosci 32:1256–1264CrossRefPubMedGoogle Scholar
  9. Carey KA, Farnfield MM, Tarquinio SD, Cameron-Smith D (2007) Impaired expression of Notch signaling genes in aged human skeletal muscle. J Gerontol 62:9–17CrossRefGoogle Scholar
  10. Chowdhury S et al (2006) Arc/Arg3. 1 interacts with the endocytic machinery to regulate AMPA receptor trafficking. Neuron 52:445–459CrossRefPubMedPubMedCentralGoogle Scholar
  11. Costa M, Honjo T, Silva AJ (2003) Learning and memory deficits in notch mutant mice. Curr Biol 13:1348–1354CrossRefPubMedGoogle Scholar
  12. De Strooper B et al (1999) A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 398:518–522CrossRefPubMedGoogle Scholar
  13. Eriksson PS, Perfilieva E, Björkeriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH (1998) Neurogenesis in the adult human hippocampus. Nat Med 4:1313–1317CrossRefPubMedGoogle Scholar
  14. Fitchett AE, Collins SA, Barnard CJ, Cassaday HJ (2005) Subordinate male mice show long-lasting differences in spatial learning that persist when housed alone. Neurobiol Learn Mem 84:247–251CrossRefPubMedGoogle Scholar
  15. Franklin KBJ, Paxinos G (2001) The mouse brain: in stereotaxic coordinates. Academic Press, San DiegoGoogle Scholar
  16. Fu J, Hui W, Jing G, Mei Y, Wang R, Zhuo Y, Tao Z (2016) Rapamycin effectively impedes melamine-induced impairments of cognition and synaptic plasticity in Wistar rats. Mol Neurobiol 54:819–832CrossRefPubMedGoogle Scholar
  17. Fuss J et al (2010) Voluntary exercise induces anxiety-like behavior in adult C57BL/6J mice correlating with hippocampal neurogenesis. Hippocampus 20:364–376PubMedGoogle Scholar
  18. Gao J, Zhang X, Yu M, Ren G, Yang Z (2015) Cognitive deficits induced by multi-walled carbon nanotubes via the autophagic pathway. Toxicology 337:21–29CrossRefPubMedGoogle Scholar
  19. Garcia-Segura LM, Azcoitia I, Doncarlos LL (2001) Neuroprotection by estradiol. Prog Neurobiol 63:29CrossRefPubMedGoogle Scholar
  20. Irvin DK, Zurcher SD, Nguyen T, Weinmaster G, Kornblum HI (2001) Expression patterns of Notch1, Notch2, and Notch3 suggest multiple functional roles for the Notch-DSL signaling system during brain development. J Comp Neurol 436:167–181CrossRefPubMedGoogle Scholar
  21. Jean-Claude BQ, Rodrigo A (2003) PSD-95 regulates synaptic transmission and plasticity in rat cerebral cortex. J Physiol 546:859–867CrossRefGoogle Scholar
  22. Jiang M-L, Han T-Z, Pang W, Li L (2004) Gender-and age-specific impairment of rat performance in the Morris water maze following prenatal exposure to an MRI magnetic field. Brain Res 995:140–144CrossRefPubMedGoogle Scholar
  23. Jin YH et al (2009) Beta-catenin modulates the level and transcriptional activity of Notch1/NICD through its direct interaction. Biochem Biophys Acta 1793:290–299CrossRefPubMedGoogle Scholar
  24. Johnson M, Ables J, Eisch A (2009) Cell-intrinsic signals that regulate adult neurogenesis in vivo: insights from inducible approaches. BMB Rep 42:245–259CrossRefPubMedPubMedCentralGoogle Scholar
  25. Li J, Wen PY, Li WW, Zhou J (2015) Upregulation effects of Tanshinone IIA on the expressions of NeuN, Nissl body, and IκB and downregulation effects on the expressions of GFAP and NF-κB in the brain tissues of rat models of Alzheimer’s disease. Neuroreport 26:758–766CrossRefPubMedGoogle Scholar
  26. Li Z, Hao S, Yin H, Gao J, Yang Z (2016) Autophagy ameliorates cognitive impairment through activation of PVT1 and apoptosis in diabetes mice. Behav Brain Res 305:265–277CrossRefPubMedGoogle Scholar
  27. Lindsell CE, Shawber CJ, Boulter J, Weinmaster G (1995) Jagged: a mammalian ligand that activates Notch1. Cell 80:909–917CrossRefPubMedGoogle Scholar
  28. Malenka RC, Nicoll RA (1999) Long-term potentiation–a decade of progress? Science 285:1870–1874CrossRefPubMedGoogle Scholar
  29. Mclean S, Grayson B, Harris M, Protheroe C, Woolley M, Neill J (2010) Isolation rearing impairs novel object recognition and attentional set shifting performance in female rats. J Psychopharmacol 24:57–63CrossRefPubMedGoogle Scholar
  30. Mei Y, Yuan Z, Chen X, Tao Z (2015) Antidepressant-like effects and possible mechanisms of amantadine on cognitive and synaptic deficits in a rat model of chronic stress. Stress 65:1–32Google Scholar
  31. Nan Z, Xing M, Wang Y, Hao L, Zhuo Y, Shi F, Yan C (2014) Hydroxysafflor yellow A improves learning and memory in a rat model of vascular dementia by increasing VEGF and NR1 in the hippocampus. Neurosci Bull 30:417–424CrossRefGoogle Scholar
  32. Nishijima T, Tejeda GS, Inoue K, Yamamura Y, Soya H, Trejo JL, Torres-Alemán I (2013) Cessation of voluntary wheel running increases anxiety-like behavior and impairs adult hippocampal neurogenesis in mice. Behav Brain Res 245:34–41CrossRefPubMedGoogle Scholar
  33. Niu R, Sun Z, Wang J, Cheng Z, Wang J (2008) Effects of fluoride and lead on locomotor behavior and expression of nissl body in brain of adult rats. Fluoride 41:276–282Google Scholar
  34. Pan-Vazquez A et al (2015) Impact of voluntary exercise and housing conditions on hippocampal glucocorticoid receptor, miR-124 and anxiety Molecular. Brain 8:1–12Google Scholar
  35. Price DL, Porter KR (1972) The response of ventral horn neurons to axonal transection. J Cell Biol 53:24–37CrossRefPubMedPubMedCentralGoogle Scholar
  36. Qi Y, Hu N-W, Rowan MJ (2013) Switching off LTP: mGlu and NMDA receptor-dependent novelty exploration-induced depotentiation in the rat hippocampus. Cereb Cortex 23:932–939CrossRefPubMedGoogle Scholar
  37. Sattler R, Xiong Z, Lu WY, Hafner M, Macdonald JF, Tymianski M (1999) Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein. Science 284:1845–1848CrossRefPubMedGoogle Scholar
  38. Schroeter EH, Kisslinger JA, Kopan R (1998) Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature 393:382–386CrossRefPubMedGoogle Scholar
  39. Sibbe M, Häussler U, Dieni S, Althof D, Haas CA, Frotscher M (2012) Experimental epilepsy affects Notch1 signalling and the stem cell pool in the dentate gyrus. Eur J Neurosci 36:3643CrossRefPubMedGoogle Scholar
  40. Stranahan AM, Khalil D, Gould E (2006) Social isolation delays the positive effects of running on adult neurogenesis. Nat Neurosci 9:526–533CrossRefPubMedPubMedCentralGoogle Scholar
  41. Sugioka K, Setsu T, Terashima T (2006) Social isolation delays the positive effects of running on adult neurogenesis. Nat Neurosci 9:526–533CrossRefGoogle Scholar
  42. Tatsuya I, Larry K, Yasuo H (2003) HES and HERP families: multiple effectors of the Notch signaling pathway. J Cell Physiol 194:237–255CrossRefGoogle Scholar
  43. Valtorta F, Pennuto MD, Benfenati F (2004) Synaptophysin: leading actor or walk-on role in synaptic vesicle exocytosis? Bioessays News Rev Mol Cell Dev Biol 26:445–453CrossRefGoogle Scholar
  44. Van Praag H, Christie BR, Sejnowski TJ, Gage FH (1999) Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci 96:13427–13431CrossRefPubMedPubMedCentralGoogle Scholar
  45. Võikar V, Polus A, Vasar E, Rauvala H (2005) Long-term individual housing in C57BL/6J and DBA/2 mice: assessment of behavioral consequences. Genes Brain Behav 4:240–252CrossRefPubMedGoogle Scholar
  46. Wang Y et al (2004) Involvement of Notch signaling in hippocampal synaptic plasticity. Proc Natl Acad Sci USA 101:9458–9462CrossRefPubMedPubMedCentralGoogle Scholar
  47. Yang J, Yang C, Liu C, Tao Z, Zhuo Y (2015) Paradoxical effects of VEGF on synaptic activity partially involved in notch1 signaling in the mouse hippocampus. Hippocampus 26:589–600CrossRefPubMedGoogle Scholar
  48. Yau SY et al (2014) Physical exercise-induced hippocampal neurogenesis and antidepressant effects are mediated by the adipocyte hormone adiponectin. Proc Natl Acad Sci 111:15810–15815CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  1. 1.College of Medicine, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials for Ministry of EducationNankai UniversityTianjinChina
  2. 2.College of Life SciencesNankai UniversityTianjinChina

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