Environmental Enrichment Induces Increased Cerebral Capillary Density and Improved Cognitive Function in Mice

  • Chuan He
  • Constantinos P. Tsipis
  • Joseph C. LaManna
  • Kui XuEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 977)


Enrichment provides an environment that fosters increased physical activity and sensory stimulation as compared to standard housing. Promoting and sustaining stimulation increases neuronal activity and, consequently, brain oxygen demand. The mammalian brain modulates its microvascular network to accommodate tissue energy demand in a process referred to as angioplasticity. In this study we investigated the effect of an environmental enrichment on cerebral capillary density and cognitive performance in mice. Microvascular density (N/mm2) was determined by GLUT-1 immunohistochemistry in mice (3 months old) after 3 weeks of placement in a non-enriched or an enriched environment. The Y-maze test and a novel object recognition test were used to evaluate cognitive function in the aged mice (18 months old) after 4 weeks of environmental enrichment. Compared to the non-enriched control mice, the mice with environmental enrichment had significantly higher (~30%) capillary density in cortical brain. The enriched aged mice (n = 12) showed improved cognitive function, presented as a significantly higher alternation rate in the Y-Maze test compared to the non-enriched controls (n = 8). Our data suggest that environmental enrichment may result in increased brain capillary density and improved cognitive performance.


Angiogenesis Preconditioning Cognitive performance Angioplasicity Aged mouse 



This study was supported by NIH grant NIH R01 NS 38632.


  1. 1.
    Mora F (2013) Successful brain aging: plasticity, environmental enrichment, and lifestyle. Dialogues Clin Neurosci 15(1):45–52PubMedPubMedCentralGoogle Scholar
  2. 2.
    Ekstrand J, Hellsten J, Tingstrom A (2008) Environmental enrichment, exercise and corticosterone affect endothelial cell proliferation in adult rat hippocampus and prefrontal cortex. Neurosci Lett 442(3):203–207CrossRefPubMedGoogle Scholar
  3. 3.
    Mustroph ML, Chen S, Desai SC et al (2012) Aerobic exercise is the critical variable in an enriched environment that increases hippocampal neurogenesis and water maze learning in male C57BL/6J mice. Neuroscience 219:62–71CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Hosseiny S, Pietri M, Petit-Paitel A et al (2015) Differential neuronal plasticity in mouse hippocampus associated with various periods of enriched environment during postnatal development. Brain Struct Funct 220(6):3435–3448CrossRefPubMedGoogle Scholar
  5. 5.
    Pang TY, Hannan AJ (2013) Enhancement of cognitive function in models of brain disease through environmental enrichment and physical activity. Neuropharmacology 64:515–528CrossRefPubMedGoogle Scholar
  6. 6.
    Barak B, Shvarts-Serebro I, Modai S et al (2013) Opposing actions of environmental enrichment and Alzheimer's disease on the expression of hippocampal microRNAs in mouse models. Transl Psychiatry 3(9):e304CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Benderro GF, LaManna JC (2012) Hypoxia-induced angiogenesis is delayed in aging mouse brain. Brain Res 1389:50–60CrossRefGoogle Scholar
  8. 8.
    Benderro GF, LaManna JC (2014) HIF-1α/COX-2 expression and mouse brain capillary remodeling during prolonged moderate hypoxia and subsequent re-oxygenation. Brain Res 1569:41–47CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Tsipis CP et al (2014) Hypoxia-induced angiogenesis and capillary density determination. Methods MolBiol 1135:69–80Google Scholar
  10. 10.
    Paxinos G, Franklin KBJ (2003) The mouse brain in stereotaxic coordinates, 2nd edn. Academic Press, San DiegoGoogle Scholar
  11. 11.
    Dellu F, Mayo W, Cherkaoui J (1992) A two-trial memory task with automated recording: study in young and aged rats. Brain Res 588(1):132–139CrossRefPubMedGoogle Scholar
  12. 12.
    Messier C (1997) Object recognition in mice: improvement of memory by glucose. Neurobiol Learn Mem 67(2):172–175CrossRefPubMedGoogle Scholar
  13. 13.
    Antunes M, Biala G (2012) The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process 13:93–110CrossRefPubMedGoogle Scholar
  14. 14.
    Fares RP, Belmeguenai A, Sanchez PE et al (2013) Standardized environmental enrichment supports enhanced brain plasticity in healthy rats and prevents cognitive impairment in epileptic rats. PLoS One 8(1):e53888CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Jain V, Baitharu I, Prasad D et al (2013) Enriched environment prevents hypobaric hypoxia induced memory impairment and neurodegeneration: role of BDNF/PI3K/GSK3 pathway coupled with CREB activation. PLoS One 8(5):e62235CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Seo JH, Yu JH, Suh H et al (2013) Fibroblast growth factor-2 induced by enriched environment enhances angiogenesis and motor function in chronic hypoxic-ischemic brain injury. PLoS One 8(9):e74405CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Chuan He
    • 1
  • Constantinos P. Tsipis
    • 2
  • Joseph C. LaManna
    • 2
  • Kui Xu
    • 2
    Email author
  1. 1.Department of NeurologyJiangsu-Shengze Hospital of Nanjing Medical UniversitySuzhouChina
  2. 2.Department of Physiology and BiophysicsCase Western Reserve University, School of MedicineClevelandUSA

Personalised recommendations