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Enriched Environment Minimizes Anxiety/Depressive-Like Behavior in Rats Exposed to Immobilization Stress and Augments Hippocampal Neurogenesis (In Vitro)

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Abstract

Chronic exposure to stress disturbs the homeostasis of the brain, thus, deleteriously affecting the neurological circuits. In literature, there are investigations about the stress-related alterations in behavioral response and adult neurogenesis; however, an effective combating strategy to evade stress is still at stake. Hence, the present study is designed to investigate the effect of an enriched environment in alleviating the anxiety/depressive-like behavioral response and enhancing the adult neurogenesis in the hippocampal region of rats exposed to chronic immobilization stress. The rats were exposed to chronic immobilization stress (IS) for 4 h/day followed by the enriched environment (EE) for 2 h/day for 28 days, and finally, the hippocampal region was dissected out after the behavioral analyses. IS group showed increased behavioral despair to tail suspension test, decrement in the activity for light/dark box test, and less grooming activity towards splash test. In contrast, IS + EE rats exhibited a decrease in the activity of tail suspension test and an increase in the behavioral response to light/dark box test and splash test. The in vitro assessment of primary cultures of neurospheres from the IS group resulted in decreased levels of proliferation in the cell number and metabolic activity of both MTT assay and lactate levels. IS + EE group revealed an increase in the growth curve of neurospheres and higher metabolic activities of MTT and lactate. The IS cultures had reduced neurite length, while the neurite outgrowths were increased in IS + EE group. The IS group showed significant reduction in the protein and mRNA levels of nestin, GFAP, CD11b, MOG, and synaptophysin, whereas the IS + EE cultures exhibited significant increase in the levels of these stem cell markers. Our data highlight the positive impact of EE against stress-related behavioral changes in rats exposed to chronic immobilization stress perhaps by interfering with the differentiation of neurospheres and neurogenesis.

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References

  • Adami R, Pagano J, Colombo M et al (2018) Reduction of movement in neurological diseases: effects on neural stem cells characteristics. Front Neurosci 12:336

    Article  PubMed  PubMed Central  Google Scholar 

  • Ahlenius H, Kokaia Z (2010) Isolation and generation of neurosphere cultures from embryonic and adult mouse brain. Methods Mol Biol 633:241–252

    Article  CAS  PubMed  Google Scholar 

  • Baamonde C, Martínez-Cué C, Flórez J, Dierssen M (2011) G-protein-associated signal transduction processes are restored after postweaning environmental enrichment in Ts65Dn, a Down syndrome mouse model. Dev Neurosci 33(5):442–450. https://doi.org/10.1159/000329425

    Article  CAS  PubMed  Google Scholar 

  • Baltan S (2015) Can lactate serve as an energy substrate for axons in good times and in bad, in sickness and in health? Metab Brain Dis 30(1):25–30

    Article  CAS  PubMed  Google Scholar 

  • Beauquis J, Roig P, De Nicola AF, Saravia F (2010) Short-term environmental enrichment enhances adult neurogenesis, vascular network and dendritic complexity in the hippocampus of type 1 diabetic mice. PLoS One 5(11):e13993

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bottai D, Cigognini D, Nicora E et al (2012) Third trimester amniotic fluid cells with the capacity to develop neural phenotypes and with heterogeneity among sub-populations. Restor Neurol Neurosci 30(1):55–68

    PubMed  Google Scholar 

  • Bremner JD (2006) Stress and brain atrophy. CNS Neurol Disord Drug Targets 5(5):503–512

    Article  PubMed  PubMed Central  Google Scholar 

  • Brewer GJ, Torricelli JR (2007) Isolation and culture of adult neurons and neurospheres. Nat Protoc 2(6):1490–1498

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Chigr F, Rachidi F, Segura S et al (2009) Neurogenesis inhibition in the dorsal vagal complex by chronic immobilization stress in the adult rat. Neuroscience 158(2):524–536

    Article  CAS  PubMed  Google Scholar 

  • Cryan JF, Mombereau C, Vassout A (2005) The tail suspension test as a model for assessing antidepressant activity: review of pharmacological and genetic studies in mice. Neurosci Biobehav Rev 29(4–5):571–625

    Article  CAS  PubMed  Google Scholar 

  • David DJ, Samuels BA, Rainer Q et al (2009) Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of depressive/depression. Neuron 62(4):479–493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Daviu N, Rabasa C, Nadal R, Armario A (2014) Comparison of the effects of single and daily repeated immobilization stress on resting activity and heterotypic sensitization of the hypothalamic–pituitary–adrenal axis. Stress 17(2):176–185

    Article  CAS  PubMed  Google Scholar 

  • Ehninger D, Kempermann G (2003) Regional effects of wheel running and environmental enrichment on cell genesis and microglia proliferation in the adult murine neocortex. Cereb Cortex 13(8):845–851

    Article  PubMed  Google Scholar 

  • Feng GU, Juan WANG, Li FU (2011) Co-culture with microglia promotes neural stem cells differentiation into astrocytes. Chin Med J 124(20):3394–3398

    Google Scholar 

  • Folmes CD, Dzeja PP, Nelson TJ, Terzic A (2012) Metabolic plasticity in stem cell homeostasis and differentiation. Cell Stem Cell 11(5):596–606

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Francis DD, Diorio J, Plotsky PM, Meaney MJ (2002) Environmental enrichment reverses the effects of maternal separation on stress reactivity. J Neurosci 22(18):7840–7843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Frisbee JC, Brooks SD, Stanley SC, d’Audiffret AC (2015) An unpredictable chronic mild stress protocol for instigating depressive symptoms, behavioral changes and negative health outcomes in rodents. JoVE (Journal of Visualized Experiments) 106:e53109

    Google Scholar 

  • Gourley SL, Wu FJ, Taylor JR (2008) Corticosterone regulates pERK1/2 map kinase in a chronic depression model. Ann N Y Acad Sci 1148:509–514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Herman JP, Figueiredo H, Mueller NK, Ulrich-Lai Y, Ostrander MM, Choi DC, Cullinan WE (2003) Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo–pituitary–adrenocortical responsiveness. Front Neuroendocrinol 24(3):151–180

    Article  CAS  Google Scholar 

  • Holmes TC, de Lacalle S, Su X, Liu G, Rich A, Zhang S (2009) Extensive neurite outgrowth and active synapse formation on self-assembling peptide scaffolds. Proc Natl Acad Sci U S A 97(12):6728–6733

    Article  Google Scholar 

  • Ickes BR, Pham TM, Sanders LA, Albeck DS, Mohammed AH, Granholm AC (2000) Long-term environmental enrichment leads to regional increases in neurotrophin levels in rat brain. Exp Neurol 164:45–52

    Article  CAS  PubMed  Google Scholar 

  • Joëls M, Sarabdjitsingh RA, Karst H (2012) Unraveling the time domains of corticosteroid hormone influences on brain activity: rapid, slow, and chronic modes. Pharmacol Rev 64(4):901–938

    Article  PubMed  CAS  Google Scholar 

  • Johnson SA, Fournier NM, Kalynchuk LE (2006) Effect of different doses of corticosterone on depression-like behavior and HPA axis responses to a novel stressor. Behav Brain Res 168(2):280–288

    Article  CAS  PubMed  Google Scholar 

  • Koe AS, Ashokan A, Mitra R (2016) Short environmental enrichment in adulthood reverses depressive and basolateral amygdala hypertrophy induced by maternal separation. Transl Psychiatry 6(2):e729–e729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kumar P, Nagarajan A, Uchil PD. Analysis of cell viability by the lactate dehydrogenase assay. Cold Spring Harb Protoc. 2018;2018(6). https://doi.org/10.1101/pdb.prot095497.

  • Kuvacheva NV, Morgun AV, Komleva YK et al (2015) In vitro modeling of brain progenitor cell development under the effect of environmental factors. Bull Exp Biol Med 159(4):546–549

    Article  CAS  PubMed  Google Scholar 

  • Lee JH, Shaker MR, Lee E, Lee B, Sun W (2020) NeuroCore formation during differentiation of neurospheres of mouse embryonic neural stem cells. Stem Cell Res 43:101691

    Article  CAS  PubMed  Google Scholar 

  • Leon M, Woo C (2018) Environmental enrichment and successful aging. Front Behav Neurosci 12:155

    Article  PubMed  PubMed Central  Google Scholar 

  • Lowry OH, Rosenbrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin Phenol Reagent. J Biol Chem 193:265–275

    Article  CAS  Google Scholar 

  • McCreary JK, Metz GAS (2016) Environmental enrichment as an intervention for adverse health outcomes of prenatal stress. Environ Epigenet 2(3):dvw013

  • McDonald MW, Hayward KS, Rosbergen ICM, Jeffers MS, Corbett D (2018) Is environmental enrichment ready for clinical application in human post-stroke rehabilitation? Front Behav Neurosci 12:135

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • McEwen BS, Bowles NP, Gray JD et al (2015) Mechanisms of stress in the brain. Nat Neurosci 18(10):1353–1363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McEwen BS, Gianaros PJ (2011) Stress- and allostasis-induced brain plasticity. Annu Rev Med 62:431–445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Medina JM, Tabernero A (2005) Lactate utilization by brain cells and its role in CNS development. J Neurosci Res 79(1–2):2–10

    Article  CAS  PubMed  Google Scholar 

  • Mohyeldin A, Garzón-Muvdi T, Quiñones-Hinojosa A (2010) Oxygen in stem cell biology: a critical component of the stem cell niche. Cell Stem Cell 7(2):150–161

    Article  CAS  PubMed  Google Scholar 

  • Niu W, Zang T, Smith DK, Vue TY, Zou Y, Bachoo R, Zhang CL (2015) SOX2 reprograms resident astrocytes into neural progenitors in the adult brain. Stem cell reports 4(5):780–794

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ortega-Martínez S (2015) A new perspective on the role of the CREB family of transcription factors in memory consolidation via adult hippocampal neurogenesis. Frontiers in molecular neuroscience 8:46

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Paizanis E, Hamon M, Lanfumey L (2007) Hippocampal neurogenesis, depressive disorders, and antidepressant therapy. Neural Plast 2007:73754

    Article  PubMed  PubMed Central  Google Scholar 

  • Park D, Xiang AP, Mao FF et al (2010) Nestin is required for the proper self-renewal of neural stem cells. Stem Cells 28(12):2162–2171

    Article  CAS  Google Scholar 

  • Patel D, Anilkumar S, Chattarji S, Buwalda B (2018) Repeated social stress leads to contrasting patterns of structural plasticity in the amygdala and hippocampus. Behav Brain Res 347:314–324

    Article  CAS  PubMed  Google Scholar 

  • Planchez B, Surget A, Belzung C (2019) Animal models of major depression: drawbacks and challenges. J Neural Transm (Vienna) 126(11):1383–1408

    Article  CAS  Google Scholar 

  • Radley J, Morilak D, Viau V, Campeau S (2015) Chronic stress and brain plasticity: mechanisms underlying adaptive and maladaptive changes and implications for stress-related CNS disorders. Neurosci Biobehav Rev 58:79–91

    Article  PubMed  PubMed Central  Google Scholar 

  • Radley JJ, Morrison JH (2005) Repeated stress and structural plasticity in the brain. Ageing research reviews 4(2):271–287

    Article  PubMed  Google Scholar 

  • Radley JJ, Sawchenko PE (2011) A common substrate for prefrontal and hippocampal inhibition of the neuroendocrine stress response. J Neurosci 31(26):9683–9695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ramboer E, De Craene B, De Kock J, Berx G, Rogiers V, Vanhaecke T, Vinken M (2015) Development and characterization of a new human hepatic cell line. EXCLI journal 14:875

    PubMed  PubMed Central  Google Scholar 

  • Salmin VV, Komleva YK, Kuvacheva NV et al (2017) Differential roles of environmental enrichment in Alzheimer’s type of neurodegeneration and physiological aging. Front Aging Neurosci 9:245

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Santilli G, Lamorte G, Carlessi L et al (2010) Mild hypoxia enhances proliferation and multipotency of human neural stem cells. PLoS One 5(1):e8575

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Speisman RB, Kumar A, Rani A et al (2013) Environmental enrichment restores neurogenesis and rapid acquisition in aged rats. Neurobiol Aging 34(1):263–274

    Article  PubMed  Google Scholar 

  • Studer L, Csete M, Lee SH et al (2000) Enhanced proliferation, survival, and dopaminergic differentiation of CNS precursors in lowered oxygen. J Neurosci 20(19):7377–7383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Suzuki S, Namiki J, Shibata S, Mastuzaki Y, Okano H (2010) The neural stem/progenitor cell marker nestin is expressed in proliferative endothelial cells, but not in mature vasculature. J Histochem Cytochem 58(8):721–730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takao K, Miyakawa T (2006) Light/dark transition test for mice. J Vis Exp 1:104

    Google Scholar 

  • Teegarden S (2012) Behavioral phenotyping in rats and mice. Mater Methods 2:122

    Article  Google Scholar 

  • Thamizhoviya G, Vanisree AJ (2019) Enriched environment modulates behavior, myelination and augments molecules governing the plasticity in the forebrain region of rats exposed to chronic immobilization stress. Metab Brain Dis 34(3):875–887

    Article  CAS  PubMed  Google Scholar 

  • Vachon P, Millecamps M, Low L et al (2013) Alleviation of chronic neuropathic pain by environmental enrichment in mice well after the establishment of chronic pain. Behav Brain Funct 9:22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Veena J, Srikumar BN, Mahati K, Bhagya V, Raju TR, Shankaranarayana Rao BS (2009) Enriched environment restores hippocampal cell proliferation and ameliorates cognitive deficits in chronically stressed rats. J Neurosci Res 87(4):831–843. https://doi.org/10.1002/jnr.21907

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Cui Y, Yu Z, Wang W, Cheng X, Ji W, Chen Y (2019) Brain endothelial cells maintain lactate homeostasis and control adult hippocampal neurogenesis. Cell Stem Cell 25(6):754–767

    Article  CAS  PubMed  Google Scholar 

  • Weng L, Guo X, Li Y, Yang X, Han Y (2016) Apigenin reverses depression-like behavior induced by chronic corticosterone treatment in mice. Eur J Pharmacol 774:50–54

    Article  CAS  PubMed  Google Scholar 

  • Williamson LL, Chao A, Bilbo SD (2012) Environmental enrichment alters glial antigen expression and neuroimmune function in the adult rat hippocampus. Brain Behav Immun 26(3):500–510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yuan SH, Martin J, Elia J et al (2011) Cell-surface marker signatures for the isolation of neural stem cells, glia and neurons derived from human pluripotent stem cells. PLoS One 6(3):e17540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

The authors received financial support from the University Grants Commission-Special Assistance Programme, New Delhi, India, in the form of fellowship.

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  1. Department of Biochemistry, University of Madras, Guindy Campus, Chennai, 600 025, India

    Arambakkam Janardhanam Vanisree & Gangadharan Thamizhoviya

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  1. Arambakkam Janardhanam Vanisree
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AJV designed the experiments and manuscript preparation; GT conducted the experiments and performed the data analysis.

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Correspondence to Arambakkam Janardhanam Vanisree.

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All the institutional and national guidelines for the care and welfare of the laboratory animals were followed (IAEC No:02/15/2017). The ethical approval was obtained as per the norms of IAEC (Institutional Animal Ethical Clearance-205/GO/ReBi/SL/2000/CPCSEA).

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Vanisree, A.J., Thamizhoviya, G. Enriched Environment Minimizes Anxiety/Depressive-Like Behavior in Rats Exposed to Immobilization Stress and Augments Hippocampal Neurogenesis (In Vitro). J Mol Neurosci 71, 2071–2084 (2021). https://doi.org/10.1007/s12031-021-01798-7

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