Environmental Enrichment Ameliorates Anxiety-Like Behavior in Rats without Altering Plasma Corticosterone Level


  • Muthmainah Muthmainah Department of Anatomy, Faculty of Medicine Universitas Sebelas Maret, Indonesia
  • Winda Atika Sari Study Program in Medicine, Faculty of Medicine Universitas Sebelas Maret, Indonesia
  • Nanang Wiyono Department of Anatomy, Faculty of Medicine Universitas Sebelas Maret, Indonesia
  • Dhoni Akbar Ghazali Department of Anatomy, Faculty of Medicine Universitas Sebelas Maret, Indonesia
  • Ratih Dewi Yudhani Department of Pharmacology, Faculty of Medicine Universitas Sebelas Maret, Indonesia https://orcid.org/0000-0001-6781-8251
  • Brian Wasita Department of Anatomic Pathology, Faculty of Medicine Universitas Sebelas Maret, Indonesia




Environmental enrichment, Anxiety, Stress, Corticosterone, Rats


BACKGROUND: Anxiety disorder is one of the most common psychiatric problems. Prolonged stress gives rise to anxiety-like behavior in animals. Environmental interventions influence the outcome of anxiety treatment. Environmental enrichment (EE) can modulate brain’s structure and function.

AIM: The objective of the study was to evaluate EE effects on anxiety-like behavior and corticosterone (CORT) level after unpredictable chronic mild stress (UCMS).

METHODS: A total of 28 rats were assigned into four groups randomly: Control, UCMS, UCMS+EE, and UCMS+fluoxetine. UCMS, EE, and fluoxetine were given for 21 days. Anxiety behavior was measured on day 22nd using Elevated Plus Maze. Behavioral measurement was based on the total time spent and total entries onto open and closed arms. CORT was measured using ELISA.

RESULTS: UCMS increased anxiety-like behavior as seen from reduced number of entries and time spent in open arms as well as increased number of entries and time spent in in closed arms in UCMS group than control. Rats in EE group spent more time and made more entries in the open arms than UCMS group (both p = 0.002). Anxiolytic effect of EE was stronger than fluoxetine. Plasma CORT level among groups did not differ significantly (p = 0.351).

CONCLUSION: EE can ameliorate stress-induced anxiety-like behavior without affecting CORT level.


Download data is not yet available.


Metrics Loading ...

Plum Analytics Artifact Widget Block


Calcia MA, Bonsall DR, Bloomfield PS, Selvaraj S, Barichello T, Howes OD. Stress and neuroinflammation: A systematic review of the effects of stress on microglia and the implications for mental illness. Psychopharmacology (Berl). 2016;233(9):1637-50. https://doi.org/10.1007/s00213-016-4218-9 PMid:26847047 DOI: https://doi.org/10.1007/s00213-016-4218-9

Kinlein SA, Phillips DJ, Keller CR, Karatsoreos IN. Role of corticosterone in altered neurobehavioral responses to acute stress in a model of compromised hypothalamic-pituitary-adrenal axis function. Psychoneuroendocrinology 2019;102():248-55. https://doi.org/10.1016/j.psyneuen.2018.12.010 PMid:30594817 DOI: https://doi.org/10.1016/j.psyneuen.2018.12.010

Skórzewska A, Lehner M, Wisłowska-Stanek A, Krząścik P, Ziemba A, Płaźnik A. The effect of chronic administration of corticosterone on anxiety-and depression-like behavior and the expression of GABA-A receptor alpha-2 subunits in brain structures of low-and high-anxiety rats. Horm Behav. 2014;65(1):6-13. https://doi.org/10.1016/j.yhbeh.2013.10.011 PMid:24200620 DOI: https://doi.org/10.1016/j.yhbeh.2013.10.011

Anacker C. Adult hippocampal neurogenesis in depression: Behavioral implications and regulation by the stress system. Curr Top Behav Neurosci. 2014;18:25-43. https://doi.org/10.1007/7854_2014_275 PMid:24478038 DOI: https://doi.org/10.1007/7854_2014_275

Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the national comorbidity survey replication. Arch Gen Psychiatry. 2005;62(6):617-27. https://doi.org/10.1001/archpsyc.62.6.617 PMid:15939839 DOI: https://doi.org/10.1001/archpsyc.62.6.617

Farhan M, Ho J, Woo JH, Lim CL, Poon DJJ, Lamba B, et al. Concordance and incongruence in preclinical anxiety models: Systematic review and meta-analyses. Neurosci Biobehav Rev. 2016;68:504-29. https://doi.org/10.1016/j.neubiorev.2016.04.011 PMid:27328783 DOI: https://doi.org/10.1016/j.neubiorev.2016.04.011

Darwin C, Prodger P. The Expression of the Emotions in Man and Animals. USA: Oxford University Press; 1998.

Prut L, Belzung C. The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: A review. Eur J Pharmacol. 2003;463(1-3):3-33. https://doi.org/10.1016/S0014-2999(03)01272-X PMid:12600700 DOI: https://doi.org/10.1016/S0014-2999(03)01272-X

Vesterinen HM, Sena ES, Egan KJ, Hirst TC, Churolov L, Currie GL, et al. Meta-analysis of data from animal studies: A practical guide. J Neurosci Methods. 2014;221:92-102. https://doi.org/10.1016/j.jneumeth.2013.09.010 PMid:24099992 DOI: https://doi.org/10.1016/j.jneumeth.2013.09.010

Hirase H, Shinohara Y. Transformation of cortical and hippocampal neural circuit by environmental enrichment. Neuroscience. 2014;280:282-98. https://doi.org/10.1016/j.neuroscience.2014.09.031 PMid:25242640 DOI: https://doi.org/10.1016/j.neuroscience.2014.09.031

Rosenzweig MR. Environmental complexity, cerebral change, and behavior. Am Psychol. 1966;21(4):321-32. https://doi.org/10.1037/h0023555 PMid:5910063 DOI: https://doi.org/10.1037/h0023555

Mileva GR, Bielajew C. Environmental manipulation affects depressive-like behaviors in female Wistar Kyoto rats. Behav Brain Res. 2015;293:208-16. https://doi.org/10.1016/j.bbr.2015.07.035 PMid:26215574 DOI: https://doi.org/10.1016/j.bbr.2015.07.035

Hutchinson KM, McLaughlin KJ, Wright RL, Ortiz JB, Anouti DP, Mika A, et al. Conrad, Environmental enrichment protects against the effects of chronic stress on cognitive and morphological measures of hippocampal integrity. Neurobiol Learn Mem. 2012;97(2):250-60. https://doi.org/10.1016/j.nlm.2012.01.003 PMid:22266288 DOI: https://doi.org/10.1016/j.nlm.2012.01.003

Benaroya-Milshtein N, Hollander N, Apter A, Kukulansky T, Raz N, Wilf AI, et al. Environmental enrichment in mice decreases anxiety, attenuates stress responses and enhances natural killer cell activity. Eur J Neurosci. 2004;20(5):1341-7. https://doi.org/10.1111/j.1460-9568.2004.03587.x PMid:15341605 DOI: https://doi.org/10.1111/j.1460-9568.2004.03587.x

Seetharaman S, Fleshner M, Park CR, Diamond DM. Influence of daily social stimulation on behavioral and physiological outcomes in an animal model of PTSD. Brain Behav. 2016;6(5):e00458. https://doi.org/10.1002/brb3.458 PMid:27110436 DOI: https://doi.org/10.1002/brb3.458

Wright RL, Conrad CD. Enriched environment prevents chronic stress-induced spatial learning and memory deficits. Behav. Brain Res. 2008;187(1):41-7. https://doi.org/10.1016/j.bbr.2007.08.025 PMid:17904657 DOI: https://doi.org/10.1016/j.bbr.2007.08.025

Silva RCB, Brandão ML. Acute and chronic effects of gepirone and fluoxetine in rats tested in the elevated plus-maze: An ethological analysis. Pharmacol Biochem Behav. 2000;65(2):209-16. https://doi.org/10.1016/S0091-3057(99)00193-8 PMid:10672971 DOI: https://doi.org/10.1016/S0091-3057(99)00193-8

Park HJ, Hyun YK, Yoon KH, Kyung SK, Shim I. The effects of Astragalus membranaceus on repeated restraint stress-induced biochemical and behavioral responses. Korean J Physiol Pharmacol. 2009;13(4):315-9. https://doi.org/10.4196/kjpp.2009.13.4.315 PMid:19885016 DOI: https://doi.org/10.4196/kjpp.2009.13.4.315

Komada M, Takao K, Miyakawa T. Elevated plus maze for mice. J Vis Exp 2008;22(22):e1088. https://doi.org/10.3791/1088 PMid:19229173 DOI: https://doi.org/10.3791/1088

Leo LM, Pamplona FA. Elevated plus maze test to assess anxiety-like behavior in the mouse. Bio-Protocol. 2014;4(16):e1211. https://doi.org/10.21769/bioprotoc.1211 DOI: https://doi.org/10.21769/BioProtoc.1211

Caruso MJ, Crowley NA, Reiss DE, Caulfield JI, Luscher B, Cavigelli SA, et al. Adolescent social stress increases anxiety-like behavior and alters synaptic transmission without influencing nicotine responses in a sex-dependent manner. Neuroscience. 2018;373:182-98. https://doi.org/10.1016/j.neuroscience.2018.01.006 PMid:29343455 DOI: https://doi.org/10.1016/j.neuroscience.2018.01.006

Muthmainah, Nurwati I. Acupuncture for depression: The mechanism underlying its therapeutic effect. Med. Acupunct. 2016;28(6):301-7. https://doi.org/10.1089/acu.2016.1180 DOI: https://doi.org/10.1089/acu.2016.1180

Faravelli C, Lo Sauro C, Lelli L, Pietrini F, Lazzeretti L, Godini L, et al. The role of life events and HPA axis in anxiety disorders: A review. Curr Pharm Des. 2012;18(35):5663-74. https://doi.org/10.2174/138161212803530907 PMid:22632471 DOI: https://doi.org/10.2174/138161212803530907

Daniel SE, Rainnie DG. Stres modulation of opposing circuits in the bed nucleus of the stria terminalis. Neuropsychopharmacology. 2015;41(1):103-25. https://doi.org/10.1038/npp.2015.178 PMid:26096838 DOI: https://doi.org/10.1038/npp.2015.178

Padurariu M, Antioch I, Balmus I, Ciobica A, El-Lethey HS, Kamel MM. Describing some behavioral animal models of anxiety and their mechanistics with special reference to oxidative stress and oxytocin relevance. Int J Vet Sci Med. 2017;5(2):98-104. https://doi.org/10.1016/j.ijvsm.2017.08.003 PMid:30255057 DOI: https://doi.org/10.1016/j.ijvsm.2017.08.003

Bondar NP, Lepeshko AA, Reshetnikov VV. Effects of early-life stress on social and anxiety-like behaviors in adult mice: Sex-specific effects. Behav Neurol. 2018;2018:1538931. https://doi.org/10.1155/2018/1538931 PMid:29619126 DOI: https://doi.org/10.1155/2018/1538931

Koval JJ, Pederson LL, Chan SS. Psychosocial variables in a cohort of students in grades 8 and 11: A comparison of current and never smokers. Prev Med. 2004;39(5):1017-25. https://doi.org/10.1016/j.ypmed.2004.04.006 PMid:15475037 DOI: https://doi.org/10.1016/j.ypmed.2004.04.006

Stephens MA, Wand G. Stress and the HPA axis role of glucocorticoids in alcohol dependence. Alcohol Res. 2012;34(4):468-83. PMid:23584113

Sink KS, Walker DL, Freeman SM, Elizabeth BS, Flandreau I, Ressler KJ, et al. Effects of continuously enhanced corticotropin releasing factor expression within the bed nucleus of the stria terminalis on conditioned and unconditioned anxiety. Mol Psychiatry. 2013;18(3):308-19. https://doi.org/10.1038/mp.2011.188 PMid:22290119 DOI: https://doi.org/10.1038/mp.2011.188

Lehner M, Taracha E, Skórzewska A, Turzyńska D, Sobolewska A, Maciejak P, et al. Expression of c-Fos and CRF in the brains of rats differing in the strength of a fear response. Behav Brain Res. 2008;188(1):154-67. https://doi.org/10.1016/j.bbr.2007.10.033 PMid:18067977 DOI: https://doi.org/10.1016/j.bbr.2007.10.033

Rogers J, Li S, Lanfumey L, Hannan AJ, Renoir T. Environmental enrichment reduces innate anxiety with no effect on depression-like behavior in mice lacking the serotonin transporter. Behav Brain Res. 2017;332:355-61. https://doi.org/10.1016/j.bbr.2017.06.009 PMid:28629963 DOI: https://doi.org/10.1016/j.bbr.2017.06.009

Hendershott TR, Cronin ME, Langella S, McGuinness PS, Basu AC. Effects of environmental enrichment on anxiety-like behavior, sociability, sensory gating, and spatial learning in male and female C57BL/6J mice. Behav Brain Res. 2016;314:215-25. https://doi.org/10.1016/j.bbr.2016.08.004 PMid:27498148 DOI: https://doi.org/10.1016/j.bbr.2016.08.004

Meshi D, Drew MR, Saxe M, Ansorge MS, David D, Santarelli L, et al. Hippocampal neurogenesis is not required for behavioral effects of environmental enrichment. Nat Neurosci. 2006;9(6):729-31. https://doi.org/10.1038/nn1696 PMid:16648847 DOI: https://doi.org/10.1038/nn1696

Goes TC, Antunes FD, Teixeira-Silva F. Environmental enrichment for adult rats: Effects on trait and state anxiety. Neurosci Lett. 2015;584:93-6. https://doi.org/10.1016/j.neulet.2014.10.004 PMid:25316162 DOI: https://doi.org/10.1016/j.neulet.2014.10.004

Kazlauckas V, Pagnussat N, Mioranzza S, Kalinine E, Nunes F, Pettenuzzo L, et al. Enriched environment effects on behavior, memory and BDNF in low and high exploratory mice. Physiol Behav. 2011;102(5):475-80. https://doi.org/10.1016/j.physbeh.2010.12.025 PMid:21236277 DOI: https://doi.org/10.1016/j.physbeh.2010.12.025

Nutt DJ, Glue P. Imipramine in panic disorder: Clinical response and pharmacological changes. J Psychopharmacol. 1991;5(1):56-64. https://doi.org/10.1177/026988119100500108 PMid:22282120 DOI: https://doi.org/10.1177/026988119100500108

Dincheva I, Yang J, Li A, Marinic BS, Freilingsdorf H, Huang C, et al. Early-life fluoxetine rescues anxiety-like behaviors in BDNF Val66Met mice. Am J Psychiatry. 2017;174(12):1203-13. https://doi.org/10.1176/appi.ajp.2017.15121592 PMid:29084453 DOI: https://doi.org/10.1176/appi.ajp.2017.15121592

Gan H, Zhang Q, Zhu B, Wu S, Chai D. Fluoxetine reverses brain radiation and temozolomide-induced anxiety and spatial learning and memory defect in mice. J Neurophysiol. 2019;121(1):298-305. https://doi.org/10.1152/jn.00581.2018 PMid:30517049 DOI: https://doi.org/10.1152/jn.00581.2018

Diamond MC. Response of the brain to enrichment. An Acad Bras Cienc. 2001;73(2):211-20. https://doi.org/10.1590/S0001-37652001000200006 PMid:11404783 DOI: https://doi.org/10.1590/S0001-37652001000200006

Rosenzweig MR, Bennett EL. Psychobiology of plasticity: Effects of training and experience on brain and behavior. Behav Brain Res. 1996;78(1):57-65. https://doi.org/10.1016/0166-4328(95)00216-2 PMid:8793038 DOI: https://doi.org/10.1016/0166-4328(95)00216-2

Birch AM, McGarry NB, Kelly AM. Short-term environmental enrichment in the absence of exercise, improves memory, and increases NGF concentration, early neuronal survival, and synaptogenesis in the dentate gyrus in a time-dependent manner. Hippocampus. 2013;23(6):437-50. https://doi.org/10.1002/hipo.22103 PMid:23460346 DOI: https://doi.org/10.1002/hipo.22103

Fares RP, Belmeguenai A, Sanchez PE, Kouchi HY, Bodennec J, Morales A, et al. Standardized environmental enrichment supports enhanced brain plasticity in healthy rats and prevents cognitive impairment in epileptic rats. PLoS One. 2013;8(1):e53888. https://doi.org/10.1371/journal.pone.0053888 PMid:23342033 DOI: https://doi.org/10.1371/journal.pone.0053888

Clemenson GD, Deng W, Gage FH. Environmental enrichment and neurogenesis: From mice to humans. Curr Opin Behav Sci. 2015;4:56-62. https://doi.org/10.1016/j.cobeha.2015.02.005 DOI: https://doi.org/10.1016/j.cobeha.2015.02.005

Hestermann D, Temel Y, Blokland A, Lim LW. Acute serotonergic treatment changes the relation between anxiety and HPA-axis functioning and periaqueductal gray activation. Behav Brain Res. 2014;273:155-65. https://doi.org/10.1016/j.bbr.2014.07.003 PMid:25043730 DOI: https://doi.org/10.1016/j.bbr.2014.07.003

Herman JP, McKlveen JM, Ghosal S, Kopp B, Wulsin A, Makinson R, et al. Regulation of the hypothalamic-pituitary-adrenocortical stress response. Compr Physiol. 2016;6(2):603-21. https://doi.org/10.1002/cphy.c150015 PMid:27065163 DOI: https://doi.org/10.1002/cphy.c150015

Ulrich-Lai YM, Herman, JP. Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci. 2009;10(6):397-409. https://doi.org/10.1038/nrn2647 PMid:19469025 DOI: https://doi.org/10.1038/nrn2647

Windle RJ, Shanks N, Lightman SL, Ingram CD. Central oxytocin administration reduces stress-induced corticosterone release and anxiety behavior in rats. Endocrinology. 1997;138(7):2829-34. https://doi.org/10.1210/endo.138.7.5255 PMid:9202224 DOI: https://doi.org/10.1210/endo.138.7.5255

Mitra R, Sapolsky RM. Acute corticosterone treatment is sufficient to induce anxiety and amygdaloid dendritic hypertrophy. Proc Natl Acad Sci USA. 2008;105(14):5573-78. https://doi.org/10.1073/pnas.0705615105 PMid:920222 DOI: https://doi.org/10.1073/pnas.0705615105

Moncek F, Duncko R, Johansson BB, Jezova D. Effect of environmental enrichment on stress related systems in rats. J Neuroendocrinol. 2004;16(5):423-31. https://doi.org/10.1111/j.1365-2826.2004.01173.x PMid:15117335 DOI: https://doi.org/10.1111/j.1365-2826.2004.01173.x

Pham TM, Ickes B, Albeck D, Soderstrom S, Granholm AC, Mohammed AH. Changes in brain nerve growth factor levels and nerve growth factor receptors in rats exposed to environmental enrichment for one year. Neuroscience. 1999;94(1):279-86. https://doi.org/10.1016/S0306-4522(99)00316-4 PMid:10613518 DOI: https://doi.org/10.1016/S0306-4522(99)00316-4

Schrijver NC, Bahr NI, Weiss IC, Wurbel H. Dissociable effects of isolation rearing and environmental enrichment on exploration, spatial learning and HPA activity in adult rats. Pharmacol Biochem Behav. 2002;73(1):209-24. https://doi.org/10.1016/S0091-3057(02)00790-6 PMid:12076740 DOI: https://doi.org/10.1016/S0091-3057(02)00790-6

Carrasco A, van de Kar LD. Neuroendocrine pharmacology of stress. Eur J Pharmacol. 2003;463(1-3):235-72. https://doi.org/10.1016/S0014-2999(03)01285-8 PMid:12600714 DOI: https://doi.org/10.1016/S0014-2999(03)01285-8

Salim S, Chugh G, Ashgar M. Inflammation in anxiety. Adv Protein Chem Struct Biol. 2012;88:1-25. https://doi.org/10.1016/B978-0-12-398314-5.00001-5 PMid:22814704 DOI: https://doi.org/10.1016/B978-0-12-398314-5.00001-5

Vogelzangs N, Beekman AT, de Jonge P, Penninx BW. Anxiety disorders and inflammation in a large adult cohort. Transl Psychiatry. 2013;3(4):e249. https://doi.org/10.1038/tp.2013.27 PMid:23612048 DOI: https://doi.org/10.1038/tp.2013.27

Ossowska G, Nowak G, Kata R, Klenk-Majewska B, Danilczuk Z, Żebrowska-Lupina I. Brain monoamine receptors in a chronic unpredictable stress model in rats. J Neural Transm. 2001;108(3):311-9. https://doi.org/10.1007/s007020170077 PMid:11341483 DOI: https://doi.org/10.1007/s007020170077

Flügge G, van Kampen M., Mijnste MJ. Perturbations in brain monoamine systems during stress. Cell Tissue Res. 2004;315(1):1-14. https://doi.org/10.1007/s00441-003-0807-0 PMid:14579145 DOI: https://doi.org/10.1007/s00441-003-0807-0

Diamond DM, Park CR, Campbell AM, Woodson JC. Competitive interactions between endogenous LTD and LTP in the hippocampus underlie the storage of emotional memories and stress-induced amnesia. Hippocampus. 2005;15(8):1006-25. https://doi.org/10.1002/hipo.20107 PMid:16086429 DOI: https://doi.org/10.1002/hipo.20107

Kumar V, Bhat ZA, Kumar D. Animal models of anxiety: A comprehensive review. J Pharmacol Toxicol Method. 2013;68(2):175-83. https://doi.org/10.1016/j.vascn.2013.05.003 PMid:23684951 DOI: https://doi.org/10.1016/j.vascn.2013.05.003




How to Cite

Muthmainah M, Sari WA, Wiyono N, Ghazali DA, Yudhani RD, Wasita B. Environmental Enrichment Ameliorates Anxiety-Like Behavior in Rats without Altering Plasma Corticosterone Level. Open Access Maced J Med Sci [Internet]. 2021 Nov. 22 [cited 2024 Jun. 15];9(A):1074-80. Available from: https://oamjms.eu/index.php/mjms/article/view/6396

Most read articles by the same author(s)

1 2 > >>