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Review Article | Open Access

Influence of enriched environment on anxiety-related behavior: evidence and mechanisms

Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University, Haining 314400, China
Department of Neurobiology and Department of Psychiatry of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Institute, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou 310058, China
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Anxiety disorders are one of the most prevalent mental disorders that are in a great demand of developing new treatments. Both genetic and environmental factors play essential roles in the pathophysiology of anxiety disorders. Increasing evidence implicates environmental enrichment that shapes neural plasticity exerts beneficial effects on anxiety-related behavior in animal models. Here, we summarize the effects of enriched environment on anxiety-related behavior in rats and mice, highlight the potential mechanisms underlying the beneficial effects of environmental enrichment on emotionality at cellular/molecular level, and discuss the potential directions for further research.


Griebel, G., Holmes, A. 50 years of hurdles and hope in anxiolytic drug discovery. Nature Reviews Drug Discovery, 2013, 12(9): 667–687.
Vahabzadeh, A., Gillespie, C. F., Ressler, K. J. Fear-related anxiety disorders and post-traumatic stress disorder. In: Zigmond, M. J., Rowland, L. P., and Coyle, J. T. (eds.) Neurobiology of Brain Disorders. Amsterdam: Elsevier, 2015: 612–620.
Huang, Y. Q., Wang, Y., Wang, H., Liu, Z. R., Yu, X., Yan, J., Yu, Y. Q., Kou, C. G., Xu, X. F., Lu, J. et al. Prevalence of mental disorders in China: A cross-sectional epidemiological study. The Lancet. Psychiatry, 2019, 6(3): 211–224.
Baxter, A. J., Scott, K. M., Vos, T., Whiteford, H. A. Global prevalence of anxiety disorders: A systematic review and meta-regression. Psychological Medicine, 2013, 43(5): 897–910.
Wittchen, H. U., Jacobi, F., Rehm, J., Gustavsson, A., Svensson, M., Jönsson, B., Olesen, J., Allgulander, C., Alonso, J., Faravelli, C. et al. The size and burden of mental disorders and other disorders of the brain in Europe 2010. European Neuropsychopharmacology, 2011, 21(9): 655–679.
Kessler, R. C., Chiu, W. T., Demler, O., Merikangas, K. R., Walters, E. E. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry, 2005, 62(6): 617–627.
Regier, D. A., Farmer, M. E., Rae, D. S., Locke, B. Z., Keith, S. J., Judd, L. L., Goodwin, F. K. Comorbidity of mental disorders with alcohol and other drug abuse: Results from the epidemiologic catchment area (ECA) study. JAMA, 1990, 264: 2511–2518.
Locke, A. B., Kirst, N., Shultz, C. G. Diagnosis and management of generalized anxiety disorder and panic disorder in adults. American Family Physician, 2015, 91(9): 617–624.
Bandelow, B., Michaelis, S., Wedekind, D. Treatment of anxiety disorders. Dialogues in Clinical Neuroscience, 2017, 19(2): 93–107.
Hoffman, E. J., Mathew, S. J. Anxiety disorders: A comprehensive review of pharmacotherapies. The Mount Sinai Journal of Medicine, 2008, 75(3): 248–262.
Uliaszek, A. A., Zinbarg, R. E., Mineka, S., Craske, M. G., Griffith, J. W., Sutton, J. M., Epstein, A., Hammen, C. A longitudinal examination of stress generation in depressive and anxiety disorders. Journal of Abnormal Psychology, 2012, 121(1): 4–15.
Smoller, J. W. The genetics of stress-related disorders: PTSD, depression, and anxiety disorders. Neuropsychopharmacology, 2016, 41(1): 297–319.
Shimada-Sugimoto, M., Otowa, T., Hettema, J. M. Genetics of anxiety disorders: Genetic epidemiological and molecular studies in humans. Psychiatry and Clinical Neurosciences, 2015, 69(7): 388–401.
Meier, S. M., Deckert, J. Genetics of anxiety disorders. Current Psychiatry Reports, 2019, 21(3): 16.
Schiele, M. A., Domschke, K. Epigenetics at the crossroads between genes, environment and resilience in anxiety disorders. Genes, Brain, and Behavior, 2018, 17(3): e12423.
Maccari, S., Krugers, H. J., Morley-Fletcher, S., Szyf, M., Brunton, P. J. The consequences of early-life adversity: Neurobiological, behavioural and epigenetic adaptations. Journal of Neuroendocrinology, 2014, 26(10): 707–723.
Roy, V., Belzung, C., Delarue, C., Chapillon, P. Environmental enrichment in BALB/c mice: Effects in classical tests of anxiety and exposure to a predatory odor. Physiology & Behavior, 2001, 74(3): 313–320.
Benaroya-Milshtein, N., Hollander, N., Apter, A., Kukulansky, T., Raz, N., Wilf, A., Yaniv, I., Pick, C. G. Environmental enrichment in mice decreases anxiety, attenuates stress responses and enhances natural killer cell activity. European Journal of Neuroscience, 2004, 20(5): 1341–1347.
Simpson, J., Kelly, J. P. The impact of environmental enrichment in laboratory rats—behavioural and neurochemical aspects. Behavioural Brain Research, 2011, 222(1): 246–264.
van Praag, H., Kempermann, G., Gage, F. H. Neural consequences of environmental enrichment. Nature Reviews. Neuroscience, 2000, 1(3): 191–198.
Nithianantharajah, J., Hannan, A. J. Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nature Reviews Neuroscience, 2006, 7(9): 697–709.
Sale, A., Berardi, N., Maffei, L. Enrich the environment to empower the brain. Trends in Neurosciences, 2009, 32(4): 233–239.
Novaes, L. S., dos Santos, N. B., Perfetto, J. G., Goosens, K. A., Munhoz, C. D. Environmental enrichment prevents acute restraint stress-induced anxiety-related behavior but not changes in basolateral amygdala spine density. Psychoneuroendocrinology, 2018, 98: 6–10.
Morley-Fletcher, S., Rea, M., Maccari, S., Laviola, G. Environmental enrichment during adolescence reverses the effects of prenatal stress on play behaviour and HPA axis reactivity in rats. European Journal of Neuroscience, 2003, 18(12): 3367–3374.
Bahi, A. Environmental enrichment reduces chronic psychosocial stress-induced anxiety and ethanol-related behaviors in mice. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 2017, 77: 65–74.
Sparling, J. E., Mahoney, M., Baker, S., Bielajew, C. The effects of gestational and postpartum environmental enrichment on the mother rat: A preliminary investigation. Behavioural Brain Research, 2010, 208(1): 213–223.
Sparling, J. E., Baker, S. L., Bielajew, C. Effects of combined pre- and post-natal enrichment on anxiety-like, social, and cognitive behaviours in juvenile and adult rat offspring. Behavioural Brain Research, 2018, 353: 40–50.
Urakawa, S., Takamoto, K., Hori, E., Sakai, N., Ono, T., Nishijo, H. Rearing in enriched environment increases parvalbumin-positive small neurons in the amygdala and decreases anxiety-like behavior of male rats. BMC Neuroscience, 2013, 14(1): 1–11.
Leal-Galicia, P., Saldívar-González, A., Morimoto, S., Arias, C. Exposure to environmental enrichment elicits differential hippocampal cell proliferation: Role of individual responsiveness to anxiety. Developmental Neurobiology, 2007, 67(4): 395–405.
Hendershott, T. R., Cronin, M. E., Langella, S., McGuinness, P. S., Basu, A. C. Effects of environmental enrichment on anxiety-like behavior, sociability, sensory gating, and spatial learning in male and female C57BL/6J mice. Behavioural Brain Research, 2016, 314: 215–225.
Calhoon, G. G., Tye, K. M. Resolving the neural circuits of anxiety. Nature Neuroscience, 2015, 18(10): 1394–1404.
Tovote, P., Fadok, J. P., Lüthi, A. Neuronal circuits for fear and anxiety. Nature Reviews Neuroscience, 2015, 16(6): 317–331.
Degroot, A., Treit, D. Anxiety is functionally segregated within the septo-hippocampal system. Brain Research, 2004, 1001(1–2): 60–71.
Kheirbek, M. A., Drew, L. J., Burghardt, N. S., Costantini, D. O., Tannenholz, L., Ahmari, S. E., Zeng, H. K., Fenton, A. A., Hen, R. Differential control of learning and anxiety along the dorsoventral axis of the dentate gyrus. Neuron, 2013, 77(5): 955–968.
Sampedro-Piquero, P., Castilla-Ortega, E., Zancada-Menendez, C., Santín, L. J., Begega, A. Environmental enrichment as a therapeutic avenue for anxiety in aged Wistar rats: Effect on cat odor exposition and GABAergic interneurons. Neuroscience, 2016, 330: 17–25.
González-Pardo, H., Arias, J. L., Vallejo, G., Conejo, N. M. Environmental enrichment effects after early stress on behavior and functional brain networks in adult rats. PLoS One, 2019, 14(12): e0226377.
Etkin, A., Keller, K. E., Schatzberg, A. F., Menon, V., Greicius, M. D. Disrupted amygdalar subregion functional connectivity and evidence for a compensatory network in generalized anxiety disorder. NeuroImage, 2009, 47: S71.
Teicher, M. H., Samson, J. A., Anderson, C. M., Ohashi, K. The effects of childhood maltreatment on brain structure, function and connectivity. Nature Reviews. Neuroscience, 2016, 17(10): 652–666.
Tye, K. M., Prakash, R., Kim, S. Y., Fenno, L. E., Grosenick, L., Zarabi, H., Thompson, K. R., Gradinaru, V., Ramakrishnan, C., Deisseroth, K. Amygdala circuitry mediating reversible and bidirectional control of anxiety. Nature, 2011, 471(7338): 358–362.
Ashokan, A., Hegde, A., Mitra, R. Short-term environmental enrichment is sufficient to counter stress-induced anxiety and associated structural and molecular plasticity in basolateral amygdala. Psychoneuroendocrinology, 2016, 69: 189–196.
Koe, A. S., Ashokan, A., Mitra, R. Short environmental enrichment in adulthood reverses anxiety and basolateral amygdala hypertrophy induced by maternal separation. Translational Psychiatry, 2016, 6(2): e729.
Babaev, O., Piletti Chatain, C., Krueger-Burg, D. Inhibition in the amygdala anxiety circuitry. Experimental & Molecular Medicine, 2018, 50(4): 18.
Hale, M. W., Johnson, P. L., Westerman, A. M., Abrams, J. K., Shekhar, A., Lowry, C. A. Multiple anxiogenic drugs recruit a parvalbumin-containing subpopulation of GABAergic interneurons in the basolateral amygdala. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 2010, 34(7): 1285–1293.
Wolff, S. B. E., Gründemann, J., Tovote, P., Krabbe, S., Jacobson, G. A., Müller, C., Herry, C., Ehrlich, I., Friedrich, R. W., Letzkus, J. J. et al. Amygdala interneuron subtypes control fear learning through disinhibition. Nature, 2014, 509(7501): 453–458.
Janak, P. H., Tye, K. M. From circuits to behaviour in the amygdala. Nature, 2015, 517(7534): 284–292.
Shoshan, N., Akirav, I. The effects of cannabinoid receptors activation and glucocorticoid receptors deactivation in the amygdala and hippocampus on the consolidation of a traumatic event. Neurobiology of Learning and Memory, 2017, 144: 248–258.
Arnett, M. G., Pan, M. S., Doak, W., Cyr, P. P., Muglia, L. M., Muglia, L. J. The role of glucocorticoid receptor-dependent activity in the amygdala central nucleus and reversibility of early-life stress programmed behavior. Translational Psychiatry, 2015, 5(4): e542.
Qian, J., Zhou, D., Pan, F., Liu, C. X., Wang, Y. W. Effect of environmental enrichment on fearful behavior and gastrin-releasing peptide receptor expression in the amygdala of prenatal stressed rats. Journal of Neuroscience Research, 2008, 86(13): 3011–3017.
Zhao, C. M., Deng, W., Gage, F. H. Mechanisms and functional implications of adult neurogenesis. Cell, 2008, 132(4): 645–660.
Santarelli, L., Saxe, M., Gross, C., Surget, A., Battaglia, F., Dulawa, S., Weisstaub, N., Lee, J., Duman, R., Arancio, O. et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science, 2003, 301(5634): 805–809.
Tsetsenis, T., Ma, X. H., Lo Iacono, L., Beck, S. G., Gross, C. Suppression of conditioning to ambiguous cues by pharmacogenetic inhibition of the dentate gyrus. Nature Neuroscience, 2007, 10(7): 896–902.
Kempermann, G., Kuhn, H. G., Gage, F. H. More hippocampal neurons in adult mice living in an enriched environment. Nature, 1997, 386: 493–495.
Segovia, G., Yagüe, A. G., García-Verdugo, J. M., Mora, F. Environmental enrichment promotes neurogenesis and changes the extracellular concentrations of glutamate and GABA in the hippocampus of aged rats. Brain Research Bulletin, 2006, 70(1): 8–14.
Petrik, D., Lagace, D. C., Eisch, A. J. The neurogenesis hypothesis of affective and anxiety disorders: Are we mistaking the scaffolding for the building? Neuropharmacology, 2012, 62(1): 21–34.
Schloesser, R. J., Lehmann, M., Martinowich, K., Manji, H. K., Herkenham, M. Environmental enrichment requires adult neurogenesis to facilitate the recovery from psychosocial stress. Molecular Psychiatry, 2010, 15(12): 1152–1163.
Meshi, D., Drew, M. R., Saxe, M., Ansorge, M. S., David, D., Santarelli, L., Malapani, C., Moore, H., Hen, R. Hippocampal neurogenesis is not required for behavioral effects of environmental enrichment. Nature Neuroscience, 2006, 9(6): 729–731.
Green, E. J., Greenough, W. T. Altered synaptic transmission in dentate gyrus of rats reared in complex environments: Evidence from hippocampal slices maintained in vitro. Journal of Neurophysiology, 1986, 55(4): 739–750.
Irvine, G. I., Logan, B., Eckert, M., Abraham, W. C. Enriched environment exposure regulates excitability, synaptic transmission, and LTP in the dentate gyrus of freely moving rats. Hippocampus, 2006, 16(2): 149–160.
Rocher, C., Spedding, M., Munoz, C., Jay, T. M. Acute stress-induced changes in hippocampal/prefrontal circuits in rats: Effects of antidepressants. Cerebral Cortex, 2004, 14(2): 224–229.
Zhang, T. Y., Keown, C. L., Wen, X. L., Li, J. H., Vousden, D. A., Anacker, C., Bhattacharyya, U., Ryan, R., Diorio, J., O'Toole, N. et al. Environmental enrichment increases transcriptional and epigenetic differentiation between mouse dorsal and ventral dentate gyrus. Nature Communications, 2018, 9(1): 298.
Vertes, R. P. Differential projections of the infralimbic and prelimbic cortex in the rat. Synapse, 2004, 51(1): 32–58.
Kirry, A. J., Twining, R. C., Gilmartin, M. R. Prelimbic input to basolateral amygdala facilitates the acquisition of trace cued fear memory under weak training conditions. Neurobiology of Learning and Memory, 2020, 172: 107249.
Maren, S., Quirk, G. J. Neuronal signalling of fear memory. Nature Reviews Neuroscience, 2004, 5(11): 844–852.
Bi, L. L., Wang, J., Luo, Z. Y., Chen, S. P., Geng, F., Chen, Y. H., Li, S. J., Yuan, C. H., Lin, S., Gao, T. M. Enhanced excitability in the infralimbic cortex produces anxiety-like behaviors. Neuropharmacology, 2013, 72: 148–156.
Ronzoni, G., Antón, M., Mora, F., Segovia, G., Del Arco, A. Infralimbic cortex controls the activity of the hypothalamus-pituitary-adrenal axis and the formation of aversive memory: Effects of environmental enrichment. Behavioural Brain Research, 2016, 297: 338–344.
Lehmann, M. L., Herkenham, M. Environmental enrichment confers stress resiliency to social defeat through an infralimbic cortex-dependent neuroanatomical pathway. Journal of Neuroscience, 2011, 31(16): 6159–6173.
McQuaid, R. J., Dunn, R., Jacobson-Pick, S., Anisman, H., Audet, M. C. Post-weaning environmental enrichment in male CD-1 mice: Impact on social behaviors, corticosterone levels and prefrontal cytokine expression in adulthood. Frontiers in Behavioral Neuroscience, 2018, 12: 145.
Rossi, S., Studer, V., Motta, C., Polidoro, S., Perugini, J., Macchiarulo, G., Giovannetti, A. M., Pareja-Gutierrez, L., Calò, A., Colonna, I. et al. Neuroinflammation drives anxiety and depression in relapsing-remitting multiple sclerosis. Neurology, 2017, 89(13): 1338–1347.
Ulrich, K., Spriggs, M. J., Abraham, W. C., Dalrymple-Alford, J. C., McNaughton, N. Environmental enrichment increases prefrontal EEG power and synchrony with the hippocampus in rats with anterior thalamus lesions. Hippocampus, 2019, 29(2): 128–140.
Adhikari, A., Topiwala, M. A., Gordon, J. A. Synchronized activity between the ventral hippocampus and the medial prefrontal cortex during anxiety. Neuron, 2010, 65(2): 257–269.
Novkovic, T., Mittmann, T., Manahan-Vaughan, D. BDNF contributes to the facilitation of hippocampal synaptic plasticity and learning enabled by environmental enrichment. Hippocampus, 2015, 25(1): 1–15.
Bekinschtein, P., Oomen, C. A., Saksida, L. M., Bussey, T. J. Effects of environmental enrichment and voluntary exercise on neurogenesis, learning and memory, and pattern separation: BDNF as a critical variable? Seminars in Cell & Developmental Biology, 2011, 22(5): 536–542.
Chen, Z. Y., Jing, D. Q., Bath, K. G., Ieraci, A., Khan, T., Siao, C. J., Herrera, D. G., Toth, M., Yang, C., McEwen, B. S. et al. Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science, 2006, 314(5796): 140–143.
Hellemans, K. G. C., Nobrega, J. N., Olmstead, M. C. Early environmental experience alters baseline and ethanol-induced cognitive impulsivity: Relationship to forebrain 5-HT1A receptor binding. Behavioural Brain Research, 2005, 159(2): 207–220.
Olivier, B., Pattij, T., Wood, S. J., Oosting, R., Sarnyai, Z., Toth, M. The 5-HT 1A receptor knockout mouse and anxiety. Behavioural Pharmacology, 2001, 12(6): 439–450.
Gross, C., Zhuang, X. X., Stark, K., Ramboz, S., Oosting, R., Kirby, L., Santarelli, L., Beck, S., Hen, R. Serotonin1A receptor Acts during development to establish normal anxiety-like behaviour in the adult. Nature, 2002, 416(6879): 396–400.
Lesch, K. P., Bengel, D., Heils, A., Sabol, S. Z., Greenberg, B. D., Petri, S., Benjamin, J., Müller, C. R., Hamer, D. H., Murphy, D. L. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science, 1996, 274(5292): 1527–1531.
Stein, M. B., Schork, N. J., Gelernter, J. Gene-by-environment (serotonin transporter and childhood maltreatment) interaction for anxiety sensitivity, an intermediate phenotype for anxiety disorders. Neuropsychopharmacology, 2008, 33(2): 312–319.
Rickels, K., Weisman, K., Norstad, N., Singer, M., Stoltz, D., Brown, A., Danton, J. Buspirone and diazepam in anxiety: A controlled study. The Journal of Clinical Psychiatry, 1983, 43(12 Pt. 2): 81–86.
Reinhold, J. A., Mandos, L. A., Rickels, K., Lohoff, F. W. Pharmacological treatment of generalized anxiety disorder. Expert Opinion on Pharmacotherapy, 2011, 12(16): 2457–2467.
Daws, L. C., Munn, J. L., Valdez, M. F., Frosto-Burke, T., Hensler, J. G. Serotonin transporter function, but not expression, is dependent on brain-derived neurotrophic factor (BDNF): In vivo studies in BDNF-deficient mice. Journal of Neurochemistry, 2007, 101(3): 641–651.
Monteggia, L. M., Barrot, M., Powell, C. M., Berton, O., Galanis, V., Gemelli, T., Meuth, S., Nagy, A., Greene, R. W., Nestler, E. J. Essential role of brain-derived neurotrophic factor in adult hippocampal function. Proceedings of the National Academy of Sciences of the United States of America, 2004, 101(29): 10827–10832.
Mora, F., Segovia, G., del Arco, A. Aging, plasticity and environmental enrichment: Structural changes and neurotransmitter dynamics in several areas of the brain. Brain Research Reviews, 2007, 55(1): 78–88.
Mora-Gallegos, A., Rojas-Carvajal, M., Salas, S., Saborío-Arce, A., Fornaguera-Trías, J., Brenes, J. C. Age-dependent effects of environmental enrichment on spatial memory and neurochemistry. Neurobiology of Learning and Memory, 2015, 118: 96–104.
Mora-Gallegos, A., Fornaguera, J. The effects of environmental enrichment and social isolation and their reversion on anxiety and fear conditioning. Behavioural Processes, 2019, 158: 59–69.
Semple, B. D., Blomgren, K., Gimlin, K., Ferriero, D. M., Noble-Haeusslein, L. J. Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species. Progress in Neurobiology, 2013, 106–107: 1–16.
Gong, X. R., Chen, Y. M., Chang, J., Huang, Y., Cai, M., Zhang, M. Z. Environmental enrichment reduces adolescent anxiety- and depression-like behaviors of rats subjected to infant nerve injury. Journal of Neuroinflammation, 2018, 15(1): 262.
Lopes, D. A., Souza, T. M. O., de Andrade, J. S., Silva, M. F. S., Antunes, H. K. M., Sueur-Maluf, L. L., Céspedes, I. C., Viana, M. B. Environmental enrichment decreases avoidance responses in the elevated T-maze and delta FosB immunoreactivity in anxiety-related brain regions. Behavioural Brain Research, 2018, 344: 65–72.
Stress and Brain
Pages 33-45
Cite this article:
Li W-Y, Wang X-D. Influence of enriched environment on anxiety-related behavior: evidence and mechanisms. Stress and Brain, 2021, 1(1): 33-45.








Received: 02 March 2020
Accepted: 22 July 2020
Published: 07 March 2021
© The Author(s) 2020

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