Environmental enrichment in mice decreases anxiety, attenuates stress responses and enhances natural killer cell activity
Abstract
The importance of environment in the regulation of brain, behaviour and physiology has long been recognized in biological, social and medical sciences. Animals maintained under enriched conditions have clearly been shown to have better learning abilities than those maintained under standard conditions. However, the effects of environmental enrichment (EE) on immunity and emotionality have been less documented and remain questionable. Therefore, we investigated the effect of EE on natural killer (NK) cell activity, psychological stress responses and behavioural parameters. Male C3H mice were housed either in enriched or standard conditions for 6 weeks. Behaviour was then examined by the grip-strength test, staircase and elevated plus maze, and corticosterone levels and NK cell activity were measured. Furthermore, animals exposed to the stress paradigm, achieved by electric shock with reminders, were tested for freezing time in each reminder. Corticosterone levels were also measured. The EE mice showed decreased anxiety-like behaviour and higher activity compared to standard mice, as revealed by a greater percentage of time spent in the open arms of the elevated plus maze, and a higher rate of climbing the staircase. A shorter freezing time in the stress paradigm and no corticosterone level reactivity were measured in EE mice. In addition, NK cell activity in spleens of EE mice was higher than that demonstrated in those of standard mice. Thus, EE has a beneficial effect on anxiety-like behaviour, stress response and NK cell activity. The effect on NK cell activity is promising, due to the role of NK cells in host resistance.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Environmental enrichment reduces anxiety and promotes positive affective states in rodents.
“Environmental enrichment has previously been shown to reduce anxiety and promote positive affective states in rodents [10–12], making it a suitable paradigm to study long-term positive olfactory memory.”
From Positive early-life olfactory memory is rooted in the olfactory bulb and triggers large-scale changes beyond the olfactory system (2026) · cites this paper as [11]
An enriched playful environment enhances animal well-being.
“an enriched playful environment, which is reported to enhance animal well-being [10–12].”
From Positive early-life olfactory memory is rooted in the olfactory bulb and triggers large-scale changes beyond the olfactory system (2026) · cites this paper as [11]
Cites
Neural consequences of enviromental enrichment
van Praag, H., Kempermann, G., & Gage, F. H. (2000) · Nature Reviews Neuroscience · doi:10.1038/35044558 · Cited by 2,468 · see citing works
Estimates of the worldwide incidence of 25 major cancers in 1990
Parkin, D. M., Pisani, P., & Ferlay, J. (1999) · International Journal of Cancer · doi:10.1002/(sici)1097-0215(19990315)80:6 · Cited by 2,013 · see citing works
Exercise and the immune system: regulation, integration, and adaptation
Pedersen, B. K., & Hoffman-Goetz, L. (2000) · Physiological Reviews · doi:10.1152/physrev.2000.80.3.1055 · Cited by 1,710 · see citing works
A review of the validity and variability of the Elevated Plus-Maze as an animal model of anxiety
Hogg, S. (1996) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(95)02126-4 · Cited by 1,169 · see citing works
Improving housing conditions for laboratory mice: a review of 'environmental enrichment'
Olsson, I. A. S., & DAHLBORN, K. (2002) · Laboratory Animals · doi:10.1258/002367702320162379 · Cited by 395 · see citing works
Social grouping cannot account for cerebral effects of enriched environments
Rosenzweig, M. R., Bennett, E. L., Hébert, M., & Morimoto, H. (1978) · Brain Research · doi:10.1016/0006-8993(78)90340-2 · Cited by 383 · see citing works
Shakhar, G., & Ben‐Eliyahu, S. (1998) · PubMed · Cited by 253 · see citing works
Marashi, V., Barnekow, A., Ossendorf, E., & Sachser, N. (2003) · Hormones and Behavior · doi:10.1016/s0018-506x(03)00002-3 · Cited by 250 · see citing works
Shakhar, G., & Ben‐Eliyahu, S. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.160.7.3251 · Cited by 231 · see citing works
Psychological stress and environmental adaptation in enriched vs. impoverished housed rats
Larsson, F., Winblad, B. G., & Mohammed, A. H. S. (2002) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(02)00782-7 · Cited by 205 · see citing works
Rearing environmental enrichment in two inbred strains of mice: 1. Effects on emotional reactivity
Chapillon, P., Manneché, C., Belzung, C., & Caston, J. (1999) · Behavior Genetics · doi:10.1023/a:1021437905913 · Cited by 202 · see citing works
Pynoos, R. S., Ritzmann, R. F., Steinberg, A. M., Goenjian, A. K., & Prisecaru, I. (1996) · Biological Psychiatry · doi:10.1016/0006-3223(95)00088-7 · Cited by 200 · see citing works
Simiand, J., Keane, P. E., & Morre, M. (1984) · Psychopharmacology · doi:10.1007/bf00432023 · Cited by 190 · see citing works
Stress, opioid peptides, the immune system, and cancer
Shavit, Y., Terman, G. W., Martin, F. C., Lewis, J. W., Liebeskind, J. C., & Gale, R. (1985) · The Journal of Immunology · doi:10.4049/jimmunol.135.2.834 · Cited by 188 · see citing works
Environmental enrichment in BALB/c mice
Roy, V., Belzung, C., Delarue, C., & Chapillon, P. (2001) · Physiology & Behavior · doi:10.1016/s0031-9384(01)00561-3 · Cited by 187 · see citing works
Early-life handling stimulation and environmental enrichment
Fernández-Teruel, A., Giménez-Llort, L., Escorihuela, R. M., Gil, L., Aguilar, R., Steimer, T., & Tobeña, A. (2002) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(02)00787-6 · Cited by 171 · see citing works
On the development of psychoneuroimmunology
Ader, R. (2000) · European Journal of Pharmacology · doi:10.1016/s0014-2999(00)00550-1 · Cited by 156 · see citing works
Strain specific behavioural response to environmental enrichment in the mouse.
de Weerd, H. A. V., Baumans, V., Koolhaas, J. M., & van Zutphen, L. F. M. (1994) · PubMed · Cited by 134 · see citing works
Evaluation of an Anxiety-Related Phenotype in Galanin Overexpressing Transgenic Mice
Holmes, A., Yang, R. J., & Crawley, J. N. (2002) · Journal of Molecular Neuroscience · doi:10.1385/jmn:18:1-2:151 · Cited by 126 · see citing works
Effects of Age on the Generalization and Incubation of Memory in the F344 RatPreprint
Houston, F. P., Stevenson, G. D., McNaughton, B. L., & Barnes, C. A. (1999) · Learning & Memory · doi:10.1101/lm.6.2.111 · Cited by 104 · see citing works
Tsai, P.-Y., Pachowsky, U., Stelzer, H. D., et al. (2002) · Laboratory Animals · doi:10.1258/002367702320389071 · Cited by 103 · see citing works
Cohen, H., Benjamin, J., Kaplan, Z., et al. (2000) · European Neuropsychopharmacology · doi:10.1016/s0924-977x(00)00105-x · Cited by 100 · see citing works
Environmental Enrichment, Immunocompetence, and Resistance to Babesia microti in Male Mice
Barnard, C. J., Behnke, J. M., & SEWELL, J. (1996) · Physiology & Behavior · doi:10.1016/s0031-9384(96)00174-6 · Cited by 100 · see citing works
Chronic exercise enhances in vivo and in vitro cytotoxic mechanisms of natural immunity in mice
Macneil, B. J., & Hoffman‐Goetz, L. (1993) · Journal of Applied Physiology · doi:10.1152/jappl.1993.74.1.388 · Cited by 90 · see citing works
Influence of environmental enrichment and sex on predator stress response in rats
Klein, S. L., Lambert, K. G., Durr, D. P., Schaefer, T., & Waring, R. E. (1994) · Physiology & Behavior · doi:10.1016/0031-9384(94)90197-x · Cited by 84 · see citing works
Repeated Blood Collection in the Laboratory Mouse by Tail Incision—Modification of an Old Technique
DÜRSCHLAG, M., Würbel, H., Stauffacher, M., et al. (1996) · Physiology & Behavior · doi:10.1016/s0031-9384(96)00307-1 · Cited by 82 · see citing works
Kingston, S. G., & Hoffman‐Goetz, L. (1996) · Physiology & Behavior · doi:10.1016/0031-9384(95)02241-4 · Cited by 55 · see citing works
Handling, genetic and housing effects on the mouse stress system, dopamine function, and behavior
Gariépy, J., Rodriguiz, R. M., & Jones, B. C. (2002) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(02)00789-x · Cited by 54 · see citing works
Katzav, A., Kloog, Y., Korczyn, A. D., et al. (2001) · Clinical & Experimental Immunology · doi:10.1046/j.1365-2249.2001.01674.x · Cited by 47 · see citing works
Lu, Z., Song, C., Ravindran, A. V., Merali, Z., & Anisman, H. (1998) · Brain Behavior and Immunity · doi:10.1006/brbi.1997.0510 · Cited by 42 · see citing works
Exercise Immunology: Neuroendocrine Regulation of NK-Cells
Jonsdottir, I. H. (2000) · International Journal of Sports Medicine · doi:10.1055/s-2000-1447 · Cited by 39 · see citing works
Environmental manipulations in rodents and primates
Pryce, C. R., Mohammed, A. K., & Feldon, J. (2002) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(02)00861-4 · Cited by 28 · see citing works
Schapiro, S. J., Nehete, P. N., Perlman, J. E., et al. (1998) · Applied Animal Behaviour Science · doi:10.1016/s0168-1591(97)00087-7 · Cited by 26 · see citing works
Stressor-induced alterations of natural killer cell activity and central catecholamines in mice
Zalcman, S., Irwin, J., & Anisman, H. (1991) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(91)90192-5 · Cited by 17 · see citing works
Weizman, R., Paz, L., Peter, Y., et al. (2001) · Brain Research · doi:10.1016/s0006-8993(01)02331-9 · Cited by 15 · see citing works
Effect of diazepam on the immune response of rats exposed to acute and chronic swim stress
Salman, H., Bergman, M., Weizman, A., et al. (2000) · Biomedicine & Pharmacotherapy · doi:10.1016/s0753-3322(00)80053-0 · Cited by 13 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Enriched environments, experience-dependent plasticity and disorders of the nervous system
Nithianantharajah, J., & Hannan, A. J. (2006) · Nature Reviews Neuroscience · doi:10.1038/nrn1970 · Cited by 1,771 · see citing works
Early behavioral intervention, brain plasticity, and the prevention of autism spectrum disorder
Dawson, G. (2008) · Development and Psychopathology · doi:10.1017/s0954579408000370 · Cited by 1,138 · see citing works
Mirescu, C., & Gould, E. (2006) · Hippocampus · doi:10.1002/hipo.20155 · Cited by 701 · see citing works
From mRNP trafficking to spine dysmorphogenesis: the roots of fragile X syndrome
Bagni, C., & Greenough, W. T. (2005) · Nature Reviews Neuroscience · doi:10.1038/nrn1667 · Cited by 475 · see citing works
Environment and Brain Plasticity: Towards an Endogenous Pharmacotherapy
Sale, A., Berardi, N., & Maffei, L. (2014) · Physiological Reviews · doi:10.1152/physrev.00036.2012 · Cited by 402 · see citing works
Restivo, L., Ferrari, F., Passino, E., Sgobio, C., Bock, J., Oostra, B. A., Bagni, C., & Ammassari-Teule, M. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0504984102 · Cited by 299 · see citing works
Cellular and molecular mechanisms of immunomodulation in the brain through environmental enrichment
Singhal, G., Jaehne, E. J., Corrigan, F., & Baune, B. T. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00097 · Cited by 186 · see citing works
Environmental enrichment and the sensory brain: The role of enrichment in remediating brain injury
Alwis, D. S., & Rajan, R. (2014) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2014.00156 · Cited by 129 · see citing works
Enriched environment reduces glioma growth through immune and non-immune mechanisms in mice
Garofalo, S., D’Alessandro, G., Chece, G., Brau, F., Maggi, L., Rosa, A., Porzia, A., Mainiero, F., Esposito, V., Lauro, C., et al. (2015) · Nature Communications · doi:10.1038/ncomms7623 · Cited by 129 · see citing works
Environmental enrichment decreases the rewarding but not the activating effects of heroin
El Rawas, R., Thiriet, N., Lardeux, V., Jaber, M., & Solinas, M. (2009) · Psychopharmacology · doi:10.1007/s00213-008-1402-6 · Cited by 121 · see citing works
Effects of cage enrichment on behavior, welfare and outcome variability in female mice
Bailoo, J. D., Murphy, E., Boada-Saña, M., Varholick, J. A., Hintze, S., Baussière, C., Hahn, K. C., Göpfert, C., Palme, R., Voelkl, B., et al. (2018) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2018.00232 · Cited by 120 · see citing works
Individual differences in temperament and behavioral management practices for nonhuman primates
Coleman, K. (2012) · Applied Animal Behaviour Science · doi:10.1016/j.applanim.2011.08.002 · Cited by 94 · see citing works
Harati, H., Barbelivien, A., Herbeaux, K., Muller, M.-A., Engeln, M., Kelche, C., Cassel, J.-C., & Majchrzak, M. (2013) · AGE · doi:10.1007/s11357-012-9424-8 · Cited by 58 · see citing works
Coping with Stress During Aging: The Importance of a Resilient Brain
Sampedro-Piquero, P., Alvarez-Suarez, P., & Begega, A. (2018) · Current Neuropharmacology · doi:10.2174/1570159x15666170915141610 · Cited by 41 · see citing works
Sotnikov, S. V., Markt, P. O., Malik, V, Chekmareva, N. Y., Naik, R. R., Sah, A., Singewald, N., Holsboer, F., Czibere, L., & Landgraf, R. (2014) · Translational Psychiatry · doi:10.1038/tp.2013.127 · Cited by 49 · see citing works
Vedovelli, K., Silveira, E., Velho, E., Stertz, L., Kapczinski, F., Schröder, N., & Bromberg, E. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.08.012 · Cited by 26 · see citing works
Tang, Y.-F., Duan, Y.-J., Ge, R.-D., Lu, X., Gao, B.-Y., Guo, J.-W., & Jiang, S. (2022) · Journal of Integrative Neuroscience · doi:10.31083/j.jin2201005 · Cited by 5 · see citing works
Dejou, J., Athanassi, A., Brunel, T., Thevenet, M., Didier, A., & Mandairon, N. (2026) · PLOS Biology · doi:10.1371/journal.pbio.3003845 · Cited by 1 · see citing works
- Authors
- Benaroya‐Milshtein, N., Hollander, N., Apter, A., Kukulansky, T., Raz, N., Wilf, A., Yaniv, I., & Pick, C. G.
- Affiliations
- Tel Aviv University (IL)
- ORCID
- Venue
- European Journal of Neuroscience
- Publisher
- Wiley
- Published
- 2004-09
- Volume
- 20
- Issue
- 5
- Pages
- 1341-1347
- ISSN
- 0953-816X (ISSN-L)
- 1460-9568
- OpenAlex
- W1998578651
- Cited by
- 439
- References
- 36
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 21 · 2023: 20 · 2022: 20 · 2021: 22 · 2020: 29 · 2019: 22 · 2018: 30 · 2017: 21 · 2016: 19 · 2015: 16 · 2014: 25 · 2013: 28 · 2012: 26
- FWCI
- 5.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Tel Aviv University
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Veterinary › Small Animals › Animal Behavior and Welfare Studies
- Health Sciences › Medicine › Psychiatry and Mental health › Cancer, Stress, Anesthesia, and Immune Response
- Keywords
- environmental enrichment, anxiety-like behavior, stress response, natural killer cells, corticosterone, immune function, C3H mice, electric shock stress, elevated plus maze, host resistance
- MeSH terms
- Animals, Anxiety, Behavior, Animal, Corticosterone, Cytotoxicity, Immunologic, Environment, Killer Cells, Natural, Male, Mice, Inbred C3H, Stress, Psychological, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review