Environmental Enrichment Restores Memory Functioning in Mice with Impaired IL-1 Signaling via Reinstatement of Long-Term Potentiation and Spine Size Enlargement
Open accessAbstract
Environmental enrichment (EE) was found to facilitate memory functioning and neural plasticity in normal and neurologically impaired animals. However, the ability of this manipulation to rescue memory and its biological substrate in animals with specific genetically based deficits in these functions has not been extensively studied. In the present study, we investigated the effects of EE in two mouse models of impaired memory functioning and plasticity. Previous research demonstrated that mice with a deletion of the receptor for the cytokine interleukin-1 (IL-1rKO), and mice with CNS-specific transgenic over-expression of the IL-1 receptor antagonist (IL-1raTG) display impaired hippocampal memory and long-term potentiation (LTP). We report here a corrective effect of EE on spatial and contextual memory in IL-1rKO and IL-1raTG mice and reveal two mechanisms for this beneficial effect: Concomitantly with their disturbed memory functioning, LTP in IL-1rKO mice that were raised in a regular environment is impaired, and their dendritic spine size is reduced. Both of these impairments were corrected by environmental enrichment. No deficiencies in neurogenesis or hippocampal BDNF and vascular endothelial growth factor secretion were found in IL-1rKO mice that were raised in a regular environment, and both of these variables were increased to a similar degree in enriched IL-1rKO and wild-type mice. These findings suggest that exposure to an enriched environment may be beneficial for individuals with impaired learning and memory related to genetic impairments of IL-1 signaling (and possibly other genetic causes), by reversing impairments in dentate gyrus LTP and spine size and by promoting neurogenesis and trophic factors secretion.
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When administered to naive animals, IL-1β is sufficient to induce depressive-like behaviors.
“when administered to naive animals, IL-1β is sufficient to induce depressive-like behaviors (Goshen et al, 2009).”
From Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders (2017) · cites this paper as Goshen et al, 2009
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“The findings that environmental enrichment restored LTP in IL-1rKO mice, and strengthened LTP in their WT controls, are consistent with previous reports on the beneficial effects of environmental enrichment on hippocampal LTP in normal animals (Duffy et al., 2001; Huang et al., 2006; Li et al., 2006), even 3–5 weeks a…”
ResultThe Role of Pro-inflammatory Cytokines in Memory Processes and Neural Plasticity
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“Furthermore, mice lacking IL-1β receptor had reduced dendritic spine size (Goshen et al., 2009) and IL-6 over-expression in cerebellar granule cells caused impairments in granule cell adhesion, migration, and increased formation of excitatory synapses on granule cells (Wei et al., 2011).”
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“Interestingly, it has been recently reported that mice lacking type 1 receptor for interleukin 1 (IL-1) display impaired hippocampal memory and LTP that are restored by EE (Goshen et al., 2009).”
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“NMDARs and BDNF both appear to be necessary for synaptic competition during neuronal network development, for increases in dendritic spine number driven by environmental enrichment [148, 149], and for induction of some forms of LTP [150, 151].”
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“Both experiments were conducted using a random protocol, in which the entrance point to the maze was varied randomly between trials, and the platform remained in a permanent position (see Avital et al., 2003; Goshen et al., 2009 for additional details).”
BackgroundMethodResultInfluentialSelf-citationNeuroinflammatory changes negatively impact on LTP: A focus on IL-1β
Lynch, M. A. (2015) · Brain Research · doi:10.1016/j.brainres.2014.08.040 · Cited by 115 · see citing works
“Neither BDNF expression nor neurogenesis were affected in IL-1R1 knock out mice but the authors suggested that environmental enrichment induced its effect because it increased dendritic spine size (Goshen et al., 2009).”
Reduced hippocampus volume in the mouse model of Posttraumatic Stress Disorder
Golub, Y., Kaltwasser, S. F., Mauch, C. P., Herrmann, L., Schmidt, U., Holsboer, F., Czisch, M., & Wotjak, C. T. (2010) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2010.10.014 · Cited by 117 · see citing works
Central and Peripheral Cytokines Mediate Immune-Brain Connectivity
Besedovsky, H. O., & del Rey, A. (2010) · Neurochemical Research · doi:10.1007/s11064-010-0252-x · Cited by 111 · see citing works
“The same authors have recently reported that enrichment can reverse the alterations in LTP and memory in mice with defective IL-1 signalling, indicating that genetically manipulated animals develop mechanisms that compensate to a certain extent the absence of effects of this cytokine [ 23 ].”
BackgroundResultDelpech, J.-C., Thomazeau, A., Madore, C., Bosch‐Bouju, C., Larrieu, T., Lacabanne, C., Rémus-Borel, J., Aubert, A., Joffre, C., Nadjar, A., et al. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2015.127 · Cited by 104 · see citing works
“…the hippocampal inflammatory state and cognitive functions, whereby a small increase in the inflammatory state is beneficial, whereas a larger increase is detrimental to behavioral and neuronal plasticity (Goshen et al, 2007; Goshen et al, 2009; Yirmiya and Goshen, 2011; Reshef et al, 2014).”
Nithianantharajah, J., & Hannan, A. J. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2012.05.043 · Cited by 91 · see citing works
“In particular, a number of studies have found that EE and wheel running in mice and rats change expression levels of various growth factors, including BDNF (Torasdotter et al., 1998; Ickes et al., 2000; Smith and Zigmond, 2003; Zhu et al., 2006; Goshen et al., 2009; O’Callaghan et al., 2009).”
Reshef, R., Kreisel, T., Kay, D. B., & Yirmiya, R. (2014) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2014.04.009 · Cited by 82 · see citing works
“A video camera above the pool was connected to a computerized video tracking system (Noldus Ethovision SE, The Netherlands), which automatically monitored the latency to reach the platform in each training trial and the location of the mice in the probe trial (see (Avital et al., 2003; Goshen et al., 2009) for details…”
Self-citationBen-Menachem-Zidon, O., Ben-Menahem, Y., Ben-Hur, T., & Yirmiya, R. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2013.208 · Cited by 78 · see citing works
“…tracking system (VP118 tracking system, HVS Image, Hampton, England), which monitored the latency to reach the platform in each training trial and the crossings over the platform in the probe trial (refre to studies by Avital et al (2003) and Goshen et al (2009a) for additional details).”
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Birch, A. M., & Kelly, Á. M. (2018) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.03.042 · Cited by 64 · see citing works
Ramírez-Rodríguez, G. B., Ocaña-Fernández, M. D. Á., Vega‐Rivera, N. M., Torres-Pérez, O. M., Gómez‐Sánchez, A., Estrada-Camarena, E. M., & Ortiz-López, L. I. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.12.026 · Cited by 62 · see citing works
Endogenous IL-1 in Cognitive Function and Anxiety: A Study in IL-1RI−/− Mice
Murray, C., Obiang, P., Bannerman, D. M., & Cunningham, C. M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0078385 · Cited by 57 · see citing works
“Thus a 129/Sv X C57BL/6 cross was used as the control strain for their initial and subsequent studies [3,7,8,11].”
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Werner, J. K., & Stevens, R. D. (2015) · Current Opinion in Neurology · doi:10.1097/wco.0000000000000265 · Cited by 55 · see citing works
Long-term environmental enrichment affects microglial morphology in middle age mice
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“In addition, EE increases dendritic branching and length, the number of spines, and the size of synapses (Connor et al., 1982; Faherty et al., 2003; Goshen et al., 2009; Greenough et al., 1973; Greenough and Volkmar, 1973; Rampon et al., 2000).”
Synapse formation in adult barrel cortex following naturalistic environmental enrichment
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“Moreover, both of the KO mouse model for the IL-1R and the transgenic mouse overexpressing the IL1-Receptor antagonist (IL-1Ra) in the central nervous system have deficit in theta-burst induced LTP in the CA1 area of the hippocampus as well as impairments in spatial memory.(14,15) Interestingly, preliminary data of be…”
BackgroundExploring the effect of inducing long-term potentiation in the human motor cortex on motor learning
Rajji, T. K., Liu, S.-K., Frantseva, M. V., Mulsant, B. H., Thoma, J., Chen, R. E., Fitzgerald, P. B., & Daskalakis, Z. J. (2010) · Brain stimulation · doi:10.1016/j.brs.2010.09.007 · Cited by 40 · see citing works
Preventive effects of an enriched environment on rodent psychiatric disorder models.
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The role of cognitive activity in cognition protection: from Bedside to Bench
Li, B., Wang, Y., Tang, H., & Chen, S. (2017) · Translational Neurodegeneration · doi:10.1186/s40035-017-0078-4 · Cited by 32 · see citing works
“Numbers of studies have shown that EE in animals increased the expression levels of brainderived neurotrophic factor (BDNF), nerve growth factor (NGF) and vascular endothelial growth factor (VEGF) [182].”
BackgroundChohan, T. W., Boucher, A. A., Spencer, J. R., Kassem, M. S., Hamdi, A. A., Karl, T., Fok, S., Bennett, M. R., & Arnold, J. C. (2014) · Schizophrenia Bulletin · doi:10.1093/schbul/sbt193 · Cited by 31 · see citing works
MicroRNA Therapeutics in Neurological Disease
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“Neuro-inflammation processes notably contribute to anxiety-related [33] and neurodegenerative syndromes (reviewed in [29]).”
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“While effects of EE have been investigated in a number of models of behavioral or learning dysfunction and most report positive effects of enrichment on dendrite or spine measures (Turner et al. 2003; Parsley et al. 2007; Fréchette et al. 2009; Goshen et al. 2009; Zhu et al. 2009), others do not (Dierssen et al.”
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Hsp72, inflammation, and aging: causes, consequences, and perspectives
Ortega, E., Bote, E., Besedovsky, H. O., & del Rey, A. (2012) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2012.06619.x · Cited by 26 · see citing works
Rademacher, T.-D., Meuth, S. G., Wiendl, H., Johnen, A., & Landmeyer, N. C. (2023) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2023.105035 · Cited by 26 · see citing works
Motor System Development of the Preterm and Low Birthweight Infant
Pitcher, J. B., Schneider, L. A., Drysdale, J. L., Ridding, M. C., & Owens, J. A. (2011) · Clinics in Perinatology · doi:10.1016/j.clp.2011.08.010 · Cited by 25 · see citing works
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Ortíz‐López, L., Gonzalez-Olvera, J. J., Vega‐Rivera, N. M., García‐Anaya, M., Carapia-Hernández, A. K., Velázquez-Escobar, J. C., & Ramírez-Rodríguez, G. B. (2017) · Neuroscience · doi:10.1016/j.neuroscience.2017.04.047 · Cited by 22 · see citing works
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Tip60 HAT Action Mediates Environmental Enrichment Induced Cognitive Restoration
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“At low levels of expression, these cytokines are required for, or may enhance, certain learning and memory processes, including consolidation of newly acquired memories that depend on the integrity of the hippocampus [6–11].”
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“In support of this, several groups have shown that acute increases in IL-1β decrease adult hippocampal neurogenesis and blocking IL-signaling can abrogate this effect (Koo and Duman, 2008; BenMenachem-Zidon et al., 2008; Goshen et al., 2009).”
Towers, A. E., Oelschlager, M. L., Lorenz, M. R., Gainey, S. J., McCusker, R. H., Krauklis, S. A., & Freund, G. G. (2019) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2019.05.025 · Cited by 13 · see citing works
“While IL-1β appears vital to some aspects of memory formation (Cho et al., 2015; Goshen et al., 2009), how stress impacts IL-1β-associated memory is much less clear.”
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Single cell molecular alterations reveal target cells and pathways of conditioned fear memory
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“…2009; Holloway, 1966; Hu et al., 2010), and improving cognitive and motor functions in various behavioral tasks (Cotel, Jawhar, Christensen, Bayer, & Wirths, 2012; Frick & Fernandez, 2003; Goshen et al., 2009). c‐Fos is a proto‐ oncogene that is expressed in some neurons following depolariza‐ tion.”
BackgroundSinghal, G., & Baune, B. T. (2024) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2024.1501377 · Cited by 6 · see citing works
Improved learning in microencephalic rats
Ueda, S., Yoshimoto, K., Kadowaki, T., Hirata, K., & Sakakibara, S. (2009) · Congenital Anomalies · doi:10.1111/j.1741-4520.2009.00265.x · Cited by 6 · see citing works
“Beneficial effects of EE on hippocampus-dependent learning and hippocampal LTP in normal and disease model rodents have recently been reported (Duffy et al. 2001; Huang et al. 2006; Goshen et al. 2009).”
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“Additional processes that may explain the observed positive association between IL-1β polygenic scores and hippocampal volume, are the effects of IL-1β on long term potentiation (LTP; Avital et al., 2003) and dendritic spine size (Goshen et al., 2009).”
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“…the new findings on neuroplasticity, which reveal the mutability of both structural and functional aspects (Bakos et al., 2009; Farina et al., 2009; Goshen et al., 2009; Ilin and Richter-Levin, 2009; Kitanishi et al., 2009; Penn et al., 2009; Veyrac et al., 2009; Workman et al., 2009; Zhu et al.,…”
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Exposure to Environmental Factors rescues spine defects of Eps8 KO mice
Ferrara, S., Zambetti, S., Braida, D., Morini, R., Sala, M., Matteoli, M., & Menna, E. (2019) · Matters · doi:10.19185/matters.201903000024
“Environmental Enrichment has been performed as described with slight modifications [30].”
MethodSaha, P. K., Rowe, R. K., Boison, D., & Shandra, O. O. (2026) · Experimental Neurology · doi:10.1016/j.expneurol.2026.115981
- Authors
- Goshen, I., Avital, A., Kreisel, T., Licht, T., Segal, M., & Yirmiya, R.
- Affiliations
- Hebrew University of Jerusalem (IL)
- The Max Stern Yezreel Valley College (IL)
- Weizmann Institute of Science (IL)
- Corresponding author
- Yirmiya, Raz
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2009-03-18
- Volume
- 29
- Issue
- 11
- Pages
- 3395-3403
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6665266
- OpenAlex
- W2123089095
- Cited by
- 82
- References
- 49
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 2 · 2020: 2 · 2019: 6 · 2018: 6 · 2017: 6 · 2016: 6 · 2015: 6 · 2014: 12 · 2013: 10 · 2012: 5
- FWCI
- 3.72
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Hebrew University of Jerusalem
- Israel Science Foundation
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- environmental enrichment, IL-1 signaling, hippocampal-dependent memory, spatial memory, contextual memory, long-term potentiation, dentate gyrus, neurogenesis, brain-derived neurotrophic factor, vascular endothelial growth factor, neuroplasticity, memory impairment
- MeSH terms
- Animals, Environment, Environmental Exposure, Male, Memory, Memory Disorders, Mice, Inbred CBA, Mice, Inbred C57BL, Mice, Transgenic, Signal Transduction, Receptors, Interleukin-1, Long-Term Potentiation, Mice, Knockout, Maze Learning, Excitatory Postsynaptic Potentials, Dendritic Spines, Mice
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