Amanda C. Kentner

Anthony J. Hannan

Kelly G. Lambert

S. Tifffany Donaldson

Frontiers in Behavioral Neuroscience

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EDITORIALpublished: 16 April 2019doi: 10.3389/fnbeh.2019.00075Frontiers in Behavioral Neuroscience | www.frontiersin.org 1 April 2019 | Volume 13 | Article 75Edited and reviewed by:Nuno Sousa,University of Minho, Portugal*Correspondence:Amanda C. Kentneramanda.kentner@mcphs.eduS. Tifffany Donaldsontiffany.donaldson@umb.edu†These authors have contributedequally to this workReceived: 22 March 2019Accepted: 27 March 2019Published: 16 April 2019Citation:Kentner AC, Lambert KG, Hannan AJand Donaldson ST (2019) Editorial:Environmental Enrichment: EnhancingNeural Plasticity, Resilience, andRepair. Front. Behav. Neurosci. 13:75.doi: 10.3389/fnbeh.2019.00075Editorial: Environmental Enrichment:Enhancing Neural Plasticity,Resilience, and RepairAmanda C. Kentner 1*†, Kelly G. Lambert 2, Anthony J. Hannan 3,4 andS. Tifffany Donaldson 5*†1 School of Arts & Sciences, Health Psychology Program, Massachusetts College of Pharmacy and Health Sciences, Boston,MA, United States, 2Department of Psychology, University of Richmond, Richmond, VA, United States, 3Melbourne BrainCentre, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia, 4Department ofAnatomy and Neuroscience, University of Melbourne, Parkville, VIC, Australia, 5Developmental and Brain Sciences,Department of Psychology, University of Massachusetts Boston, Boston, MA, United StatesKeywords: environmental enrichment (EE), neuroprotection, rehabilitation, standardization, reproducibility, animalwelfare, translationalEditorial on the Research TopicEnvironmental Enrichment: Enhancing Neural Plasticity, Resilience, and RepairINTRODUCTIONUp until themiddle of the twentieth century, neuroscience dogma emphasized the fixed, immutablenature of the brain. In the 1960s, however, in what was arguably one of the most revolutionaryresearch programs in neuroscience, a team of researchers at UC Berkeley generated data revealingthe dynamic characteristics of mature neural systems.Working with Edward Bennett, David Krech,and Mark Rosenzweig, Marian Diamond (1926-2017) documented the neuroanatomical changesin rats exposed to enriched environments—findings that threatened prior notions of brains being“fixed in stone” (Bennett et al., 1964). In an interview (with KL) several years ago, Diamonddescribed her experience presenting these unexpected results for the first time at a professionalconference. After delivering her talk, she heard an audience member shout, “young lady, that braincannot change!”Although Diamond confirmed that she had replicated the findings, perceptions about thechanging nature of the brain were initially met with resistance and skepticism (personalcommunication, October, 2009). Not to be dissuaded, Diamond continued her neuroanatomicalexplorations, verifying that rats exposed to novel and complex environments experienced equallycomplex neural changes, especially in the cerebral cortex. Although hints of neural plasticity hadbeen introduced by individuals such as Charles Darwin and Donald Hebb prior to Diamond’sresearch, she has been credited for providing tangible evidence of neuroplasticity. One of hercolleagues at the University of California at Berkeley, George Brooks, wrote in her obituary, “Dr.Diamond showed anatomically, for the first time, what we now call plasticity of the brain” (Sanders,2017). She was also remembered as the neuroscientist who gave a newmeaning to the idea of “use itor lose it,” as she shattered previous notions of a static unchangeable brain that simply degeneratedthroughout life (Smith, 2017). Through her pioneering work with enriched environments, MarianDiamond most certainly enriched the field of neuroscience, as the notion of neuroplasticity hasbecome a corner stone of contemporary neuroscience. Moreover, her research has inspired manyother important investigations into the translational nature of environmental enrichment.Kentner et al. Enhancing Neural Plasticity, Resilience, and RepairDedicated to Dr. Diamond, the current ResearchTopic focuses on environmental enrichment in terms ofneuroprotection/rehabilitation and the use of this system in thelaboratory to promote species-typical behavior and generalizable,rigorous investigation into the effects of experience on behaviorand physiology.STANDARDIZATION ANDENVIRONMENTAL ENRICHMENTConcerns that environmental enrichment may increasevariability in experimental endpoints, affecting reproducibility,have impeded the expansion of its use in research. Data describedby Bailoo et al. demonstrate that this may be an unfoundedassumption. The coefficient of variation across housingconditions did not differ on measures of behavior, growth, orstress physiology. Additionally, the more enrichment provided,the more engagement mice had with their environment.Similarly, Neal et al. report that enhanced social environmentsfacilitate affiliative behaviors and appear to promote problemsolving behaviors. Together, this underscores the importance ofenrichment for healthy species-typical behaviors.PHYSIOLOGICAL ANDNEUROBEHAVIORAL EFFECTS OFENVIRONMENTAL ENRICHMENTMorano et al. demonstrated that removing female rats fromenvironmental enrichment mimics an experience of “loss,”leading to increased passive coping behavior, hyperphagia,and evidence of HPA axis dysregulation. These behavioraland physiological changes are associated with an array ofpsychiatric disease states, suggestive of the utility of this modelfor understanding loss-related dysfunctions. In contrast, Cutuliet al. review the effects of enrichment exposure across criticalperiods of development, particularly on parental care andoffspring outcomes. Moreover, they provide a specific emphasison the importance of pre-reproductive vs. post-reproductiveexperiences and transgenerational effects, highlighting some oftheir own research findings.While environmental enrichment can be stressful tosome male animals, McQuaid et al. show that post-weaningenrichment increases demonstrations of social behavior, bufferedcorticosterone, and central cytokine levels, and elevated brain-derived neurotrophic factor in the prefrontal cortex of malemice, following stressor exposure in adulthood.ENVIRONMENTAL ENRICHMENTAND CLINICAL/NEUROPROTECTIONEnvironmental enrichment has been demonstrated to inducetherapeutic effects in a wide range of preclinical modelsof neurological and psychiatric disorders. Various articlesin this Research Topic have addressed this importantissue, providing new insights into molecular and cellularmechanisms of experience-dependent plasticity, andidentifying novel candidate targets for enviromimetics(Nithianantharajah and Hannan, 2006).The first demonstration that EE can be beneficial in agenetic model of a human disorder utilized a transgenic mousemodel of Huntington’s disease (Van Dellen et al., 2000). Zajacet al. have now demonstrated that one of the molecular effectsof EE, even when delivered for a relatively short period (2weeks), is transcriptional modulation of components of theserotonergic system. Furthermore, these investigators comparedEE with an exercise (voluntary wheel running) interventionand found key differences between these two environmentalinterventions, as well as interesting region-specific and sexuallydimorphic effects on gene expression. Finally, they were ableto demonstrate functional consequences of the EE effect, viabehavioral pharmacology.The effects of EE on a different mouse model, withhaploinsufficiency in the brain-derived neurotrophic factor(BDNF) gene, were described by Grech et al. The authorsuse a model in which they combine the two negativefactors (heterozygosity for the BDNF null allele and chronicadministration of the stress hormone corticosterone) to createa “two hit model” of relevance to specific neurodevelopmentaland psychiatric disorders. Interestingly, these authors also foundsexually dimorphic effects of EE, and were able to correlatetheir behavioral data with expression levels of the neurotrophinreceptor TrkB (and its signaling, via quantification of phospho-TrkB) and specific NMDA receptor subunits, reinforcing theevidence for a role of neurotrophic and glutamatergic signalingin mediating the therapeutic effects of EE.Another key aspect of EE, which has been often overlooked,is enrichment of the nest conditions in rodent models. Masonet al. have addressed this via a form of nesting enrichment called“closed nest boxes.” This form of nesting enrichment was shownto induce beneficial effects in a model of neonatal hypoxia-ischemia. Interestingly, molecular correlates included BDNFand glial-derived neurotrophic factor (GDNF), and sexuallydimorphic effects were observed, which has become a recurringtheme in EE studies.Finally, the combination of EE with other therapeuticapproaches is an area that has been under-explored andhas substantial translational potential. Bhaskar et al. havecombined EE with deep-brain stimulation (DBS) and foundthat the combination increased anxiolytic effects relative to thesame DBS intervention performed in standard-housed animals.Combining EE with other interventions, both pharmacological(e.g., enviromimetics; Nithianantharajah and Hannan, 2006)and non-pharmacological (in this case a model of medicaldevice), could reveal additive and synergistic effects that greatlyenhance therapeutic efficacy in a wide range of neurological andpsychiatric disorders.ENVIRONMENTAL ENRICHMENTAND AGINGEnvironmental enrichment may help protect against the effectsof cognitive decline. As discussed in Leon and Woo, stimulationFrontiers in Behavioral Neuroscience | www.frontiersin.org 2 April 2019 | Volume 13 | Article 75Kentner et al. Enhancing Neural Plasticity, Resilience, and Repairoffered through sensory enhancement may also offset the effectsof aging on not only the brain, but on multiple body systemssignificantly impacted by time.Rapley et al. measured C-type Natriuretic Peptide (CNP)to determine its expression across normal aging and itsinteraction with the environment. Enrichment housingtransiently increased CNP availability in young, but not olderrats. This may be suggestive of age-related losses in sensitivity toenvironmental stimulation.TRANSLATIONThe benefits of environmental enrichment are reported inpreclinical settings with little focus on translation. McDonaldet al. describe many obstacles to application of environmentalenrichment paradigms to patients experiencing stroke. The workhighlights the variation between animal and clinical models ofenrichment, suggesting that greater alignment is required toimprove translation.FUTURE DIRECTIONSThe potential for the environment to influence behavior hasa long history, and subsequent work implicating correlativebrain changes were pioneered by Dr. Marian Diamond. Thecontributions to this Research Topic offer findings regardingenrichment promoting healthy species-typical behavior in thelab and reversing insult. It is the hope of the editors that thisevidence will support wider adoption of enrichment in normalhousing protocols.Moreover, it is important to devote attention to the aspectsof enrichment in preclinical settings that promote plasticity, toenable the recreation of these components in clinical settings.As McDonald et al. intimate, this may very well present anopportunity to translate successful interventions to clinicalpopulations. Additional work that advances understanding ofthe mechanisms underlying the benefits of enrichment inhealthy and injured/adverse populations is also warranted(Kentner et al., 2019).We also hope that further work is accomplished thatdelineates when and how long enrichment is needed foractivating benefits and promoting plasticity across the lifespan.Since many disease states show gender disparities, anotherline of inquiry should include a focus on biological sexdifferences in enrichment paradigms. Enrichment showsdistinct sex-specific benefits following early insult (Grechet al.; Mason et al). Few researchers are attending to theintergenerational benefits of enrichment (Cutuli et al.) andvariation across the age axis, so continued efforts in these areasare also necessary.After more than six decades of work on environmentalenrichment, we applaud the advances in understanding relevantbiological parameters and key mechanisms, and emphasize itspotential for adaptation to clinical populations, across a broadspectrum of neurological and psychiatric disorders.AUTHOR CONTRIBUTIONSAll authors contributed to the writing of the editorial. AK andSD facilitated the concept, design, and overall development ofthe manuscript.FUNDINGAK receives funding from the National Institute of MentalHealth under Award Number Rl5MH114035. KL is supportedby the University of Richmond Psychology Department. AHis an NHMRC Principal Research Fellow and is supported byNHMRC Project Grants and ARC Discovery Project Grants.ST was supported by Award Number P20MD002290 from theNational Institute on Minority Health and Health Disparities(Celia Moore, Ph.D., P.I.). The content is solely the responsibilityof the authors and does not necessarily represent the official viesof any of the financial supporters.REFERENCESBennett, E. L., Diamond, M. C., Krech, D., and Rosenzweig, M. R. (1964).Chemical and anatomical plasticity of the brain. Science 146, 610–619.doi: 10.1126/science.146.3644.610Kentner, A. C., Cryan, J. F., and Brummelte, S. (2019). Resilience Priming:translational models for understanding resiliency and adaptation toearly-life adversity. Dev. Psychobiol. 61, 350–375. doi: 10.1002/dev.21775Nithianantharajah, J., and Hannan, A. J. (2006). Enriched environments,experiencedependent plasticity and disorders of the nervoussystem. Nat. Rev. Neurosci. 206, 697–709. doi: 10.1038/nrn1970Sanders, R. (2017, July 28). Marion Diamond, known for studies of Einstein’s brain,dies at 90. Berkeley News. Available online at: https://news.berkeley.edu/2017/07/28/marian-diamond-known-for-studies-of-einsteins-brain-dies-at-90/Smith, H. (2017, July 30). Marian Diamond, neuroscientist who gave newmeaningto “use it or lose it.” The Washington Post. Available online at: https://www.washingtonpost.com/local/obituaries/marian-diamond-neuroscientist-who-gave-new-meaning-to-use-it-or-lose-it-dies-at-90/2017/07/30/ff10060c-752a-11e7-8f39-eeb7d3a2d304_story.html?utm_term=.7f0bf2df4a38Van Dellen, A., Blackmore, C., Deacon, R., York, D., and Hannan, A. J.(2000). Delaying the onset of Huntington’s in mice. Nature 404, 721–722.doi: 10.1038/35008142Conflict of Interest Statement: The authors declare that the research wasconducted in the absence of any commercial or financial relationships that couldbe construed as a potential conflict of interest.Copyright © 2019 Kentner, Lambert, Hannan and Donaldson. This is an open-accessarticle distributed under the terms of the Creative Commons Attribution License (CCBY). The use, distribution or reproduction in other forums is permitted, providedthe original author(s) and the copyright owner(s) are credited and that the originalpublication in this journal is cited, in accordance with accepted academic practice.No use, distribution or reproduction is permitted which does not comply with theseterms.Frontiers in Behavioral Neuroscience | www.frontiersin.org 3 April 2019 | Volume 13 | Article 75

Editorial: Environmental Enrichment: Enhancing Neural Plasticity, Resilience, and Repair

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Editorial: Environmental Enrichment: Enhancing Neural Plasticity, Resilience, and Repair

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