Enriched Environments, Experience- Dependent Plasticity and Disorders of the Nervous System

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Enriched environments, experience- dependent plasticity and disorders of the nervous system

Jess Nithianantharajah and Anthony J. Hannan Abstract | Behavioural, cellular and molecular studies have revealed significant effects of enriched environments on rodents and other species, and provided new insights into mechanisms of experience-dependent plasticity, including adult neurogenesis and synaptic plasticity. The demonstration that the onset and progression of Huntington’s disease in transgenic mice is delayed by environmental enrichment has emphasized the importance of understanding both genetic and environmental factors in nervous system disorders, including those with Mendelian inheritance patterns. A range of rodent models of other brain disorders, including Alzheimer’s disease and Parkinson’s disease, fragile X and Down syndrome, as well as various forms of brain injury, have now been compared under enriched and standard housing conditions. Here, we review these findings on the environmental modulators of pathogenesis and gene–environment interactions in CNS disorders, and discuss their therapeutic implications.

The mammalian brain is generated by complex genetic During the last decade, enrichment studies using and epigenetic programs that ensure that most cells and transgenic mouse models of Huntington’s disease structural areas are in place by birth. However, sensory, (HD)2–4 and Alzheimer’s disease (AD)5–8 have opened cognitive and motor stimulation through interaction the way for exploring gene–environment interactions in with the environment from birth to old age has a key role neurodegeneration. Impressive effects of environmental in refining the neuronal circuitry required for normal enrichment have also been recently identified in other brain function. Genetic and pharmacological factors brain disorders such as Parkinson’s disease (PD), amyo- that modulate brain function and dysfunction have been trophic lateral sclerosis (ALS), fragile X syndrome, Down explored in detail over recent decades, but environmental syndrome and various forms of brain injury (TABLE 1). parameters have received far less attention. These findings have implications for clinical occupa- Epidemiological investigations of neurological and tional therapies and related approaches. However, these psychiatric disorders, including studies involving mono- environmental manipulations can also provide powerful zygotic twins, have provided important clues as to the rel- tools to dissect cause and effect among molecular and evant contribution of genetic and environmental factors1. cellular correlates of pathogenesis, and so identify novel However, owing to the enormous number of environmen- targets for future development of therapeutics. Although tal variables in human populations, such studies have been the effects of environmental enrichment on the normal limited in their ability to demonstrate the involvement of animal brain have been reviewed previously9, the present specific environmental factors in particular brain disor- review will not only update this fast-moving field but ders. Animal models have proved crucial in identifying will also address the way in which enrichment and the Howard Florey Institute, National Neuroscience molecular and cellular mediators of pathogenesis, as associated experimental paradigms have provided new Facility, University of well as environmental modulators. However, most pub- insights into a wide range of CNS disorders. Melbourne, Victoria 3010, lished models of brain disorders involve animals reared Australia. in ‘standard housing’. When environmental enrichment What is environmental enrichment? Correspondence to A.J.H. e-mail: has been used to increase the levels of sensory, cognitive Environmental enrichment refers to housing conditions, [email protected] and motor stimulation in housing conditions, a range of either home cages or exploratory chambers, that facilitate doi:10.1038/nrn1970 dramatic effects have been observed. enhanced sensory, cognitive and motor stimulation (FIG. 1)

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Table 1 | Effects of environmental enrichment and enhanced physical activity on animal models of CNS disorders Disorder EE/PA Behavioural effects Cellular effects Molecular effects Refs Huntington’s EE Delayed onset and progression Decreased cortical and striatal Increased expression of 2–4,68,69, disease of motor symptoms; ameliorated volume loss; ameliorated deficit in BDNF and DARPP-32 75,81,82,85

deficit in spatial memory neurogenesis; decreased aggregate protein; enhanced CB1 size receptor levels PA Partially delayed onset of motor Altered BDNF mRNA levels 72 symptoms; delayed onset of short-term spatial memory deficits Alzheimer’s EE Enhanced learning and memory Increased, decreased or no change Increased expression of 5–8,105, disease in levels of Aβ; deficiency in synaptophysin, NGF and 111,112 enrichment-induced neurogenesis neprilysin (increased proliferation of progenitor cells but decreased survival) PA Enhanced learning and memory Decreased Aβ 110 Parkinson’s EE Increased resistance to an MPTP Decreased loss of DA neurons Increased GDNF expression 117–119 disease insult; improved recovery of motor and DA-related transporters (DAT, function VMAT2) PA Attenuated motor impairment nd Decreased loss of striatal DA 120 and its metabolites Amyotrophic EE Accelerated progression to end- nd nd 131 lateral sclerosis stage symptoms; delayed onset of motor coordination deficits PA Accelerated, delayed or no change nd nd 128–131 in disease onset Epilepsy EE Increased resistance to seizures; Decreased apoptosis; increased Increased expression of 133–137 attenuated deficit in exploratory neurogenesis GDNF, BDNF, pCREB, ARC, activity and spatial learning HOMER1A and ERG1 Stroke EE Improved functional recovery of Increased spine density; decreased Increased BDNF, NGF-A 138–145, motor and cognitive skills infarct volume; normalized astrocyte- and NGF-B; rescued deficit 157–163 to-neuron ratios; increased number of in glucocorticoid receptor putative neural stem cells, astrocytes II and mineralocorticoid and oligodendrocyte progenitors receptor expression Traumatic brain EE Attenuated motor and cognitive Decreased lesion size; enhanced Increased BDNF; decreased 146–154, injury deficits dendritic branching; increased DAT levels 164–166 survival of progenitor cells Fragile X EE Rescued alterations in exploratory Increased dendritic branching, spine Increased GluR1 expression 167 syndrome behaviour number and appearance of mature spines Down syndrome EE Enhanced and impaired learning No change in dendritic structure nd 168–170 β β A , amyloid- ; ARC, activity-regulated cytoskeleton-associated protein; BDNF, brain-derived neurotrophic factor; CB1, cannabinoid receptor 1; DA, dopamine; DAT, dopamine transporter; DARPP-32, dopamine- and cAMP-regulated phosphoprotein; EE, environmental enrichment; ERG1, ether-à-go-go related gene 1; GluR1, glutamate receptor subunit 1; GDNF, glial-derived neurotrophic factor; HOMER1A, a splice varient of the HOMER1 gene; MPTP, 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine; nd, not determined; NGF, nerve growth factor; PA, enhanced physical activity through voluntary access to running wheels or forced use of treadmills; pCREB, phosphorylated cyclic AMP responsive element-binding protein; VMAT2, vesicular monoamine transporter 2.

relative to standard housing conditions. In some relative to standard conditions. Indeed, the term ‘enrich- experimental paradigms, enrichment could also include ment’ is sometimes used interchangeably with the terms increased social stimulation through larger numbers ‘complexity’ or ‘novelty’ to describe housing conditions. of animals per cage. Here, we limit our discussion to Standard housing conditions often vary between lab- scientific studies of laboratory animals, especially rats oratories. However, they most commonly constitute cages and mice, on which most studies exploring the effects with bedding, ad libitum access to food and water, and in of environmental enrichment on brain and behaviour some cases nesting material. It is generally assumed that have been performed. standard housing constitutes single-sex housing in groups The experimental paradigm of environmental (group size being an important variable), although single enrichment was first described in a neuroscientific (isolation) housing is occasionally defined as a standard context by Donald Hebb10, when he compared rats that condition. Therefore, the choice of control housing con- were allowed to roam freely in his home with those that ditions is important when attempting to interpret the had been left in laboratory cages. Although this might effects of enrichment in a given study. have been a somewhat uncontrolled experimental The exact nature of the environmental enrichment paradigm, it included key features of enrichment: an protocols used also varies widely between labora- environment with enhanced novelty and complexity tories, and is often not fully described in published

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to adulthood (often considered to be around 8 weeks of Motor Cognitive age in rodents), then it might have additional effects on the developing brain compared with those seen in the adult brain. Enrichment paradigms that occur prior to weaning in rodents could be confounded by maternal effects, such as altered licking, grooming and lactation. Visual Somatosensory Environmental enrichment in wild-type rodents Environmental enrichment has a variety of effects on wild-type mice and rats, from cellular and molecular to behavioural. As previously reviewed9, early studies investigating the effects of differential housing showed that enrichment altered cortical weight and thick- ness11–13. Subsequently, various studies have shown that enrichment increases dendritic branching and length, the number of dendritic spines and the size of syn- Figure 1 | Environmental enrichment and the effects of enhanced sensory, apses on some neuronal populations14–21. Furthermore, cognitive and motor stimulation on different brain areas. Enrichment can promote enrichment increases hippocampal neurogenesis and neuronal activation, signalling and plasticity throughout various brain regions. Enhanced the integration of these newly born cells into functional sensory stimulation, including increased somatosensory and visual input, activates the circuits9,22–26. This increase in neurogenesis has been sug- somatosensory (red) and visual (orange) cortices. Increased cognitive stimulation — for gested to be mediated through mechanisms involving example, the encoding of information relating to spatial maps, object recognition, vascular endothelial growth factor (VEGF)27, and the novelty and modulation of attention — is likely to activate the hippocampus (blue) and recruitment of T cells and the activation of microglia28. other cortical areas. In addition, enhanced motor activity, such as naturalistic exploratory movements (including fine motor skills that differ radically from wheel running alone), Many of these cellular changes are also consistent stimulates areas such as the motor cortex and cerebellum (green). with enrichment-induced alterations in the expression of genes involved in synaptic function and cellular plas- ticity29. Enrichment can increase levels of neurotrophins, experimental methods. Enrichment objects generally such as brain-derived neurotrophic factor (BDNF) and vary in composition, shape, size, texture, smell and colour nerve growth factor (NGF), which play integral roles in (although diurnal activity patterns and the limitations of neuronal signalling30–32. Enrichment also increases the the rodent visual system could mean that somatosensory expression of synaptic proteins, such as the presynaptic and olfactory stimuli are the most salient). In addition, vesicle protein synaptophysin and postsynaptic density-95 there is variation in whether enrichment involves access protein (PSD-95) (REFS 33–35), consistent with enrichment- to running wheels, which has significant implications induced enhancement of experience-dependent synap- as enhanced voluntary exercise alone has effects on the togenesis. Furthermore, enrichment induces alterations brain (discussed below). Home cages used for enrichment in the expression of NMDA (N-methyl-d-aspartate) are generally larger than standard cages to allow room and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole for complex and varied objects, although some protocols propionic acid) receptor subunits, which are integral for involve the removal of animals from normal cages into glutamatergic signalling36,37, consistent with evidence exploratory chambers for limited periods each day. that enrichment results in increased synaptic strength, There is no consensus on which environmental including specific forms of synaptic plasticity such as enrichment paradigms are ideal with respect to benefi- long-term potentiation (LTP)38–42. cial effects on brain and behaviour. As shown in TABLE 2, At the behavioural level, enrichment enhances learn- Microglia studies that have examined the effect of enrichment on ing and memory19,36,43–45, reduces memory decline in aged Phagocytic immune cells in the various brain disorders have used a variety of method- animals46, decreases anxiety and increases exploratory brain that engulf and remove 47–50 cells that have undergone ological conditions. One key aspect appears to be the activity . Enrichment-induced enhancement of learn- apoptosis. provision of environmental complexity, with enrichment ing and memory might relate to cellular effects on syn- objects that provide a range of opportunities for visual, aptic plasticity and hippocampal neurogenesis, although Long-term potentiation somatosensory and olfactory stimulation. Another key a recent study suggests that increased hippocampal (LTP). An enduring increase in amplitude of excitatory aspect appears to be environmental novelty, achieved by cell proliferation is not necessary for improved spatial 51 postsynaptic potentials as a changing the objects and the position of the objects in the memory performance . It is possible that variations result of high-frequency enriched environment, which might provide additional in environmental enrichment methods could disrupt (tetanic) stimulation of afferent cognitive stimulation with respect to the formation of the standardization and reproducibility of behavioural pathways. It is measured both spatial maps. It is assumed that increased complexity testing results. However, a study in which three lab- as the amplitude of excitatory postsynaptic potentials and as and novelty will lead to greater levels of stimulation and oratories independently enriched the environments of the magnitude of the associated physical activity. However, this also depends mice and assessed their performance on four commonly postsynaptic cell population on whether different animal models differentially interact used behavioural tests showed that enrichment did not spike. LTP is most frequently with enriched environments. One final key parameter increase individual variability or the risk of obtaining studied in the hippocampus 52 and is often considered to be that varies widely within the literature is the age at which conflicting behavioural data in replicate studies . the cellular basis of learning enrichment commences and the duration of exposure to One component of an enriched environment can and memory in vertebrates. enriched environments. If enrichment commences prior involve increased motor stimulation. Studies have

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Table 2 | Environmental enrichment protocols and experimental outcomes in studies on rodent models of CNS disorders Disorder EE conditions Age/duration of EE Controls Gender Outcomes Refs Huntington’s Mice (4–6/cage) housed in large Weaned at 4 weeks Housed in same Both Delayed onset and 2,4 disease standard cages (44 x 28 x 12.5 cm), of age into EE or sized cages as progression of motor containing paper, cardboard (boxes, standard housing enriched, but symptoms; rescued cortical tunnels, sheets), wooden and plastic until 5 months of age containing only volume loss; BDNF and objects, changed every 2 days normal bedding DARPP-32 expression deficits Alzheimer’s Mice (4/cage) housed in larger cages Weaned at 3 weeks Housed in Males Decreased Aβ levels and 8 disease (3.236 x 104 cm3) containing running of age and exposed standard cages amyloid deposit; elevated wheels, tunnels, toys to daily EE for 3 h/day for 5 months neprilysin activity for 1 month, then given EE 3 x/week until 6 months of age Mice (20/cage) housed in larger At ~2 months of age, Housed 3–4/cage Females Increased expression of 7 cages (1 m3), with ~625 cm2 of floor mice placed into EE in standard cages neuritic plaques; elevated space for each (>3 x space than cages (~600 cm2 floor steady-state Aβ levels; each standard-housed control) space, containing rescued spatial memory containing 2 running wheels, plastic only bedding) deficit tubes, cardboard boxes and nesting material, changed or rearranged weekly Parkinson’s Mice housed in larger cage (75 x Weaned at 3 weeks Housed in Males Increased resistance to 117 disease 45 x 25 cm) containing 6–7 toys, of age (4 mice/cage) standard cages MPTP insult; decreased loss including a wheel and a small into EE or standard (30 x 15 x 15 cm) of DA neurons; decreased ‘house’, randomly changed weekly housing for 2 months DAT expression; increased BDNF levels Epilepsy Rats (6/cage) housed in larger cage 3-week-old rats Housed Males Increased resistance 133 (1 x 1.5 x 1.5 m) containing a running assigned to EE or individually in to seizures; decreased wheel, tunnels, rubber balls, a maze, standard housing for standard cages apoptosis; increased a bar-pressing food administration 3 weeks expression of GDNF, BDNF station and nesting material with and pCREB access to edible treats Stroke Rats (12/cage) housed in a larger 9-week-old male rats Housed Males Improved functional 138 cage (815 x 610 x 450 mm) with assigned to EE or individually in recovery of motor skills boards providing exploration standard housing standard cages platforms, a chain, a swing and wooden blocks, changed weekly Traumatic Rats housed in EE cages (70 x 70 x Pups housed with Housed Both Improved performance on 147 brain injury 46 cm) containing ~6 objects, mothers from birth individually in problem solving task changed daily until weaning standard cages (P23–24), placed in EE from weaning cages either at P5–6 (P23–24) with mothers or at weaning, then housed 12–13/cage, until 65–66 days of age Fragile X Mice (3/cage) housed in clear Weaned at 3 weeks Housed in Males Rescued deficit in 167 syndrome Plexiglas cages (35 x 20 x 25 cm) of age into EE or standard exploratory behaviour; with a horizontal platform, ladder, standard housing Plexiglas cages increased dendritic running wheel, nesting material until 60 days of age (18 x 25 x 13 cm) branching, spine number, and assortment of plastic toys with 3 mice/cage appearance of mature spines (balls, tubes, boxes, bells), changed and GluR1 expression every 3 days; mice also exposed to an additional Plexiglas cage (40 x 25 x 20 cm) for 2 h/day containing polyurethane foam, cardboard boxes and metal objects Down Mice (8/cage) housed in larger Weaned into EE or Housed in Both Increased exploratory 168 syndrome cages (42 x 50 x 20 cm) with ladder standard housing standard behaviour; enhanced spatial connecting 2 levels, running wheel, for 7 weeks, then Plexiglas cages learning in females but not wooden swing, plastic and wooden returned to standard (20 x 12 x 12 cm) in males toys (including rolls, blocks and housing for 15 days with 2–3 mice/ rocks) changed every 3 days; foods before behavioural cage of different tastes were placed to testing encourage foraging Aβ, amyloid-β; BDNF, brain-derived neurotrophic factor; DA, dopamine; DAT, dopamine transporter; DARPP-32, dopamine- and cyclic AMP-regulated phosphoprotein; EE, environmental enrichment; GluR1, glutamate receptor subunit 1; GDNF, glial-derived neurotrophic factor; MPTP, 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine; P, postnatal day; pCREB, phosphorylated cyclic AMP responsive element-binding protein.

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by degeneration of the cerebral cortex and striatum, Environmental factors Mutant huntingtin (mental stimulation, (expanded polyglutamine tract) producing a progressive movement disorder (including physical activity) chorea), cognitive deficits (dementia) and psychiatric symptoms (including depression), with onset usually in the fourth or fifth decade of life. The pathogenic mech- Abnormal protein folding/cleavage anism by which the trinucleotide CAG repeat expansion mutation, expressed as an extended polyglutamine tract, induces neuronal dysfunction and death is not Abnormal protein interactions yet fully understood. There is an inverse correlation between CAG repeat length in exon 1 of the huntingtin (HTT) gene and age of onset of symptoms63. It has Abnormal gene expression/ Aggregation subsequently been discovered that at least eight other protein trafficking (nuclear, cytoplasmic) fatal neurodegenerative diseases (mainly spinocerebellar ataxias) are caused by CAG repeat mutations that encode expanded polyglutamine tracts in different proteins64. Altered Altered Altered pre- and Transgenic HD mice, in which the CAG repeat neuromodulators neurogenesis postsynaptic (for example, BDNF) signalling molecules expansion in HTT is stably expressed, provide an accurate model of this neurodegenerative disease (for a review, see REF. 65). R6/1 HD mice develop adult-onset motor and cognitive symptoms, as well as progressive degeneration of the cortex and striatum2,4,66. The absence Neuronal and synaptic dysfunction of cell death in these HD mice until very late stages67 suggests that the early disease process, including the onset of behavioural deficits, involves neuronal dysfunction Motor, cognitive and psychiatric symptoms rather than cell death (FIG. 2). Figure 2 | Gene–environment interactions in Huntington’s disease. Schematic of Despite the fact that HD is an autosomal dominant postulated molecular and cellular pathogenic mechanisms and possible ways in which disorder, we have shown that environmental enrich- environmental stimulation modulates these mechanisms. Red shading indicates ment of R6/1 HD mice greatly delays the onset of processes on which environmental factors might have a beneficial effect during disease motor symptoms2,4. Recent evidence also suggests that onset, progression and neuropathology. BDNF, brain-derived neurotrophic factor. enrichment can ameliorate spatial memory deficits in R6/1 HD mice68. We also demonstrated that environmental enrichment delays the degenerative loss of investigated the effect of exclusively enhancing motor cerebral volume in HD mice, with a greater impact in activity on the brain, through access to running wheels the cortex than the striatum2. Subsequent studies have or forced running on treadmills. Enhanced motor activ- confirmed the beneficial effects of enrichment in two ity increases BDNF levels53–55, promotes angiogenesis56–58, other transgenic models, R6/2 and N171-82Q HD increases both hippocampal cell proliferation and sur- mice3,69. A recent epidemiological study of human vival59 and the numbers of newly generated microglia HD has shown a clear role for environmental factors in the cortex60. Forced treadmill running also improves in modulating the clinical onset of HD70, although the learning61. Although increased physical activity alone nature of these factors remains unknown. Following the might result in some of the beneficial effects observed initial enrichment study in HD mice, it was reported with enrichment, it does not fully account for the broader that a more stimulating environment improved physi- behavioural, cellular and cognitive changes observed cal, mental and social functioning in a small cohort of following environmental enrichment. Recently, wheel HD patients71. Therefore, a better understanding of how running during pregnancy has even been shown to result environmental enrichment induces its beneficial effects in increased neurogenesis in the offspring62. Although might also provide direction for the development of such in utero effects of environmental manipulations other therapeutic approaches. are of great interest, they are beyond the scope of the The dramatic effects observed following environmen- present review. tal enrichment of HD mice raises the question of whether These studies in wild-type animals have propelled enhanced sensory, cognitive and/or motor stimulation our understanding of gene–environment interactions is most important in mediating these beneficial effects. in the development and plasticity of the normal brain, We have explored aspects of this question by comparing and might also provide new insights into understanding standard-housed R6/1 HD mice with those experiencing the interactions between genes and environment in the enhanced voluntary physical exercise on running wheels dysfunctional brain. in the home cages72. There was only a partial delay in the onset of motor deficits in wheel-running HD mice, with Mouse models of Huntington’s disease less of a beneficial effect than in HD mice exposed to Environmental enrichment induces significant behav- complex enriched environments. However, wheel run- ioural, cellular and molecular changes in transgenic ning did delay the onset of short-term spatial memory mouse models of the autosomal dominant brain dis- deficits in HD mice72, which might reflect the impact order HD. This is a devastating disease characterized of voluntary physical exercise on the hippocampus, and

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Environmental factors Genetic factors ing that there are experience-dependent effects on protein (mental stimulation, physical activity, diet?) (APP, PS1, PS2, APO*ε 4 mutations) aggregation, protein clearance or both.

Mouse models of Alzheimer’s disease AD is a neurodegenerative disorder that involves Altered APP processing dementia and mainly affects the neocortex and hippo- Aβ-degrading campus. The disease is characterized by two pathological proteases Altered neuronal hallmarks — senile plaques and neurofibrillary tangles (for example, β plasticity (for example, (NFTs). Plaques are extracellular deposits of amyloid, neprilysin) A plaques NFTs impaired neurogenesis) consisting mainly of Aβ peptide derived from proteoly- sis of the amyloid precursor protein (APP) by β- then γ-secretase86–89. NFTs are intraneuronal aggregations of Neuronal and synaptic dysfunction hyperphosphorylated forms of the microtubule-associated protein tau90. It is well accepted that both genes and the environ- Cognitive decline and dementia ment have roles in the complex aetiology of AD1 (FIG. 3). Most AD cases are sporadic and seem to result from an Figure 3 | Gene–environment interactions in Alzheimer’s disease. Schematic of interaction of multiple genetic and environmental factors. postulated molecular and cellular pathogenic mechanisms and possible ways in which However, there are also early- and late-onset familial forms environmental stimulation modulates these mechanisms. Red shading indicates (familial AD, FAD) that are inherited in an autosomal processes on which environmental factors might have a beneficial effect during disease dominant fashion. Linkage and cloning studies using FAD onset, progression and neuropathology. APOEε4, apolipoprotein E; APP, amyloid kindred have identified three genes — APP, presenilin 1 precursor protein; NFTs, neurofibrillary tangles; PS1, presenilin 1; PS2, presenilin 2. (PS1) and presenilin 2 (PS2), which have been the focus for transgenic modelling studies. Mutations in APP, PS1 and PS2 all increase the production or fibrillogenic prop- in particular adult neurogenesis in the dentate gyrus. It erties of Aβ leading to increased amyloid pathology 91. has been shown that adult R6/1 HD mice have reduced A genetic risk factor for the sporadic form of AD hippocampal neurogenesis73,74, and that environmental (usually late-onset) has also been found: polymorphisms enrichment can ameliorate this deficit in adult-born in the apolipoprotein E (APOE) gene, particularly the ε4 neurons in the dentate gyrus of HD mice75. allele, are thought to increase the risk of sporadic AD, There is increasing evidence for the role of synaptic while the ε2 allele seems to be protective92–95. APOE dysfunction in HD pathogenesis, which could medi- binds Aβ and localizes it to senile plaques, suggesting ate neurodegeneration. Synaptic dysfunction in HD that it might have a role in Aβ clearance. mice is associated with transcriptional dysregulation of Although both genetic and environmental factors are neurotransmitter receptors and synaptic signal transduc- likely to trigger the pathogenic pathways96,97 that eventu- tion pathways76–78. These results are consistent with a role ally lead to the neuropathology of AD, research over the for neurotransmitter receptor-mediated excitotoxicity in last decade has focused on understanding the genetic the neurodegenerative process. Abnormal in vitro hippo- contribution. This work has been advanced by the campal synaptic plasticity has been described in R6/2 HD generation of various transgenic mouse models of AD, mice and correlated with aberrant spatial memory on the which have been used to model the symptomatology and Morris water maze79. Similarly, in vivo neocortical plasticity neuropathology observed in humans97. However, studies deficits have been demonstrated in R6/1 HD mice and have recently begun to investigate the effect of environ- correlated with the onset of a discrimination learning mental factors on neuropathology and cognitive func- deficit that is contingent on the same sensory modality80. tion in transgenic models of AD. Synapse loss is a strong Increased sensory and cognitive stimulation could exert correlate of cognitive decline in AD98,99 and the plastic their greatest effects within the cortex, as suggested by our properties of synapses make them ideal candidates for cerebral volume measurements2. Gene expression studies modulation by environmental stimulation, which could demonstrate that wild-type mice exposed to an enriched lead to the slowing or reversal of cognitive decline. In environment exhibit altered regional brain expression of fact, epidemiological evidence suggests that cognitive a subset of genes that is involved in neuronal signalling stimulation and physical activity can prevent or delay and plasticity29. We therefore propose that environmental the onset of AD100–104 (BOX 1). enrichment overcomes deficiencies of gene expression81,82, Levi and colleagues105 were the first to examine the synaptic function and experience-dependent plasticity, effect of differential housing in a mouse model of AD, Morris water maze and ameliorates the deficits in HD mice. However, it is using transgenic mice containing human APOE*ε3 or A task used to assess long- ε term spatial memory, most possible that enrichment also affects the abnormal pro- APOE* 4 alleles on a null mouse Apoe background. commonly in rodents. Animals tein–protein interactions that occur in HD. For example, Mice transgenic for human APOE*ε3 that were housed use an array of extra-maze the aggregation of huntingtin protein fragments contain- in an enriched environment showed improved working cues to locate a hidden escape ing expanded polyglutamine into intracellular inclusions memory. However, mice transgenic for human APOE*ε4, platform that is submerged 83 84 below the surface of the water. occurs in HD mice and in human patients . There is which is associated with a higher risk of AD, did not Learning in this task is evidence that enrichment could reduce the size of these show this improvement in response to enrichment. hippocampus-dependent. aggregates in the cortex and other brain areas81,85, imply- Furthermore, the cognitive effects were associated with

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Box 1 | Environmental enrichment, brain plasticity and cognitive reserve and colleagues highlighted additional differences between the two studies, such as the differing num- Environmental enrichment induces various alterations in brain structure and function, bers of running wheels available in the cages and the as discussed in this review, including increasing the birth and maturation of new enrichment paradigm itself 7. 9,22–26 neurons into functional circuits , enhancing the expression of molecules involved in The exact role of Aβ levels and plaque deposition in neuronal signalling29,30–32 and promoting synaptic plasticity38–42. These changes can influence brain function and plasticity by modifying synaptic transmission, enhancing AD and their impact on cognitive function has not been signalling between neuronal ensembles and strengthening neuronal circuits. fully elucidated, and therefore it is more difficult to inter- Enrichment-induced strengthening of neuronal and synaptic connectivity provides a pret the findings of differing amyloid levels as a result of mechanism for how the brain may more efficiently utilize existing neuronal networks environmental enrichment. Although Lazarov et al. did and recruit alternative networks when required. not examine the effect of enrichment on cognitive behav- This experience-dependent increase in neuronal connectivity might represent a iour, interestingly, Jankowsky and colleagues showed that mechanism of relevance to the theory of ‘cognitive reserve’ or ‘brain reserve’180,181, and despite an increase in the expression of hippocampal explain how enrichment could make the brain more resilient, in the case of brain plaques and in the levels of Aβ, environmental enrich- disorders, and to damage or degeneration. Cognitive reserve is most likely to be a ment rescued a deficit in hippocampal-dependent spatial function of both genetic and environmental factors and has been observed particularly memory7. Therefore, enrichment had a beneficial effect in cognitive disorders (for example, Alzheimer’s Disease and other forms of dementia), where there is epidemiological evidence to show that environmental factors, such as on cognitive function, irrespective of the increased levels 5 the levels of mental and physical activity, are associated with rate of cognitive decline of amyloid. In line with this, Arendash et al. observed and onset of dementia182. We propose that environmental enrichment and the concept that aged APP transgenic mice exposed to environmen- of cognitive reserve might also be relevant to psychiatric disorders that involve tal enrichment show cognitive enhancement in spatial cognitive dysfunction as part of the symptomatology (for example, schizophrenia, learning, but no change in Aβ deposition compared with bipolar disorder and depression). standard-housed mice. Although this study used a small number of animals and the cognitive improvement was mild, there is additional evidence that increased exer- higher levels of synaptophysin and NGF in the hippo- cise can lead to enhanced cognitive function110. Mice campus of APOE*ε3, but not APOE*ε4, transgenic mice, expressing a double mutant form of APP (TgCRND8 despite similar elevations of cortical synaptophysin and mice) housed with running wheels for 5 months showed NGF levels in both APOE*ε3 and APOE*ε4 transgenic an enhanced rate of learning in the Morris water maze animals in response to environmental enrichment. and decreased expression of Aβ plaques. This effect The effect of environmental enrichment on APP/PS1 was independent of changes in neprilysin and insulin- transgenic mice was investigated by Jankowsky et al.6 degrading enzyme, and instead might have involved Mice co-expressing mutant APP and PS1 genes housed in neuronal metabolism changes that are known to affect enriched conditions developed a higher amyloid burden APP processing and to be regulated by exercise. with increased aggregated and total Aβ compared with Studies have also investigated the effects of enrich- standard-housed littermates. Furthermore, in a subsequent ment on neurogenesis in AD mouse models. Conditional study, mice overexpressing APP and/or PS1 housed in knockout mice that have the PS1 gene selectively deleted enriched conditions also showed increased expression of from excitatory neurons of the adult forebrain show a neuritic plaques in the hippocampus and elevated steady- deficiency in enrichment-induced neurogenesis in the state Aβ levels7. These results support similar in vitro stud- dentate gyrus111. Furthermore, neuronal overexpres- ies that have demonstrated that synaptic activity increases sion of either wild-type human PS1 or the FAD mutant the production of Aβ and soluble APP derivatives106,107. P117L in transgenic mice leads to an increase in the By contrast, Lazarov and colleagues8 found that enriched rate of neural progenitor proliferation in response to APP/PS1 transgenic animals have decreased hippocam- environmental enrichment112. However, both PS1 and pal and cortical Aβ levels and amyloid deposits compared FAD mutant P117L animals housed under standard with standard-housed controls. In addition, the enzymatic and enriched conditions show impaired survival of activity of neprilysin, an Aβ-degrading endopeptidase, neural progenitor cells in the hippocampus, leading to was elevated in the brains of enriched mice and inversely fewer new neurons being generated, which suggests that correlated with amyloid burden. this deficiency in enrichment-induced neurogenesis The discrepancy between the reported results from represents a lack of hippocampal plasticity, and in part Jankowsky et al. and Lazarov et al. has been a point of underlies the cognitive deficits observed in AD. 108,109 discussion . The original study by Jankowsky and Although there remains debate about the effect of 6 colleagues involved adding and removing mice from enrichment and exercise on the neuropathological enriched groups during the study, raising the possibility abnormalities in AD, these studies, together with epide- of increased stressors. However, the authors addressed miological investigations1, suggest that both mental and this point in their subsequent study, which was carried physical activity help to slow down or prevent the cogni- out under more controlled conditions, and highlighted tive decline associated with AD, possibly by preventing that even when using another strain of mice, there was neuronal dysfunction and allowing synaptic recovery. again an increase in Aβ and plaque deposition following enrichment7. The question of whether the disparate find- Models of other neurological disorders ings are due to gender has been raised, given that Lazarov Parkinson’s disease. PD is clinically characterized by a and colleagues used male mice whereas Jankowsky and tetrad of motor symptoms: muscular rigidity, postural co-workers used female mice. Furthermore, Jankowsky abnormalities, bradykinesia and a characteristic tremor.

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However, impairments in cognitive function also accom- However, another study demonstrated sex differences pany PD, with dementia as a prominent feature in the in disease onset and progression, with exercise delaying late stages (for a review, see REF. 113). Neurologically, the disease in female but not male mice129. Another study PD primarily involves the degeneration of nigrostriatal using a similar experimental paradigm showed that dopaminergic neurons that project from the substantia treadmill running delayed disease onset and increased nigra pars compacta (SNc) to the striatum, and the survival rate for males, but not females130. formation of intracytoplasmic inclusions known as Onset and progression of disease symptoms was Lewy bodies. The aetiology of PD is unknown. Various recently compared in transgenic ALS mice (with the PD-associated genes have recently been identified, SOD1G93A mutation) housed in standard conditions, including α-synuclein, parkin, PINK1 (phosphatase environmental enrichment or with access to running and tensin homologue (PTEN)-induced kinase 1), DJ1 wheels131. Environmental enrichment significantly (Parkinson disease (autosomal recessive, early onset) 7) improved motor performance but was also associated and LRRK2 (leucine-rich repeat kinase 2) (for a review, with an acceleration of overt end-stage disease symp- see REF. 114). However, environmental factors, such as tom onset. By contrast, increased physical activity using physical trauma, toxic insults and infections, have long running wheels had no effect on disease onset and pro- been thought to have a role in PD115. gression131. These results suggest that the stereotyped Although various transgenic models of PD are cur- physical activity associated with running on wheels or rently being developed, none has yet been demonstrated treadmills differs qualitatively and quantitatively from to have construct, face and predictive validity. Animal enhanced fine motor activity induced by enrichment in models that have been the most widely investigated the absence of running wheels, and therefore have impli- use toxin-induced lesions to mimic PD-like symptoms, cations for environmental manipulations using models such as the unilateral 6-hydroxydopamine (6-OHDA) of other CNS disorders. rat model and the bilateral 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) mouse model (for a review, Epilepsy. Epilepsy is a neurological condition that is char- see REF. 116). Animals exposed to an enriched environment acterized by unpredictable repeated seizures, caused by exhibit resistance to an MPTP insult117,118. Furthermore, aberrant electrical discharge in the brain, and can result rats housed in enriched conditions following a 6-OHDA in selective cell loss and gliosis in specific brain regions. insult show improved motor function119. Similarly, animals It has varied causes and manifestations, with many dis- exposed to moderate treadmill running following either a tinct seizure types and several identifiable syndromes. 6-OHDA or MPTP insult exhibit sparing of behavioural Although risk factors such as head injury, CNS infections impairment involving forelimb use and movement120. and cerebrovascular disease (particularly in the elderly) At the cellular level, treadmill running follow- have been associated with epilepsy, susceptibility to ing 6-OHDA or MPTP treatment is associated with a epilepsy has been suggested to be partly genetic132. This decreased loss of striatal dopamine and its metabolites120. indicates that the complex interplay between genetic and Similarly, animals exposed to enrichment following environmental factors might explain our incomplete MPTP injury show increased glial cell line-derived understanding of the aetiology of this disorder. neurotrophic factor (Gdnf) expression and decreased Experimental animal models of epilepsy have been loss of dopaminergic neurons and monoamine trans- generated using proconvulsant drugs and electrical stim- porters, including dopamine transporter (DAT)117,118. ulation, and have recently been used to investigate the As DAT is required for MPTP-induced dopaminergic effect of environmental experience. Rats housed under neurotoxicity, an enrichment-induced decrease in DAT enriched conditions for 3 weeks showed a resistance to levels is suggestive of a mechanism for protection from seizures and exhibited decreased hippocampal cell neurodegeneration. death133. Enrichment also resulted in increased levels of GDNF and BDNF. However, the control animals Amyotrophic lateral sclerosis. ALS is the most common in this study were individually housed, and there- form of motor neuron disease, with muscle wasting and fore these results could, in part, represent effects paralysis as prominent symptoms. ALS is characterized of isolation and deprivation rather than enrich- by the degeneration of motor neurons in the cortex, ment alone. Furthermore, enriched animals also brainstem and spinal cord. Although twin studies sup- had an altered dietary intake, with the addition of port a role for both genetic and environmental factors in ‘edible treats’ to the enrichment paradigm. In another ALS, the nature of environmental modifiers is unknown. study in which the enrichment paradigm incorporated Some epidemiological studies have suggested a relation- edible treats, animals that were environmentally enriched ship between increased physical activity and sporadic prior to amygdala kindling were shown to exhibit an ALS121–124, whereas others have found no such associa- increased latency to induce kindling epileptogenesis tion121,125–127. Therefore, the environmental influence on compared with animals housed in isolation134. ALS is still poorly understood. Following kainic acid or lithium-pilocarpine- The predominantly used mouse model of ALS over- induced seizures, beneficial effects on behaviour have expresses the mutant human form of the Cu/Zn super- been observed with enrichment increasing exploratory oxide dismutase-1 (SOD1). In one study, SOD1 animals activity135 and spatial learning performance136,137. In addi- given long-term exposure to motorized running wheels tion, exposure to enrichment following epileptogenesis showed no alterations in disease onset or progression128. increases neurogenesis134,136 and the expression of

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molecules involved in neuronal and synaptic plasticity, that environmental enrichment can exert its effect by acti- such as phosphorylated levels of cyclic AMP-responsive vating glutamatergic signalling pathways independently element binding (CREB)136, ARC, HOMER1A and of FMRP expression. ERG1135. Down syndrome. Down syndrome is the most significant Stroke and traumatic brain injury. As environmental genetic cause of mental retardation and involves tri- enrichment has numerous beneficial effects on brain somy of chromosome 21. Currently, there are several and behaviour, several studies have investigated its murine models with segmental trisomy; however, the effect on functional recovery following experimental Ts65Dn mouse model is the most commonly used. Using models of stroke and traumatic brain injury. An ischae- this model, Martinez-Cue and others168 provided some mic stroke, which results from a sustained deficit in suggestive evidence that enrichment improved learning in focal cerebral perfusion, is one of the main causes of females, but deteriorated learning in males. In a follow-up permanent disability and death. Evidence suggests that study, the authors investigated whether this negative effect the recovery of motor function following experimental of enrichment was associated with housing numbers169. stroke is enhanced by environmental enrichment138–141. Results revealed that housing numbers had no impact Enrichment also significantly attenuates deficits in learn- on learning performance in control animals but, again, ing and memory142–145. Similarly, exposure to environ- enrichment showed a negative effect on learning in male mental enrichment following experimental models of Ts65Dn mice. Interestingly, morphological analysis of brain injury enhances functional outcome and attenuates pyramidal neurons in the frontal cortex of female mice has both motor and cognitive deficits146–154. Furthermore, shown that although enriched control animals exhibit sig- enrichment combined with additional rehabilitative stim- nificantly more dendritic branching and spines compared ulation — such as multimodal early-onset stimulation with non-enriched controls, there was no effect of enrich- (MEOS), which involves increased sensory stimulation ment on dendritic structure in Ts65Dn mice170. Therefore, and specific motor training following brain injury155, or the effect of environmental stimulation on cognitive and intensive task-specific skill training following an ischaemic cellular plasticity in this model of Down syndrome, insult156 — reverses motor deficits. and the gender specificity, remain to be elucidated. In addition to aiding functional recovery, post- ischaemic environmental enrichment: decreases inf- Psychiatric disorders arct volume144; increases dendritic spine density157; Psychiatric disorders provide a challenging degree of increases trophic factors such as BDNF158, NGF-A and complexity with respect to genetic and environmental NGF-B159,160; rescues deficits in glucocorticoid receptor factors and their interactions. The most common psy- II (REF. 159) and mineralocorticoid receptor gene expres- chiatric disorders are bipolar disorder (manic depres- sion160; normalizes astrocyte-to-neuron ratios161; attenu- sion), unipolar (major) depression, schizophrenia and ates a deficit in cell proliferation in the subventricular drug addiction. As we have only recently begun to zone; and increases the number of putative neural stem understand the complex genetics of these disorders, as cells162. Most of these newly born cells were subsequently well as possible environmental triggers, current animal demonstrated to be either astrocytes or oligodendrocyte models are somewhat limited with respect to construct, progenitors/polydendrocytes, which is suggestive of a face and predictive validity. beneficial mechanism for repair and plasticity follow- The genetics of bipolar disorder has not advanced suf- ing injury163. Similarly, enrichment following traumatic ficiently for convincing animal models to be developed. brain injury has beneficial effects on the brain, such as However, there is extensive literature on animal models decreasing lesion size152, enhancing dendritic branch- of depression, including their use in the development of ing149, promoting the survival of progenitor cells164, antidepressant treatments171. Manipulations that modify increasing BDNF165 and decreasing DAT levels166. stress levels by disrupting the early-rearing environment have been combined with environmental enrichment, Disorders of nervous system development for example, to show that enrichment can reverse the Fragile X syndrome. The most common form of heredi- effects of maternal separation on both the hypothalamic- tary mental retardation, fragile X syndrome, is due to a pituitary-adrenal (HPA) and behavioural responses to mutation of the fragile X mental retardation 1 (FMR1) stress172,173. gene on the X chromosome. Affected individuals carry Although the genetics of schizophrenia has begun to be an expanded trinucleotide repeat that leads to transcrip- elucidated in recent years, it is not yet clear how accurately tional silencing of the FMR1 gene. Fmr1-knockout mice, we will be able to model this devastating disorder in ani- which lack the normal fragile X mental retardation pro- mals. One would imagine that the positive symptoms, such tein (FMRP), show both cognitive and neuronal altera- as hallucinations and delusions, will be extremely difficult Endophenotype A quantitative biological trait tions. A recent study showed that enrichment rescues to model in animals. However, the negative symptoms, associated with a complex alterations in exploratory behaviour in Fmr1-knockout such as cognitive deficits, could prove more tractable as genetic disorder that is hoped mice167. Furthermore, enrichment increased dendritic endophenotypes in animal models. A number of knockout to more directly index the branching, spine number, appearance of mature spines mouse lines exhibit behavioural phenotypes of relevance underlying pathophysiology, facilitating efforts to find or and expression of the AMPA receptor subunit GluR1 to schizophrenia. In one of these lines, involving disrup- characterize contributing in the visual cortex. Interestingly, levels of FMRP in tion of the phospholipase C-β1 pathway (PLC-β1), the key genes. wild-type mice were not altered by enrichment, suggesting behavioural abnormalities of spontaneous hyperactivity in

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Environmental Pharmacological Molecular Conclusions and future directions modulators modulators modulators Although great progress has been made in understanding mechanisms that mediate the behavioural, cellular and molecular effects of environmental enrichment, the Disease initiators — research raises many new questions. How does environ- genetic and environmental mental enrichment from early ages in animals relate to contributors gene–environment interactions in human brain development? Does environmental enrichment exert differing effects on the developing and mature brain? Are there Altered gene expression Abnormal Other molecular critical periods when environmental enrichment inter- (for example, transcriptional protein–protein mediators of dysregulation) interactions neuronal dysfunction ventions have their greatest impact on specific aspects of brain structure, function and behaviour? How do sensory, cognitive, motor and social stimulation contribute to the Region-speciﬁc neuronal/synaptic observed effects of environmental enrichment? How do dysfunction and cell death parameters such as gender and genetics affect the way in which animals interact with their environments? How can we use environmental enrichment studies to guide Disrupted neuronal circuitry development of occupational therapies, ‘enviromimetics’ and other medical treatments? Another intriguing question concerns the gender Disease symptoms differences observed between some of the studies discussed here. However, few studies have directly com- Figure 4 | Molecular mediators, environmental modulators and pharmacological pared males and females under identical experimental modulators (enviromimetics). Illustration of some mechanistic aspects of pathogenesis conditions. Enrichment could have differential effects that are common to many brain disorders, particularly neurodegenerative diseases, and on the way in which animals of each sex interact with the ways in which environmental factors (red shading) might act at multiple levels of their environments and with each other. In particular, disease pathways. Furthermore, the concept of molecular modulators of pathogenesis is illustrated (green shading), along with the proposal that experimental paradigms such as in group-housed male rodents, dominance hierarchies environmental enrichment might facilitate development of pharmacological modulators and territoriality might have additional interaction (enviromimetics) that mimic or enhance the beneficial effects of environmental effects. Furthermore, sex hormones and other gen- stimulation (overlapping area of red and green shading). der-specific aspects of brain structure and function could provide differential neural substrates for enrichment-induced plasticity. Further work is required to the open field and sensorimotor gating (prepulse inhibi- unravel the nature and contribution of gender influences tion) deficits, observed in standard-housed knockout to the effects of enriched environments. mice, were reversed by environmental enrichment174. It is also possible that strain differences and other genetic Drug addiction is a complex disorder that is strongly and epigenetic variables could alter the responsiveness of influenced by environmental factors. Enrichment has animals to the enrichment paradigm. Most of the studies been shown to increase resistance to the effects of drugs investigating the effects of environmental enrichment have such as cocaine117,175 and amphetamines176,177. This sug- been undertaken on mice and rats, and rodents exhibit gests that future enrichment studies could contribute to innate strain variances in behaviours such as anxiety, further elucidating the mechanisms underlying addiction exploratory activity and learning and memory. However, and provide opportunities for rehabilitation. as seen from this review, environmental enrichment — as a model of enhanced cognitive, sensory and motor stimula- Enviromimetics as novel therapeutics tion — has been shown to induce experience-dependent Understanding the molecular and cellular effects of plasticity at structural and functional levels in many animal environmental stimulation might not only provide models of the healthy and dysfunctional brain. mech anistic insights into the pathogenesis of environ- Most models of brain development, function and dys- mentally modulated brain disorders, but could guide function involve studying animals in only one (standard) the development of a new class of therapeutics (FIG. 4). housing condition, which affords little opportunity for Investigations of gene–environment interactions sensory, cognitive or motor stimulation. Therefore, the might reveal molecular targets for the development of dramatic effects of environmental enrichment described therapeutic agents that mimic or enhance the beneficial here have major implications for neuroscientific research effects of environmental stimulation (enviromimet- involving animals. These effects raise the question of ics)178,179. Putative enviromimetics could be developed whether most standard conditions represent a state of for the treatment of HD, AD and a range of other cur- sensory, cognitive and motor deprivation and are there- Critical period rently incurable brain disorders. Our recent demonstra- fore suboptimal for medical research. Such research aims A strict time window during tion that the antidepressant fluoxetine can mimic some to model humans, who experience an enormous range which experience provides of the beneficial effects of environmental enrichment of mental and physical activities. However, the increase information that is essential for 74 normal development and in HD mice implies that fluoxetine and perhaps other in cage sizes, costs and experimental variables associated permanently alters selective serotonin reuptake inhibitors could act as with enrichment means that most research will continue performance. enviromimetics in this instance. to be conducted under standard housing conditions.

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Finally, a key remaining question is how the environ- relevant to the human condition in animal models, par- mental enrichment of animals relates to the richness of ticularly those models that attempt to recapitulate human human living experience. Although most humans do disorders. Nevertheless, the research described here, experience high levels of complexity and novelty through- combined with the development of approaches such as out postnatal development and adult life, individuals vary functional genomics and brain imaging, paves the way for widely in their levels of mental stimulation and physical a new understanding of gene–environment interactions activity. Therefore, an important future direction will be in the healthy and diseased brain, which could eventually to model more closely the environmental factors that are lead to a range of therapeutic advances.

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