Enriched environments, experience- dependent plasticity ...

© 2006 Nature Publishing Group

The mammalian brain is generated by complex genetic and epigenetic programs that ensure that most cells and structural areas are in place by birth. However, sensory, cognitive and motor stimulation through interaction with the environment from birth to old age has a key role in refining the neuronal circuitry required for normal brain function. Genetic and pharmacological factors that modulate brain function and dysfunction have been explored in detail over recent decades, but environmental parameters have received far less attention.

Epidemiological investigations of neurological and psychiatric disorders, including studies involving mono-zygotic twins, have provided important clues as to the rel-evant contribution of genetic and environmental factors1. However, owing to the enormous number of environmen-tal variables in human populations, such studies have been limited in their ability to demonstrate the involvement of specific environmental factors in particular brain disor-ders. Animal models have proved crucial in identifying molecular and cellular mediators of pathogenesis, as well as environmental modulators. However, most pub-lished models of brain disorders involve animals reared in ‘standard housing’. When environmental enrichment has been used to increase the levels of sensory, cognitive and motor stimulation in housing conditions, a range of dramatic effects have been observed.

During the last decade, enrichment studies using transgenic mouse models of Huntington’s disease (HD)2–4 and Alzheimer’s disease (AD)5–8 have opened the way for exploring gene–environment interactions in neurodegeneration. Impressive effects of environmental enrichment have also been recently identified in other brain disorders such as Parkinson’s disease (PD), amyo-trophic lateral sclerosis (ALS), fragile X syndrome, Down syndrome and various forms of brain injury (TABLE 1). These findings have implications for clinical occupa-tional therapies and related approaches. However, these environmental manipulations can also provide powerful tools to dissect cause and effect among molecular and cellular correlates of pathogenesis, and so identify novel targets for future development of therapeutics. Although the effects of environmental enrichment on the normal animal brain have been reviewed previously9, the present review will not only update this fast-moving field but will also address the way in which enrichment and the associated experimental paradigms have provided new insights into a wide range of CNS disorders.

What is environmental enrichment?Environmental enrichment refers to housing conditions, either home cages or exploratory chambers, that facilitate enhanced sensory, cognitive and motor stimulation (FIG. 1)

Howard Florey Institute, National Neuroscience Facility, University of Melbourne, Victoria 3010, Australia. Correspondence to A.J.H. e-mail: [email protected]:10.1038/nrn1970

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

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relative to standard housing conditions. In some experimental paradigms, enrichment could also include increased social stimulation through larger numbers of animals per cage. Here, we limit our discussion to scientific studies of laboratory animals, especially rats and mice, on which most studies exploring the effects of environmental enrichment on brain and behaviour have been performed.

The experimental paradigm of environmental enrichment was first described in a neuroscientific context by Donald Hebb10, when he compared rats that were allowed to roam freely in his home with those that had been left in laboratory cages. Although this might have been a somewhat uncontrolled experimental paradigm, it included key features of enrichment: an environment with enhanced novelty and complexity

relative to standard conditions. Indeed, the term ‘enrich-ment’ is sometimes used interchangeably with the terms ‘complexity’ or ‘novelty’ to describe housing conditions.

Standard housing conditions often vary between lab-oratories. However, they most commonly constitute cages with bedding, ad libitum access to food and water, and in some cases nesting material. It is generally assumed that standard housing constitutes single-sex housing in groups (group size being an important variable), although single (isolation) housing is occasionally defined as a standard condition. Therefore, the choice of control housing con-ditions is important when attempting to interpret the effects of enrichment in a given study.

The exact nature of the environmental enrichment protocols used also varies widely between labora-tories, and is often not fully described in published

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 disease

EE Delayed onset and progression of motor symptoms; ameliorated deficit in spatial memory

Decreased cortical and striatal volume loss; ameliorated deficit in neurogenesis; decreased aggregate size

Increased expression of BDNF and DARPP-32 protein; enhanced CB1 receptor levels

2–4,68,69,75,81,82,85

PA Partially delayed onset of motor symptoms; delayed onset of short-term spatial memory deficits

Altered BDNF mRNA levels 72

Alzheimer’s disease

EE Enhanced learning and memory Increased, decreased or no change in levels of Aβ; deficiency in enrichment-induced neurogenesis (increased proliferation of progenitor cells but decreased survival)

Increased expression of synaptophysin, NGF and neprilysin

5–8,105,111,112

PA Enhanced learning and memory Decreased Aβ 110

Parkinson’s disease

EE Increased resistance to an MPTP insult; improved recovery of motor function

Decreased loss of DA neurons and DA-related transporters (DAT, VMAT2)

Increased GDNF expression 117–119

PA Attenuated motor impairment nd Decreased loss of striatal DA and its metabolites

120

Amyotrophic lateral sclerosis

EE Accelerated progression to end-stage symptoms; delayed onset of motor coordination deficits

nd nd 131

PA Accelerated, delayed or no change in disease onset

nd nd 128–131

Epilepsy EE Increased resistance to seizures; attenuated deficit in exploratory activity and spatial learning

Decreased apoptosis; increased neurogenesis

Increased expression of GDNF, BDNF, pCREB, ARC, HOMER1A and ERG1

133–137

Stroke EE Improved functional recovery of motor and cognitive skills

Increased spine density; decreased infarct volume; normalized astrocyte-to-neuron ratios; increased number of putative neural stem cells, astrocytes and oligodendrocyte progenitors

Increased BDNF, NGF-A and NGF-B; rescued deficit in glucocorticoid receptor II and mineralocorticoid receptor expression

138–145,157–163

Traumatic brain injury

EE Attenuated motor and cognitive deficits

Decreased lesion size; enhanced dendritic branching; increased survival of progenitor cells

Increased BDNF; decreased DAT levels

146–154,164–166

Fragile X syndrome

EE Rescued alterations in exploratory behaviour

Increased dendritic branching, spine number and appearance of mature spines

Increased GluR1 expression 167

Down syndrome EE Enhanced and impaired learning No change in dendritic structure nd 168–170

Aβ, amyloid-β; 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.

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Motor Cognitive

SomatosensoryVisual

MicrogliaPhagocytic immune cells in the brain that engulf and remove cells that have undergone apoptosis.

Long-term potentiation(LTP). An enduring increase in amplitude of excitatory postsynaptic potentials as a result of high-frequency (tetanic) stimulation of afferent pathways. It is measured both as the amplitude of excitatory postsynaptic potentials and as the magnitude of the postsynaptic cell population spike. LTP is most frequently studied in the hippocampus and is often considered to be the cellular basis of learning and memory in vertebrates.

experimental methods. Enrichment objects generally vary in composition, shape, size, texture, smell and colour (although diurnal activity patterns and the limitations of the rodent visual system could mean that somatosensory and olfactory stimuli are the most salient). In addition, there is variation in whether enrichment involves access to running wheels, which has significant implications as enhanced voluntary exercise alone has effects on the brain (discussed below). Home cages used for enrichment are generally larger than standard cages to allow room for complex and varied objects, although some protocols involve the removal of animals from normal cages into exploratory chambers for limited periods each day.

There is no consensus on which environmental enrichment paradigms are ideal with respect to benefi-cial effects on brain and behaviour. As shown in TABLE 2, studies that have examined the effect of enrichment on various brain disorders have used a variety of method-ological conditions. One key aspect appears to be the provision of environmental complexity, with enrichment objects that provide a range of opportunities for visual, somatosensory and olfactory stimulation. Another key aspect appears to be environmental novelty, achieved by changing the objects and the position of the objects in the enriched environment, which might provide additional cognitive stimulation with respect to the formation of spatial maps. It is assumed that increased complexity and novelty will lead to greater levels of stimulation and associated physical activity. However, this also depends on whether different animal models differentially interact with enriched environments. One final key parameter that varies widely within the literature is the age at which enrichment commences and the duration of exposure to enriched environments. If enrichment commences prior

to adulthood (often considered to be around 8 weeks of 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.

Environmental enrichment in wild-type rodentsEnvironmental 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-apses on some neuronal populations14–21. Furthermore, enrichment increases hippocampal neurogenesis and the integration of these newly born cells into functional circuits9,22–26. This increase in neurogenesis has been sug-gested to be mediated through mechanisms involving vascular endothelial growth factor (VEGF)27, and the recruitment of T cells and the activation of microglia28.

Many of these cellular changes are also consistent with enrichment-induced alterations in the expression of genes involved in synaptic function and cellular plas-ticity29. Enrichment can increase levels of neurotrophins, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), which play integral roles in neuronal signalling30–32. Enrichment also increases the expression of synaptic proteins, such as the presynaptic vesicle protein synaptophysin and postsynaptic density-95 protein (PSD-95) (REFS 33–35), consistent with enrichment-induced enhancement of experience-dependent synap-togenesis. Furthermore, enrichment induces alterations in the expression of NMDA (N-methyl-d-aspartate) and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunits, which are integral for glutamatergic signalling36,37, consistent with evidence that enrichment results in increased synaptic strength, including specific forms of synaptic plasticity such as long-term potentiation (LTP)38–42.

At the behavioural level, enrichment enhances learn-ing and memory19,36,43–45, reduces memory decline in aged animals46, decreases anxiety and increases exploratory activity 47–50. Enrichment-induced enhancement of learn-ing and memory might relate to cellular effects on syn-aptic plasticity and hippocampal neurogenesis, although a recent study suggests that increased hippocampal cell proliferation is not necessary for improved spatial memory performance51. It is possible that variations in environmental enrichment methods could disrupt the standardization and reproducibility of behavioural testing results. However, a study in which three lab-oratories independently enriched the environments of mice and assessed their performance on four commonly used behavioural tests showed that enrichment did not increase individual variability or the risk of obtaining conflicting behavioural data in replicate studies52.

One component of an enriched environment can involve increased motor stimulation. Studies have

Figure 1 | Environmental enrichment and the effects of enhanced sensory, cognitive and motor stimulation on different brain areas. Enrichment can promote neuronal activation, signalling and plasticity throughout various brain regions. Enhanced sensory stimulation, including increased somatosensory and visual input, activates the somatosensory (red) and visual (orange) cortices. Increased cognitive stimulation — for example, the encoding of information relating to spatial maps, object recognition, novelty and modulation of attention — is likely to activate the hippocampus (blue) and other cortical areas. In addition, enhanced motor activity, such as naturalistic exploratory movements (including fine motor skills that differ radically from wheel running alone), stimulates areas such as the motor cortex and cerebellum (green).

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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 disease

Mice (4–6/cage) housed in large standard cages (44 x 28 x 12.5 cm), containing paper, cardboard (boxes, tunnels, sheets), wooden and plastic objects, changed every 2 days

Weaned at 4 weeks of age into EE or standard housing until 5 months of age

Housed in same sized cages as enriched, but containing only normal bedding

Both Delayed onset and progression of motor symptoms; rescued cortical volume loss; BDNF and DARPP-32 expression deficits

2,4

Alzheimer’s disease

Mice (4/cage) housed in larger cages (3.236 x 104 cm3) containing running wheels, tunnels, toys

Weaned at 3 weeks of age and exposed to daily EE for 3 h/day for 1 month, then given EE 3 x/week until 6 months of age

Housed in standard cages for 5 months

Males Decreased Aβ levels and amyloid deposit; elevated neprilysin activity

8

Mice (20/cage) housed in larger cages (1 m3), with ~625 cm2 of floor space for each (>3 x space than each standard-housed control) containing 2 running wheels, plastic tubes, cardboard boxes and nesting material, changed or rearranged weekly

At ~2 months of age, mice placed into EE cages

Housed 3–4/cage in standard cages (~600 cm2 floor space, containing only bedding)

Females Increased expression of neuritic plaques; elevated steady-state Aβ levels; rescued spatial memory deficit

7

Parkinson’s disease

Mice housed in larger cage (75 x 45 x 25 cm) containing 6–7 toys, including a wheel and a small ‘house’, randomly changed weekly

Weaned at 3 weeks of age (4 mice/cage) into EE or standard housing for 2 months

Housed in standard cages (30 x 15 x 15 cm)

Males Increased resistance to MPTP insult; decreased loss of DA neurons; decreased DAT expression; increased BDNF levels

117

Epilepsy Rats (6/cage) housed in larger cage (1 x 1.5 x 1.5 m) containing a running wheel, tunnels, rubber balls, a maze, a bar-pressing food administration station and nesting material with access to edible treats

3-week-old rats assigned to EE or standard housing for 3 weeks

Housed individually in standard cages

Males Increased resistance to seizures; decreased apoptosis; increased expression of GDNF, BDNF and pCREB

133

Stroke Rats (12/cage) housed in a larger cage (815 x 610 x 450 mm) with boards providing exploration platforms, a chain, a swing and wooden blocks, changed weekly

9-week-old male rats assigned to EE or standard housing

Housed individually in standard cages

Males Improved functional recovery of motor skills

138

Traumatic brain injury

Rats housed in EE cages (70 x 70 x 46 cm) containing ~6 objects, changed daily

Pups housed with mothers from birth until weaning (P23–24), placed in EE cages either at P5–6 with mothers or at weaning, then housed 12–13/cage, until 65–66 days of age

Housed individually in standard cages from weaning (P23–24)

Both Improved performance on problem solving task

147

Fragile X syndrome

Mice (3/cage) housed in clear Plexiglas cages (35 x 20 x 25 cm) with a horizontal platform, ladder, running wheel, nesting material and assortment of plastic toys (balls, tubes, boxes, bells), changed 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

Weaned at 3 weeks of age into EE or standard housing until 60 days of age

Housed in standard Plexiglas cages (18 x 25 x 13 cm) with 3 mice/cage

Males Rescued deficit in exploratory behaviour; increased dendritic branching, spine number, appearance of mature spines and GluR1 expression

167

Down syndrome

Mice (8/cage) housed in larger cages (42 x 50 x 20 cm) with ladder connecting 2 levels, running wheel, wooden swing, plastic and wooden toys (including rolls, blocks and rocks) changed every 3 days; foods of different tastes were placed to encourage foraging

Weaned into EE or standard housing for 7 weeks, then returned to standard housing for 15 days before behavioural testing

Housed in standard Plexiglas cages (20 x 12 x 12 cm) with 2–3 mice/cage

Both Increased exploratory behaviour; enhanced spatial learning in females but not in males

168

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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Mutant huntingtin(expanded polyglutamine tract)

Abnormal protein folding/cleavage

Abnormal protein interactions

Neuronal and synaptic dysfunction

Aggregation(nuclear, cytoplasmic)

Abnormal gene expression/ protein trafficking

Altered neuromodulators(for example, BDNF)

Motor, cognitive and psychiatric symptoms

Altered neurogenesis

Altered pre- and postsynaptic signalling molecules

Environmental factors(mental stimulation,physical activity)

investigated the effect of exclusively enhancing motor activity on the brain, through access to running wheels or forced running on treadmills. Enhanced motor activ-ity increases BDNF levels53–55, promotes angiogenesis56–58, increases both hippocampal cell proliferation and sur-vival59 and the numbers of newly generated microglia in the cortex60. Forced treadmill running also improves learning61. Although increased physical activity alone might result in some of the beneficial effects observed with enrichment, it does not fully account for the broader behavioural, cellular and cognitive changes observed following environmental enrichment. Recently, wheel running during pregnancy has even been shown to result in increased neurogenesis in the offspring62. Although such in utero effects of environmental manipulations are of great interest, they are beyond the scope of the present review.

These studies in wild-type animals have propelled our understanding of gene–environment interactions in the development and plasticity of the normal brain, and might also provide new insights into understanding the interactions between genes and environment in the dysfunctional brain.

Mouse models of Huntington’s diseaseEnvironmental enrichment induces significant behav-ioural, cellular and molecular changes in transgenic mouse models of the autosomal dominant brain dis-order HD. This is a devastating disease characterized

by degeneration of the cerebral cortex and striatum, producing a progressive movement disorder (including chorea), cognitive deficits (dementia) and psychiatric symptoms (including depression), with onset usually in the fourth or fifth decade of life. The pathogenic mech-anism by which the trinucleotide CAG repeat expan-sion mutation, expressed as an extended polyglutamine tract, induces neuronal dysfunction and death is not yet fully understood. There is an inverse correlation between CAG repeat length in exon 1 of the hunting-tin (HTT) gene and age of onset of symptoms63. It has subsequently been discovered that at least eight other fatal neuro degenerative diseases (mainly spinocerebellar ataxias) are caused by CAG repeat mutations that encode expanded polyglutamine tracts in different proteins64.

Transgenic HD mice, in which the CAG repeat 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 of cell death in these HD mice until very late stages67 sug-gests that the early disease process, including the onset of behavioural deficits, involves neuronal dysfunction rather than cell death (FIG. 2).

Despite the fact that HD is an autosomal dominant disorder, we have shown that environmental enrich-ment of R6/1 HD mice greatly delays the onset of motor symptoms2,4. Recent evidence also suggests that enrichment can ameliorate spatial memory deficits in R6/1 HD mice68. We also demonstrated that environ-mental enrichment delays the degenerative loss of cerebral volume in HD mice, with a greater impact in the cortex than the striatum2. Subsequent studies have confirmed the beneficial effects of enrichment in two other transgenic models, R6/2 and N171-82Q HD mice3,69. A recent epidemiological study of human HD has shown a clear role for environmental factors in modulating the clinical onset of HD70, although the nature of these factors remains unknown. Following the initial enrichment study in HD mice, it was reported that a more stimulating environment improved physi-cal, mental and social functioning in a small cohort of HD patients71. Therefore, a better understanding of how environmental enrichment induces its beneficial effects might also provide direction for the development of other therapeutic approaches.

The dramatic effects observed following environmen-tal enrichment of HD mice raises the question of whether enhanced sensory, cognitive and/or motor stimulation is most important in mediating these beneficial effects. We have explored aspects of this question by comparing standard-housed R6/1 HD mice with those experiencing enhanced voluntary physical exercise on running wheels in the home cages72. There was only a partial delay in the onset of motor deficits in wheel-running HD mice, with less of a beneficial effect than in HD mice exposed to complex enriched environments. However, wheel run-ning did delay the onset of short-term spatial memory deficits in HD mice72, which might reflect the impact of voluntary physical exercise on the hippocampus, and

Figure 2 | Gene–environment interactions in Huntington’s disease. Schematic of postulated molecular and cellular pathogenic mechanisms and possible ways in which environmental stimulation modulates these mechanisms. Red shading indicates processes on which environmental factors might have a beneficial effect during disease onset, progression and neuropathology. BDNF, brain-derived neurotrophic factor.

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Altered APP processing

Neuronal and synaptic dysfunction

Cognitive decline and dementia

Aβ plaques NFTs

Aβ-degrading proteases(for example, neprilysin)

Altered neuronal plasticity (for example, impaired neurogenesis)

Genetic factors(APP, PS1, PS2, APO* 4 mutations)

Environmental factors(mental stimulation, physical activity, diet?) ε

Morris water mazeA task used to assess long-term spatial memory, most commonly in rodents. Animals use an array of extra-maze cues to locate a hidden escape platform that is submerged below the surface of the water. Learning in this task is hippocampus-dependent.

in particular adult neurogenesis in the dentate gyrus. It has been shown that adult R6/1 HD mice have reduced hippocampal neurogenesis73,74, and that environmental enrichment can ameliorate this deficit in adult-born neurons in the dentate gyrus of HD mice75.

There is increasing evidence for the role of synaptic dysfunction in HD pathogenesis, which could medi-ate neurodegeneration. Synaptic dysfunction in HD mice is associated with transcriptional dysregulation of neurotransmitter receptors and synaptic signal transduc-tion pathways76–78. These results are consistent with a role for neurotransmitter receptor-mediated excitotoxicity in the neurodegenerative process. Abnormal in vitro hippo-campal synaptic plasticity has been described in R6/2 HD mice and correlated with aberrant spatial memory on the Morris water maze79. Similarly, in vivo neocortical plasticity deficits have been demonstrated in R6/1 HD mice and correlated with the onset of a discrimination learning deficit that is contingent on the same sensory modality80.

Increased sensory and cognitive stimulation could exert their greatest effects within the cortex, as suggested by our cerebral volume measurements2. Gene expression studies demonstrate that wild-type mice exposed to an enriched environment exhibit altered regional brain expression of a subset of genes that is involved in neuronal signalling and plasticity29. We therefore propose that environmental enrichment overcomes deficiencies of gene expression81,82, synaptic function and experience-dependent plasticity, and ameliorates the deficits in HD mice. However, it is possible that enrichment also affects the abnormal pro-tein–protein interactions that occur in HD. For example, the aggregation of huntingtin protein fragments contain-ing expanded polyglutamine into intracellular inclusions occurs in HD mice83 and in human patients84. There is evidence that enrichment could reduce the size of these aggregates in the cortex and other brain areas81,85, imply-

ing that there are experience-dependent effects on protein aggregation, protein clearance or both.

Mouse models of Alzheimer’s diseaseAD is a neurodegenerative disorder that involves dementia and mainly affects the neocortex and hippo-campus. The disease is characterized by two pathological hallmarks — senile plaques and neurofibrillary tangles (NFTs). Plaques are extracellular deposits of amyloid, 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 hyperphosphorylated forms of the microtubule-associated protein tau90.

It is well accepted that both genes and the environ-ment have roles in the complex aetiology of AD1 (FIG. 3). Most AD cases are sporadic and seem to result from an interaction of multiple genetic and environmental factors. However, there are also early- and late-onset familial forms (familial AD, FAD) that are inherited in an autosomal dominant fashion. Linkage and cloning studies using FAD kindred have identified three genes — APP, presenilin 1 (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-erties of Aβ leading to increased amyloid pathology 91.

A genetic risk factor for the sporadic form of AD (usually late-onset) has also been found: polymorphisms in the apolipoprotein E (APOE) gene, particularly the ε4 allele, are thought to increase the risk of sporadic AD, while the ε2 allele seems to be protective92–95. APOE binds Aβ and localizes it to senile plaques, suggesting that it might have a role in Aβ clearance.

Although both genetic and environmental factors are likely to trigger the pathogenic pathways96,97 that eventu-ally lead to the neuropathology of AD, research over the last decade has focused on understanding the genetic contribution. This work has been advanced by the generation of various transgenic mouse models of AD, which have been used to model the symptomatology and neuropathology observed in humans97. However, studies have recently begun to investigate the effect of environ-mental factors on neuropathology and cognitive func-tion in transgenic models of AD. Synapse loss is a strong correlate of cognitive decline in AD98,99 and the plastic properties of synapses make them ideal candidates for modulation by environmental stimulation, which could lead to the slowing or reversal of cognitive decline. In fact, epidemiological evidence suggests that cognitive stimulation and physical activity can prevent or delay the onset of AD100–104 (BOX 1).

Levi and colleagues105 were the first to examine the effect of differential housing in a mouse model of AD, using transgenic mice containing human APOE*ε3 or APOE*ε4 alleles on a null mouse Apoe background. Mice transgenic for human APOE*ε3 that were housed in an enriched environment showed improved working memory. However, mice transgenic for human APOE*ε4, which is associated with a higher risk of AD, did not show this improvement in response to enrichment. Furthermore, the cognitive effects were associated with

Figure 3 | Gene–environment interactions in Alzheimer’s disease. Schematic of postulated molecular and cellular pathogenic mechanisms and possible ways in which environmental stimulation modulates these mechanisms. Red shading indicates processes on which environmental factors might have a beneficial effect during disease onset, progression and neuropathology. APOEε4, apolipoprotein E; APP, amyloid precursor protein; NFTs, neurofibrillary tangles; PS1, presenilin 1; PS2, presenilin 2.

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higher levels of synaptophysin and NGF in the hippo-campus of APOE*ε3, but not APOE*ε4, transgenic mice, despite similar elevations of cortical synaptophysin and NGF levels in both APOE*ε3 and APOE*ε4 transgenic animals in response to environmental enrichment.

The effect of environmental enrichment on APP/PS1 transgenic mice was investigated by Jankowsky et al.6 Mice co-expressing mutant APP and PS1 genes housed in enriched conditions developed a higher amyloid burden with increased aggregated and total Aβ compared with standard-housed littermates. Furthermore, in a subsequent study, mice overexpressing APP and/or PS1 housed in enriched conditions also showed increased expression of neuritic plaques in the hippocampus and elevated steady-state Aβ levels7. These results support similar in vitro stud-ies that have demonstrated that synaptic activity increases the production of Aβ and soluble APP derivatives106,107. By contrast, Lazarov and colleagues8 found that enriched APP/PS1 transgenic animals have decreased hippocam-pal and cortical Aβ levels and amyloid deposits compared with standard-housed controls. In addition, the enzymatic activity of neprilysin, an Aβ-degrading endopeptidase, was elevated in the brains of enriched mice and inversely correlated with amyloid burden.

The discrepancy between the reported results from Jankowsky et al. and Lazarov et al. has been a point of discussion108,109. The original study by Jankowsky and colleagues

6 involved adding and removing mice from enriched groups during the study, raising the possibility of increased stressors. However, the authors addressed this point in their subsequent study, which was carried out under more controlled conditions, and highlighted that even when using another strain of mice, there was again an increase in Aβ and plaque deposition following enrichment7. The question of whether the disparate find-ings are due to gender has been raised, given that Lazarov and colleagues used male mice whereas Jankowsky and co-workers used female mice. Furthermore, Jankowsky

and colleagues highlighted additional differences between the two studies, such as the differing num-bers of running wheels available in the cages and the enrichment paradigm itself 7.

The exact role of Aβ levels and plaque deposition in AD and their impact on cognitive function has not been fully elucidated, and therefore it is more difficult to inter-pret the findings of differing amyloid levels as a result of environmental enrichment. Although Lazarov et al. did not examine the effect of enrichment on cognitive behav-iour, interestingly, Jankowsky and colleagues showed that despite an increase in the expression of hippocampal plaques and in the levels of Aβ, environmental enrich-ment rescued a deficit in hippocampal-dependent spatial memory7. Therefore, enrichment had a beneficial effect on cognitive function, irrespective of the increased levels of amyloid. In line with this, Arendash et al.5 observed that aged APP transgenic mice exposed to environmen-tal enrichment show cognitive enhancement in spatial learning, but no change in Aβ deposition compared with 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-cise can lead to enhanced cognitive function110. Mice expressing a double mutant form of APP (TgCRND8 mice) housed with running wheels for 5 months showed an enhanced rate of learning in the Morris water maze and decreased expression of Aβ plaques. This effect was independent of changes in neprilysin and insulin-degrading enzyme, and instead might have involved neuronal metabolism changes that are known to affect APP processing and to be regulated by exercise.

Studies have also investigated the effects of enrich-ment on neurogenesis in AD mouse models. Conditional knockout mice that have the PS1 gene selectively deleted from excitatory neurons of the adult forebrain show a deficiency in enrichment-induced neurogenesis in the dentate gyrus111. Furthermore, neuronal overexpres-sion of either wild-type human PS1 or the FAD mutant P117L in transgenic mice leads to an increase in the rate of neural progenitor proliferation in response to environmental enrichment112. However, both PS1 and FAD mutant P117L animals housed under standard and enriched conditions show impaired survival of neural progenitor cells in the hippocampus, leading to fewer new neurons being generated, which suggests that this deficiency in enrichment-induced neurogenesis represents a lack of hippocampal plasticity, and in part underlies the cognitive deficits observed in AD.

Although there remains debate about the effect of enrichment and exercise on the neuropathological abnormalities in AD, these studies, together with epide-miological investigations1, suggest that both mental and physical activity help to slow down or prevent the cogni-tive decline associated with AD, possibly by preventing neuronal dysfunction and allowing synaptic recovery.

Models of other neurological disordersParkinson’s disease. PD is clinically characterized by a tetrad of motor symptoms: muscular rigidity, postural abnormalities, bradykinesia and a characteristic tremor.

Box 1 | Environmental enrichment, brain plasticity and cognitive reserve

Environmental enrichment induces various alterations in brain structure and function, as discussed in this review, including increasing the birth and maturation of new neurons into functional circuits9,22–26, enhancing the expression of molecules involved in neuronal signalling29,30–32 and promoting synaptic plasticity38–42. These changes can influence brain function and plasticity by modifying synaptic transmission, enhancing signalling between neuronal ensembles and strengthening neuronal circuits. Enrichment-induced strengthening of neuronal and synaptic connectivity provides a mechanism for how the brain may more efficiently utilize existing neuronal networks and recruit alternative networks when required.

This experience-dependent increase in neuronal connectivity might represent a mechanism of relevance to the theory of ‘cognitive reserve’ or ‘brain reserve’180,181, and explain how enrichment could make the brain more resilient, in the case of brain disorders, and to damage or degeneration. Cognitive reserve is most likely to be a function of both genetic and environmental factors and has been observed particularly 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 the levels of mental and physical activity, are associated with rate of cognitive decline and onset of dementia182. We propose that environmental enrichment and the concept of cognitive reserve might also be relevant to psychiatric disorders that involve cognitive dysfunction as part of the symptomatology (for example, schizophrenia, bipolar disorder and depression).

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However, impairments in cognitive function also accom-pany PD, with dementia as a prominent feature in the late stages (for a review, see REF. 113). Neurologically, PD primarily involves the degeneration of nigrostriatal dopaminergic neurons that project from the substantia nigra pars compacta (SNc) to the striatum, and the formation of intracytoplasmic inclusions known as Lewy bodies. The aetiology of PD is unknown. Various PD-associated genes have recently been identified, including α-synuclein, parkin, PINK1 (phosphatase and tensin homologue (PTEN)-induced kinase 1), DJ1 (Parkinson disease (autosomal recessive, early onset) 7) and LRRK2 (leucine-rich repeat kinase 2) (for a review, see REF. 114). However, environmental factors, such as physical trauma, toxic insults and infections, have long been thought to have a role in PD115.

Although various transgenic models of PD are cur-rently being developed, none has yet been demonstrated to have construct, face and predictive validity. Animal models that have been the most widely investigated use toxin-induced lesions to mimic PD-like symptoms, such as the unilateral 6-hydroxydopamine (6-OHDA) rat model and the bilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model (for a review, see REF. 116). Animals exposed to an enriched environment exhibit resistance to an MPTP insult117,118. Furthermore, rats housed in enriched conditions following a 6-OHDA insult show improved motor function119. Similarly, animals exposed to moderate treadmill running following either a 6-OHDA or MPTP insult exhibit sparing of behavioural impairment involving forelimb use and movement120.

At the cellular level, treadmill running follow-ing 6-OHDA or MPTP treatment is associated with a decreased loss of striatal dopamine and its metabolites120. Similarly, animals exposed to enrichment following MPTP injury show increased glial cell line-derived neurotrophic factor (Gdnf) expression and decreased loss of dopaminergic neurons and monoamine trans-porters, including dopamine transporter (DAT)117,118. As DAT is required for MPTP-induced dopaminergic neurotoxicity, an enrichment-induced decrease in DAT levels is suggestive of a mechanism for protection from neurodegeneration.

Amyotrophic lateral sclerosis. ALS is the most common form of motor neuron disease, with muscle wasting and paralysis as prominent symptoms. ALS is characterized by the degeneration of motor neurons in the cortex, brainstem and spinal cord. Although twin studies sup-port a role for both genetic and environmental factors in ALS, the nature of environmental modifiers is unknown. Some epidemiological studies have suggested a relation-ship between increased physical activity and sporadic ALS121–124, whereas others have found no such associa-tion121,125–127. Therefore, the environmental influence on ALS is still poorly understood.

The predominantly used mouse model of ALS over-expresses the mutant human form of the Cu/Zn super-oxide dismutase-1 (SOD1). In one study, SOD1 animals given long-term exposure to motorized running wheels showed no alterations in disease onset or progression128.

However, another study demonstrated sex differences in disease onset and progression, with exercise delaying the disease in female but not male mice129. Another study using a similar experimental paradigm showed that treadmill running delayed disease onset and increased survival rate for males, but not females130.

Onset and progression of disease symptoms was recently compared in transgenic ALS mice (with the SOD1G93A mutation) housed in standard conditions, environmental enrichment or with access to running wheels131. Environmental enrichment significantly improved motor performance but was also associated with an acceleration of overt end-stage disease symp-tom onset. By contrast, increased physical activity using running wheels had no effect on disease onset and pro-gression131. These results suggest that the stereotyped physical activity associated with running on wheels or treadmills differs qualitatively and quantitatively from enhanced fine motor activity induced by enrichment in the absence of running wheels, and therefore have impli-cations for environmental manipulations using models of other CNS disorders.

Epilepsy. Epilepsy is a neurological condition that is char-acterized by unpredictable repeated seizures, caused by aberrant electrical discharge in the brain, and can result in selective cell loss and gliosis in specific brain regions. It has varied causes and manifestations, with many dis-tinct seizure types and several identifiable syndromes. Although risk factors such as head injury, CNS infections and cerebrovascular disease (particularly in the elderly) have been associated with epilepsy, susceptibility to epilepsy has been suggested to be partly genetic132. This indicates that the complex interplay between genetic and environmental factors might explain our incomplete understanding of the aetiology of this disorder.

Experimental animal models of epilepsy have been generated using proconvulsant drugs and electrical stim-ulation, and have recently been used to investigate the effect of environmental experience. Rats housed under enriched conditions for 3 weeks showed a resistance to seizures and exhibited decreased hippocampal cell death133. Enrichment also resulted in increased levels of GDNF and BDNF. However, the control animals in this study were individually housed, and there-fore these results could, in part, represent effects of isolation and deprivation rather than enrich-ment alone. Furthermore, enriched animals also had an altered dietary intake, with the addition of ‘edible treats’ to the enrichment paradigm. In another study in which the enrichment paradigm incorporated edible treats, animals that were environmentally enriched prior to amygdala kindling were shown to exhibit an increased latency to induce kindling epileptogenesis compared with animals housed in isolation134.

Following kainic acid or lithium-pilocarpine-induced seizures, beneficial effects on behaviour have been observed with enrichment increasing exploratory activity135 and spatial learning performance136,137. In addi-tion, exposure to enrichment following epileptogenesis increases neurogenesis134,136 and the expression of

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EndophenotypeA quantitative biological trait associated with a complex genetic disorder that is hoped to more directly index the underlying pathophysiology, facilitating efforts to find or characterize contributing genes.

molecules involved in neuronal and synaptic plasticity, such as phosphorylated levels of cyclic AMP-responsive element binding (CREB)136, ARC, HOMER1A and ERG1135.

Stroke and traumatic brain injury. As environmental enrichment has numerous beneficial effects on brain and behaviour, several studies have investigated its effect on functional recovery following experimental models of stroke and traumatic brain injury. An ischae-mic stroke, which results from a sustained deficit in focal cerebral perfusion, is one of the main causes of permanent disability and death. Evidence suggests that the recovery of motor function following experimental stroke is enhanced by environmental enrichment138–141. Enrichment also significantly attenuates deficits in learn-ing and memory142–145. Similarly, exposure to environ-mental enrichment following experimental models of brain injury enhances functional outcome and attenuates both motor and cognitive deficits146–154. Furthermore, enrichment combined with additional rehabilitative stim-ulation — such as multimodal early-onset stimulation (MEOS), which involves increased sensory stimulation and specific motor training following brain injury155, or intensive task-specific skill training following an ischaemic insult156 — reverses motor deficits.

In addition to aiding functional recovery, post-ischaemic environmental enrichment: decreases inf-arct volume144; increases dendritic spine density157; increases trophic factors such as BDNF158, NGF-A and NGF-B159,160; rescues deficits in glucocorticoid receptor II (REF. 159) and mineralocorticoid receptor gene expres-sion160; normalizes astrocyte-to-neuron ratios161; attenu-ates a deficit in cell proliferation in the subventricular zone; and increases the number of putative neural stem cells162. Most of these newly born cells were subsequently demonstrated to be either astrocytes or oligodendrocyte progenitors/polydendrocytes, which is suggestive of a beneficial mechanism for repair and plasticity follow-ing injury163. Similarly, enrichment following traumatic brain injury has beneficial effects on the brain, such as decreasing lesion size152, enhancing dendritic branch-ing149, promoting the survival of progenitor cells164, increasing BDNF165 and decreasing DAT levels166.

Disorders of nervous system developmentFragile X syndrome. The most common form of heredi-tary mental retardation, fragile X syndrome, is due to a mutation of the fragile X mental retardation 1 (FMR1) gene on the X chromosome. Affected individuals carry an expanded trinucleotide repeat that leads to transcrip-tional silencing of the FMR1 gene. Fmr1-knockout mice, which lack the normal fragile X mental retardation pro-tein (FMRP), show both cognitive and neuronal altera-tions. A recent study showed that enrichment rescues alterations in exploratory behaviour in Fmr1-knockout mice167. Furthermore, enrichment increased dendritic branching, spine number, appearance of mature spines and expression of the AMPA receptor subunit GluR1 in the visual cortex. Interestingly, levels of FMRP in wild-type mice were not altered by enrichment, suggesting

that environmental enrichment can exert its effect by acti-vating glutamatergic signalling pathways independently of FMRP expression.

Down syndrome. Down syndrome is the most significant genetic cause of mental retardation and involves tri-somy of chromosome 21. Currently, there are several murine models with segmental trisomy; however, the Ts65Dn mouse model is the most commonly used. Using this model, Martinez-Cue and others168 provided some suggestive evidence that enrichment improved learning in females, but deteriorated learning in males. In a follow-up study, the authors investigated whether this negative effect of enrichment was associated with housing numbers169. Results revealed that housing numbers had no impact on learning performance in control animals but, again, enrichment showed a negative effect on learning in male Ts65Dn mice. Interestingly, morphological analysis of pyramidal neurons in the frontal cortex of female mice has shown that although enriched control animals exhibit sig-nificantly more dendritic branching and spines compared with non-enriched controls, there was no effect of enrich-ment on dendritic structure in Ts65Dn mice170. Therefore, the effect of environmental stimulation on cognitive and cellular plasticity in this model of Down syndrome, and the gender specificity, remain to be elucidated.

Psychiatric disordersPsychiatric disorders provide a challenging degree of complexity with respect to genetic and environmental factors and their interactions. The most common psy-chiatric disorders are bipolar disorder (manic depres-sion), unipolar (major) depression, schizophrenia and drug addiction. As we have only recently begun to understand the complex genetics of these disorders, as well as possible environmental triggers, current animal models are somewhat limited with respect to construct, face and predictive validity.

The genetics of bipolar disorder has not advanced suf-ficiently for convincing animal models to be developed. However, there is extensive literature on animal models of depression, including their use in the development of antidepressant treatments171. Manipulations that modify stress levels by disrupting the early-rearing environment have been combined with environmental enrichment, for example, to show that enrichment can reverse the effects of maternal separation on both the hypothalamic-pituitary-adrenal (HPA) and behavioural responses to stress172,173.

Although the genetics of schizophrenia has begun to be elucidated in recent years, it is not yet clear how accurately we will be able to model this devastating disorder in ani-mals. One would imagine that the positive symptoms, such as hallucinations and delusions, will be extremely difficult to model in animals. However, the negative symptoms, such as cognitive deficits, could prove more tractable as endophenotypes in animal models. A number of knockout mouse lines exhibit behavioural phenotypes of relevance to schizophrenia. In one of these lines, involving disrup-tion of the phospholipase C-β1 pathway (PLC-β1), the key behavioural abnormalities of spontaneous hyperactivity in

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Critical periodA strict time window during which experience provides information that is essential for normal development and permanently alters performance.

the open field and sensorimotor gating (prepulse inhibi-tion) deficits, observed in standard-housed knockout mice, were reversed by environmental enrichment174.

Drug addiction is a complex disorder that is strongly influenced by environmental factors. Enrichment has been shown to increase resistance to the effects of drugs such as cocaine117,175 and amphetamines176,177. This sug-gests that future enrichment studies could contribute to further elucidating the mechanisms underlying addiction and provide opportunities for rehabilitation.

Enviromimetics as novel therapeuticsUnderstanding the molecular and cellular effects of environmental stimulation might not only provide mech anistic insights into the pathogenesis of environ-mentally modulated brain disorders, but could guide the development of a new class of therapeutics (FIG. 4). Investigations of gene–environment interactions might reveal molecular targets for the development of therapeutic agents that mimic or enhance the beneficial effects of environmental stimulation (enviromimet-ics)178,179. Putative enviromimetics could be developed for the treatment of HD, AD and a range of other cur-rently incurable brain disorders. Our recent demonstra-tion that the antidepressant fluoxetine can mimic some of the beneficial effects of environmental enrichment in HD mice74 implies that fluoxetine and perhaps other selective serotonin reuptake inhibitors could act as enviro mimetics in this instance.

Conclusions and future directionsAlthough great progress has been made in understand-ing mechanisms that mediate the behavioural, cellular and molecular effects of environmental enrichment, the research raises many new questions. How does environ-mental enrichment from early ages in animals relate to gene–environment interactions in human brain develop-ment? Does environmental enrichment exert differing effects on the developing and mature brain? Are there critical periods when environmental enrichment inter-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 observed effects of environmental enrichment? How do 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 development of occupational therapies, ‘enviromimetics’ and other medical treatments?

Another intriguing question concerns the gender differences observed between some of the studies dis-cussed here. However, few studies have directly com-pared males and females under identical experimental conditions. Enrichment could have differential effects on the way in which animals of each sex interact with their environments and with each other. In particular, in group-housed male rodents, dominance hierarchies and territoriality might have additional interaction effects. Furthermore, sex hormones and other gen-der-specific aspects of brain structure and function could provide differential neural substrates for enrich-ment-induced plasticity. Further work is required to unravel the nature and contribution of gender influences to the effects of enriched environments.

It is also possible that strain differences and other genetic and epigenetic variables could alter the responsiveness of animals to the enrichment paradigm. Most of the studies investigating the effects of environmental enrichment have been undertaken on mice and rats, and rodents exhibit innate strain variances in behaviours such as anxiety, exploratory activity and learning and memory. However, as seen from this review, environmental enrichment — as a model of enhanced cognitive, sensory and motor stimula-tion — has been shown to induce experience-dependent plasticity at structural and functional levels in many animal models of the healthy and dysfunctional brain.

Most models of brain development, function and dys-function involve studying animals in only one (standard) housing condition, which affords little opportunity for sensory, cognitive or motor stimulation. Therefore, the dramatic effects of environmental enrichment described here have major implications for neuroscientific research involving animals. These effects raise the question of whether most standard conditions represent a state of sensory, cognitive and motor deprivation and are there-fore suboptimal for medical research. Such research aims to model humans, who experience an enormous range of mental and physical activities. However, the increase in cage sizes, costs and experimental variables associated with enrichment means that most research will continue to be conducted under standard housing conditions.

Molecularmodulators

Pharmacologicalmodulators

Disease initiators —genetic and environmental contributors

Altered gene expression(for example, transcriptional dysregulation)

Abnormal protein–proteininteractions

Other molecular mediators of neuronal dysfunction

Region-specific neuronal/synapticdysfunction and cell death

Disrupted neuronal circuitry

Disease symptoms

Environmentalmodulators

Figure 4 | Molecular mediators, environmental modulators and pharmacological modulators (enviromimetics). Illustration of some mechanistic aspects of pathogenesis that are common to many brain disorders, particularly neurodegenerative diseases, and the ways in which environmental factors (red shading) might act at multiple levels of disease pathways. Furthermore, the concept of molecular modulators of pathogenesis is illustrated (green shading), along with the proposal that experimental paradigms such as environmental enrichment might facilitate development of pharmacological modulators (enviromimetics) that mimic or enhance the beneficial effects of environmental stimulation (overlapping area of red and green shading).

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Finally, a key remaining question is how the environ-mental enrichment of animals relates to the richness of human living experience. Although most humans do experience high levels of complexity and novelty through-out postnatal development and adult life, individuals vary widely in their levels of mental stimulation and physical activity. Therefore, an important future direction will be to model more closely the environmental factors that are

relevant to the human condition in animal models, par-ticularly those models that attempt to recapitulate human disorders. Nevertheless, the research described here, combined with the development of approaches such as functional genomics and brain imaging, paves the way for a new understanding of gene–environment interactions in the healthy and diseased brain, which could eventually lead to a range of therapeutic advances.

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AcknowledgementsWe thank members of the Hannan laboratory, H. Grote, N. Mazarakis, S. Miller, T. Spires, A. van Dellen and C. Hannan for useful discussions and comments on earlier drafts of the manuscript. We also appreciate the constructive suggestions from the referees during peer review. A.J.H. is supported by an R. D. Wright award and project grants from the National Health and Medical Research Council (Australia).

Competing interests statementThe authors declare no competing financial interests.

DATABASESThe following terms in this article are linked online to:Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geneα-synuclein | APOE | APP | DAT | DJ1 | FMR1 | Gdnf | LRRK2 | parkin | PINK1 | PS1 | PS2 | PSD-95 | SOD1 | VEGFOMIM: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIMAlzheimer’s disease | amyotrophic lateral sclerosis | bipolar disorder | Down syndrome | fragile X syndrome | Huntington’s disease | Parkinson’s disease | schizophrenia | unipolar depression

FURTHER INFORMATIONHoward Florey Institute: http://www.hfi.unimelb.edu.auAccess to this links box is available online.

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