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Enriched environments, experiencedependent 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.
Howard Florey Institute,
National Neuroscience
Facility, University of
Melbourne, Victoria 3010,
Australia.
Correspondence to A.J.H.
e-mail:
ajh@hfi.unimelb.edu.au
doi:10.1038/nrn1970
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 monozygotic twins, have provided important clues as to the relevant contribution of genetic and environmental factors1.
However, owing to the enormous number of environmental variables in human populations, such studies have been
limited in their ability to demonstrate the involvement of
specific environmental factors in particular brain disorders. Animal models have proved crucial in identifying
molecular and cellular mediators of pathogenesis, as
well as environmental modulators. However, most published 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.
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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), amyotrophic lateral sclerosis (ALS), fragile X syndrome, Down
syndrome and various forms of brain injury (TABLE 1).
These findings have implications for clinical occupational 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)
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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
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
PA
Partially delayed onset of motor
symptoms; delayed onset of
short-term spatial memory deficits
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)
PA
Enhanced learning and memory
Decreased Aβ
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
PA
Attenuated motor impairment
nd
Decreased loss of striatal DA
and its metabolites
120
EE
Accelerated progression to endstage symptoms; delayed onset of
motor coordination deficits
nd
nd
131
PA
Accelerated, delayed or no change nd
in disease onset
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 astrocyteto-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
Enhanced and impaired learning
No change in dendritic structure
nd
Alzheimer’s
disease
Parkinson’s
disease
Amyotrophic
lateral sclerosis
Down syndrome EE
Altered BDNF mRNA levels
Increased expression of
synaptophysin, NGF and
neprilysin
Refs
2–4,68,69,
75,81,82,85
72
5–8,105,
111,112
110
117–119
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-1,2,3,6tetrahydropyridine; 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
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
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relative to standard conditions. Indeed, the term ‘enrichment’ is sometimes used interchangeably with the terms
‘complexity’ or ‘novelty’ to describe housing conditions.
Standard housing conditions often vary between laboratories. 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 conditions 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 laboratories, and is often not fully described in published
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Motor
Cognitive
Visual
Somatosensory
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).
Microglia
Phagocytic 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.
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.
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 beneficial 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 methodological 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
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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 thickness11–13. Subsequently, various studies have shown that
enrichment increases dendritic branching and length,
the number of dendritic spines and the size of synapses 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 suggested 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 plasticity29. 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 enrichmentinduced enhancement of experience-dependent synaptogenesis. 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 learning and memory19,36,43–45, reduces memory decline in aged
animals46, decreases anxiety and increases exploratory
activity 47–50. Enrichment-induced enhancement of learning and memory might relate to cellular effects on synaptic 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 laboratories 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
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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
Alzheimer’s
disease
Mice (4/cage) housed in larger cages Weaned at 3 weeks
(3.236 x 104 cm3) containing running of age and exposed
wheels, tunnels, toys
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
7
2,4
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 Females
in standard cages
(~600 cm2 floor
space, containing
only bedding)
Increased expression of
neuritic plaques; elevated
steady-state Aβ levels;
rescued spatial memory
deficit
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-1,2,3,6tetrahydropyridine; P, postnatal day; pCREB, phosphorylated cyclic AMP responsive element-binding protein.
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Mutant huntingtin
(expanded polyglutamine tract)
Environmental factors
(mental stimulation,
physical activity)
Abnormal protein folding/cleavage
Abnormal protein interactions
Abnormal gene expression/
protein trafficking
Altered
neuromodulators
(for example, BDNF)
Altered
neurogenesis
Aggregation
(nuclear, cytoplasmic)
Altered pre- and
postsynaptic
signalling molecules
Neuronal and synaptic dysfunction
Motor, cognitive and psychiatric symptoms
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.
investigated the effect of exclusively enhancing motor
activity on the brain, through access to running wheels
or forced running on treadmills. Enhanced motor activity increases BDNF levels53–55, promotes angiogenesis56–58,
increases both hippocampal cell proliferation and survival59 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 disease
Environmental enrichment induces significant behavioural, cellular and molecular changes in transgenic
mouse models of the autosomal dominant brain disorder HD. This is a devastating disease characterized
NATURE REVIEWS | NEUROSCIENCE
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 mechanism by which the trinucleotide CAG repeat expansion 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 huntingtin (HTT) gene and age of onset of symptoms63. It has
subsequently been discovered that at least eight other
fatal neurodegenerative 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 suggests 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 enrichment 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 environmental 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
mice 3,69. 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 physical, 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 environmental 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 running 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
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Environmental factors
(mental stimulation, physical activity, diet?)
Genetic factors
(APP, PS1, PS2, APO*ε 4 mutations)
Altered APP processing
Aβ-degrading
proteases
(for example,
neprilysin)
Aβ plaques
NFTs
Altered neuronal
plasticity (for example,
impaired neurogenesis)
Neuronal and synaptic dysfunction
Cognitive decline and dementia
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.
Morris water maze
A task used to assess longterm 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 mediate neurodegeneration. Synaptic dysfunction in HD
mice is associated with transcriptional dysregulation of
neurotransmitter receptors and synaptic signal transduction pathways76–78. These results are consistent with a role
for neurotransmitter receptor-mediated excitotoxicity in
the neurodegenerative process. Abnormal in vitro hippocampal 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 protein–protein interactions that occur in HD. For example,
the aggregation of huntingtin protein fragments containing 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-
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ing that there are experience-dependent effects on protein
aggregation, protein clearance or both.
Mouse models of Alzheimer’s disease
AD is a neurodegenerative disorder that involves
dementia and mainly affects the neocortex and hippocampus. 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 proteolysis 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 environment 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 properties 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 eventually 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 environmental factors on neuropathology and cognitive function 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
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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).
higher levels of synaptophysin and NGF in the hippocampus 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 steadystate Aβ levels7. These results support similar in vitro studies 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 hippocampal 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 findings 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
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and colleagues highlighted additional differences
between the two studies, such as the differing numbers 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 interpret 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 behaviour, interestingly, Jankowsky and colleagues showed that
despite an increase in the expression of hippocampal
plaques and in the levels of Aβ, environmental enrichment 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 environmental 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 exercise 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 insulindegrading 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 enrichment 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 overexpression 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 epidemiological investigations1, suggest that both mental and
physical activity help to slow down or prevent the cognitive decline associated with AD, possibly by preventing
neuronal dysfunction and allowing synaptic recovery.
Models of other neurological disorders
Parkinson’s disease. PD is clinically characterized by a
tetrad of motor symptoms: muscular rigidity, postural
abnormalities, bradykinesia and a characteristic tremor.
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However, impairments in cognitive function also accompany 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 currently 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-1,2,3,6tetrahydropyridine (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 following 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 transporters, 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 support a role for both genetic and environmental factors in
ALS, the nature of environmental modifiers is unknown.
Some epidemiological studies have suggested a relationship between increased physical activity and sporadic
ALS121–124, whereas others have found no such association121,125–127. Therefore, the environmental influence on
ALS is still poorly understood.
The predominantly used mouse model of ALS overexpresses the mutant human form of the Cu/Zn superoxide dismutase-1 (SOD1). In one study, SOD1 animals
given long-term exposure to motorized running wheels
showed no alterations in disease onset or progression128.
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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
wheels 131. Environmental enrichment significantly
improved motor performance but was also associated
with an acceleration of overt end-stage disease symptom onset. By contrast, increased physical activity using
running wheels had no effect on disease onset and progression131. 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 implications for environmental manipulations using models
of other CNS disorders.
Epilepsy. Epilepsy is a neurological condition that is characterized 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 distinct 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 stimulation, 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 therefore these results could, in part, represent effects
of isolation and deprivation rather than enrichment 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-pilocarpineinduced seizures, beneficial effects on behaviour have
been observed with enrichment increasing exploratory
activity135 and spatial learning performance136,137. In addition, exposure to enrichment following epileptogenesis
increases neurogenesis 134,136 and the expression of
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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 ischaemic 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 learning and memory142–145. Similarly, exposure to environmental enrichment following experimental models of
brain injury enhances functional outcome and attenuates
both motor and cognitive deficits146–154. Furthermore,
enrichment combined with additional rehabilitative stimulation — 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, postischaemic environmental enrichment: decreases infarct 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 expression160; normalizes astrocyte-to-neuron ratios161; attenuates 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 following injury163. Similarly, enrichment following traumatic
brain injury has beneficial effects on the brain, such as
decreasing lesion size152, enhancing dendritic branching149, promoting the survival of progenitor cells 164,
increasing BDNF165 and decreasing DAT levels166.
Endophenotype
A 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.
Disorders of nervous system development
Fragile X syndrome. The most common form of hereditary 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 transcriptional silencing of the FMR1 gene. Fmr1-knockout mice,
which lack the normal fragile X mental retardation protein (FMRP), show both cognitive and neuronal alterations. 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
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that environmental enrichment can exert its effect by activating glutamatergic signalling pathways independently
of FMRP expression.
Down syndrome. Down syndrome is the most significant
genetic cause of mental retardation and involves trisomy 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 significantly more dendritic branching and spines compared
with non-enriched controls, there was no effect of enrichment 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 disorders
Psychiatric disorders provide a challenging degree of
complexity with respect to genetic and environmental
factors and their interactions. The most common psychiatric disorders are bipolar disorder (manic depression), 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 sufficiently 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 hypothalamicpituitary-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 animals. 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 disruption of the phospholipase C-β1 pathway (PLC-β1), the key
behavioural abnormalities of spontaneous hyperactivity in
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Environmental
modulators
Pharmacological
modulators
Molecular
modulators
Disease initiators —
genetic and environmental
contributors
Altered gene expression
(for example, transcriptional
dysregulation)
Abnormal
protein–protein
interactions
Other molecular
mediators of
neuronal dysfunction
Region-specific neuronal/synaptic
dysfunction and cell death
Disrupted neuronal circuitry
Disease symptoms
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).
the open field and sensorimotor gating (prepulse inhibition) 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 suggests that future enrichment studies could contribute to
further elucidating the mechanisms underlying addiction
and provide opportunities for rehabilitation.
Critical period
A strict time window during
which experience provides
information that is essential for
normal development and
permanently alters
performance.
Enviromimetics as novel therapeutics
Understanding the molecular and cellular effects of
environmental stimulation might not only provide
mechanistic insights into the pathogenesis of environmentally 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 (enviromimetics)178,179. Putative enviromimetics could be developed
for the treatment of HD, AD and a range of other currently incurable brain disorders. Our recent demonstration 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
enviromimetics in this instance.
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Conclusions and future directions
Although great progress has been made in understanding mechanisms that mediate the behavioural, cellular
and molecular effects of environmental enrichment, the
research raises many new questions. How does environmental enrichment from early ages in animals relate to
gene–environment interactions in human brain development? Does environmental enrichment exert differing
effects on the developing and mature brain? Are there
critical periods when environmental enrichment interventions 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 discussed here. However, few studies have directly compared 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 gender-specific aspects of brain structure and function
could provide differential neural substrates for enrichment-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 stimulation — 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 dysfunction 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 therefore 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.
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Finally, a key remaining question is how the environmental enrichment of animals relates to the richness of
human living experience. Although most humans do
experience high levels of complexity and novelty throughout 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
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Acknowledgements
We 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 statement
The authors declare no competing financial interests.
DATABASES
The following terms in this article are linked online to:
Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=gene
α-synuclein | APOE | APP | DAT | DJ1 | FMR1 | Gdnf | LRRK2 |
parkin | PINK1 | PS1 | PS2 | PSD-95 | SOD1 | VEGF
OMIM: http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=OMIM
Alzheimer’s disease | amyotrophic lateral sclerosis | bipolar
disorder | Down syndrome | fragile X syndrome | Huntington’s
disease | Parkinson’s disease | schizophrenia | unipolar
depression
FURTHER INFORMATION
Howard Florey Institute: http://www.hfi.unimelb.edu.au
Access to this links box is available online.
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