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Environmental enrichment and neurogenesis: from mice
to humans
Gregory D Clemenson1, Wei Deng2 and Fred H Gage2
The brain is a dynamic structure that constantly undergoes
cellular and molecular changes in response to the environment.
Ultimately, these experience-dependent changes modify and
shape behavior. One example of this neuroplasticity is the
robust and continuous generation of new neurons that occurs
in the dentate gyrus (DG) of the hippocampus. These new
neurons are thought to play a fundamental role in
hippocampus-dependent behavior and are modulated by
experience and changes in the environment. In this review, we
will focus on the cognitive and molecular relationship between
environmental enrichment and adult neurogenesis. In addition,
we discuss some of the similarities between the human and
animal literature in regards to neurogenesis, hippocampusdependent behavior, and environmental enrichment.
Addresses
1
Center for the Neurobiology of Learning and Memory and Department
of Neurobiology and Behavior, University of California, Irvine, United
States
2
The Salk Institute for Biological Sciences, United States
Corresponding author: Gage, Fred H (gage@salk.edu)

Current Opinion in Behavioral Sciences 2015, 4:5662

This review comes from a themed issue on Cognitive enhancement
Edited by Barbara J Sahakian and Arthur F Kramer
For a complete overview see the Issue and the Editorial
Available online 2nd March 2015
http://dx.doi.org/10.1016/j.cobeha.2015.02.005
2352-1546/# 2015 Elsevier Ltd. All rights reserved.

Environmental enrichment and the influence

on neurogenesis
The term enriched environment (EE) is often used to
describe an environmental manipulation administered to
rodents. EE is often characterized as a large environment
with toys, tunnels, bedding and running wheels and
designed to provide social, physical and sensory stimulation. Often times, the environments are periodically rearranged and new toys and objects are introduced to keep
the environment novel. It is well established that EE
modulates hippocampal neurogenesis and behavior,
resulting in an increase in newborn neurons and enhanced
hippocampus-dependent cognition [1]. One of the first
reports demonstrated these pro-neurogenic effects of EE
by simply allowing mice to live in an EE for 40 days.
There was a significant increase in the number of
Current Opinion in Behavioral Sciences 2015, 4:5662

hippocampal granule cells and these mice showed a

marked improvement in learning the Morris water maze
(MWM) compared to mice in standard housing [2].

EE factors that interact with neurogenesis

It is important to remember that there is no standardization of EE with regard to procedure and methodology.
Studies vary drastically in terms of environment size,
stimulation used (various tunnels and toys), with or without running wheels, as well as BrdU injection paradigms
and timing of EE exposures. Despite these differences,
we address several key factors that influence neurogenesis. Exercise is often studied independently of EE and
for the purposes of this review, we will attempt to
highlight influences specifically of EE without a running
wheel and refer to these as EE-only.
Due to the complexity of EE, there are many components, including social, sensory, spatial and physical
stimulation that may contribute to the observed effects.
The physical stimulation of EE provided by access to
running wheels has been singled out as a robust regulator
of neurogenesis. Exposure to a running wheel led to not
only increased hippocampal neurogenesis but also improved spatial learning in the MWM and enhanced DG
long-term potentiation (LTP) in mice [3,46]. A wealth
of information exists on the positive effects of exercise
and running [7,8]. In addition to numerous effects of
exercise, independent of neurogenesis, wheel running
has been shown to significantly influence hippocampus
dependent cognition, synaptic plasticity, spine density,
neurotransmitter release, and even angiogenesis in the
hippocampus of the brain.
While physical exercise has been shown repeatedly to
play a crucial role in EE, the impact of the complexity and
exploration of the EE cage itself on neurogenesis and
cognition should not be underestimated. Despite variable
results when using EE-only without a running wheel
[5,6], a number of studies have shown that EE-only is
capable of inducing neurogenesis [3,9,10,11,12,13,14].
Acute exposure (24 hours) to either EE-only or running
wheel suggested that these two manipulations may influence different proliferative populations of granule cells
[10]. One hour prior to the 24-hour exposure, animals
received one injection of BrdU. Immediately following
the initial start of the EE-only and exercise (running
wheel) manipulation, there was no difference in BrdU+
cells between any of the groups. Upon completion of the
24-hour exposure, however, both EE-only and exercise
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Environmental enrichment and neurogenesis Clemenson, Deng and Gage 57

groups showed a significant increase in absolute BrdU+

cells and BrdU+/Nestin-GFP+/Prox1+ (type-2b) cells
when compared to controls. Interestingly, exercise animals showed a specific increase in the number of BrdU+/
Nestin-GFP+/Prox1 (type-2a) cells and EE-only animals
showed a specific increase in the number of BrdU+/nesting-GFP /Prox1+ (type-3) cells. Despite the short exposure to EE-only and exercise, these results suggest a
differential influence on hippocampal neurogenesis. Exercise increases proliferation in early type-2a progenitor
cells whereas EE-only may exert a more specific influence on postmitotic type-3 cells.
In addition to neurogenesis, animals exposed to EE-only
show increased expression of the neurotrophic factor,
nerve growth factor (NGF), and enhanced synaptogenesis
[13,15]. Cognitively, animals exposed to EE-only showed
improvements in spatial memory (object displacement
task), working memory (T-maze), recognition memory
(novel object recognition), and contextual fear memory
[13,14]. These studies illustrate the molecular and behavioral changes associated with EE-only in mice.
Many of these enhancements observed with EE-only
may be attributed to the exploration of these intricate
environments. Mice living in a large, multi-tiered
enriched environment (no running wheel) for 3 months
were tagged with radio-frequency identification transponders and their movements were monitored for the duration of their time in the EE [12]. Using roaming entropy
as a measure of explorative behavior, mice with higher
roaming entropy correlated with more neurogenesis. Interestingly, although the mice are expected to have
higher levels of physical exercise in a larger EE, the total
locomotion of individual mice did not correlate with
neurogenesis. This study highlighted the range of exploratory behavior in mice and, in light of its results, it is
important to keep in mind that there are individual
differences in the animals, and their individual experiences within the EE may vary drastically.
Although we discuss slight individual differences between exercise and EE-only, it is important to remember
that EE and exercise work together and the majority of
EE studies use environments with running wheels inside.
When exposed to EE, physical activity can increase
simply because more space is provided to the animal,
regardless of whether a running wheel is present or not.
To demonstrate the effects of EE and exercise together,
one study showed that both manipulations together could
enhance neurogenesis beyond both EE alone and exercise alone [11]. By pre-exercising animals for 10 days and
exposing these animals to EE afterwards for 30 days, they
saw a 30% increase in new neurons compared to all other
groups. Supporting the notion that physical activity has a
greater effect on cell proliferation and EE influences
survival [2,3,9,16], the authors suggest that exercise
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can prime the neurogenic niche for cognitive stimulation, such as EE.
Another influential factor of EE is the timing of EE
exposure. More specifically, the age of the newborn neuron during EE exposure may be critical to the morphological and behavioral changes observed in these animals.
Newborn neurons in the DG undergo a prolonged maturation process characteristic of an early period of hyperexcitability [1720]. Interestingly, the effects of EE are
most prominent when newborn neurons are 2 weeks old
[21]. Multiple groups of animals received BrdU injections
to label a newborn population of neurons. Each group of
animals received 1 week of EE exposure but over different
1-week periods of maturation. The first group received the
1-week EE exposure immediately after BrdU injection;
the second group received the 1-week EE exposure
1 week after BrdU injection, and so on. Although there
were observable increases in neurogenesis when EE was
presented within the first 3 weeks of neuronal birth, there
was no difference in neurogenesis levels when 4-week-old
neurons were exposed to EE. In addition, BrdU-labeled
newborn neurons that experienced the EE during their
second week responded greatest, as determined by
co-expression of the immediate early gene c-fos, when
re-exposed to the same EE 6 weeks after birth. This
activation by the newborn neurons upon re-exposure to
the same EE but not a different environmental exposure,
suggest that they functional integrate into the existing DG
circuitry, encoding information specifically about the previously seen EE. Together, these results highlight the
sensitivity of newborn neurons to timing of EE exposure.
In addition to timing of EE exposure, the overall age of the
animal has a dramatic effect on hippocampal neurogenesis
and cognition. Aging in animals is known to have a strong
negative impact on hippocampal neurogenesis and cognition [22]; however, EE can reverse many of these deficits.
Exposing aged mice to EE over a period of 10 months
resulted in an almost 5-fold increase in the number of
surviving newborn neurons [16]. This increase was also
associated with enhanced spatial acquisition of the MWM.
In a more recent study, aged rats underwent a 10-week EE
exposure [23]. Spatial learning on the MWM and spatial
memory during a 60-s probe trial were significantly
improved in aged rats exposed to EE. Exposing aged rats
to EE also resulted in an increase in the total number of
new neurons, despite having no effect on neuronal differentiation. The age of the animals, along with the other
factors of EE experiments, have not been standardized in
previous EE studies, often resulting in variability when
interpreting the effects of EE on neurogenesis.

Molecular mechanism for EE

The molecular mechanisms for EE-induced hippocampal
neurogenesis were studied with genomic approaches.
Gene expression alteration caused by EE were explored
Current Opinion in Behavioral Sciences 2015, 4:5662

58 Cognitive enhancement

using microarrays and other genomic methods [24,25,26].

Genes involved in neuronal activity and synaptic plasticity were induced by both short-term and long-term EE
treatment; the exact sets of genes altered had little
overlap, probably due to the gradual adaptation of the
neuronal function to EE. Moreover, the effects of EE on
gene expression were not evenly distributed across different brain regions, with the hippocampus being more
influenced by EE [27]. EE-induced changes in noncoding genes such as miRNA have also been studied
[28]. Despite such progress, how these changes in gene
expression are related to the enhanced neurogenesis
remains to be further investigated. In contrast to these
genome-wide studies, several candidate genes have been
well characterized for their role in EE-induced and exercise-induced neurogenesis. We will discuss two molecules BDNF and VEGF in detail.
Both EE exposure and voluntary exercise can induce the
expression of BDNF [2930,31,32], a neurotrophin that
supports survival, differentiation and neurite growth in
existing neurons. BDNF and its receptor, TrkB, play
important roles in adult hippocampal neurogenesis. Direct infusion of BDNF into the hippocampus resulted in
an increase in neurogenesis [33]. On the other hand,
disruption of BDNFTrkB signaling by selective knockout of TrkB in adult neural progenitor cells (NPCs) led to
decreased survival of newborn neurons at the immatureto-mature neuronal transition [34]. In addition, TrkBnull
newborn neurons were defective in dendritic growth and
synapse formation, consistent with the role of BDNF
TrkB pathway in neuronal differentiation. In another
study, Li and colleagues reported that TrkB had a cell
autonomous role in NPC proliferation in the hippocampus [35]. Furthermore, compared to that seen in wildtype
control mice, the enhanced neurogenesis by EE was not
observed in heterozygous knockout mice for BDNF
(BDNF +/ ) [31]. Similarly, the running-induced increase in NPC proliferation was compromised in mice
with TrkB deleted in the NPCs [35]. These findings
suggest that BDNFTrkB signaling plays important roles
in both NPC proliferation and newborn neuron survival
during adult neurogenesis and is a key mediator for
EE-induced enhancement of neurogenesis.
Another molecule whose expression is induced by EE is
VEGF [36,37], a growth factor associated with vasculogenesis and angiogenesis. The dividing NSCs were found
clustered at the tips of capillaries [38], suggesting that
factors related to vasculature may affect neurogenesis.
The role of VEGF in mediating EE-induced neurogenesis has been studied extensively. First, exogenous
VEGF can effectively increase neurogenesis, bypassing
the EE [36]. In addition, infusion of VEGF antagonists
or down-regulation of VEGF by RNA interference
blocked the EE-induced neurogenesis [36,39]. Similarly,
administration of soluble Flt1, an antagonist for VEGF,
Current Opinion in Behavioral Sciences 2015, 4:5662

prevented the running-induced NPC proliferation [40].

Thus, VEGF is an important factor for mediating
enhanced neurogenesis by EE and voluntary exercise.

EE and neurogenesis, a causal link

Beneficial cognitive effects of EE exposure are well
documented, but whether these behavioral effects are a
direct result of EE-induced neurogenesis is still unclear.
Here we present the few studies that have addressed the
specific influence of EE-induced neurogenesis on hippocampus behavior. To address this question, a number of
techniques have been used to target neurogenesis in the
DG and a variety of behavioral measures. Eliminating
neurogenesis systemically with the antimitotic agent
methylazomethanol acetate (MAM) has produced mixed
results. In some cases, MAM treatment of rats during EE
impaired performance in object recognition memory and
a trace fear conditioning paradigm, but not contextual fear
conditioning or spatial navigation learning in the MWM
[41,42]. Similarly, although focal irradiation almost
completely ablated hippocampal neurogenesis in the
DG of EE-exposed mice, it did not hinder the irradiated
EE mice in their enhanced ability to learn the MWM [43],
suggesting that the behavioral effects of EE are independent of neurogenesis.
Although these studies focus on hippocampus-dependent
behaviors, the relationship between EE and neurogenesis
may be more pronounced with behaviors associated with
the DG such as pattern separation [20,4448]. Behaviorally, pattern separation is thought to be a critical component of episodic memory, allowing the encoding of similar
experiences as distinct events, without interference
[49,50]. A number of studies have been performed to
demonstrate the involvement of the DG in pattern separation. Lesion of the DG (but not CA1) in rats specifically
interfered with spatial pattern separation when choosing
between two similar spatial locations [44]. Specifically
knocking out NMDA receptors in the DG impaired the
animals ability to distinguish between two similar contexts, but not traditional contextual fear conditioning [45].
Knocking out DG neurogenesis through irradiation and a
lentiviral method impaired animals ability to pattern
separation in a radial arm maze and an object-in-place
touch screen task [47]. In vivo recordings of rats show that
although both DG and CA3 can perform pattern separation functions, the DG is especially sensitive to small
changes in the environment [46].
Only a handful of studies have observed the influence of
EE and neurogenesis on pattern separation, however,
increasing neurogenesis through EE is capable of enhancing pattern separation in mice. Mice were presented
with a touch-screen task where they were taught to
distinguish between spatially similar objects. In both
young and aged mice, exercise, one of the key components of EE, enhanced their ability to recognize spatially
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Environmental enrichment and neurogenesis Clemenson, Deng and Gage 59

similar objects, indicating an enhancement in pattern

separation [51]. In addition, discriminating between
two closely related contextual fear conditioning environments with extremely short exposures was known to be
extremely difficult for rodents [52]. Without sufficient
time to explore the context, animals were unable to
associate shock and context. Interestingly, despite an
increase in neurogenesis and successful discrimination
between two different contexts, running animals were
unable to perform this task whereas animals exposed to
EE-only discriminated between two similar contexts
(Figure 1). Exposure to an EE not only allowed mice
to successfully discriminate in this difficult task, but
ablating neurogenesis through focal irradiation also inhibited their performance, suggesting that newborn neurons
induced through EE may contribute to environmentspecific behavior [14]. While these presented studies
attempt to unravel the link between EE-induced neurogenesis and behavior, more work is needed to confirm and
further understand the role of these newborn neurons.

a number of similarities that exist between rodents and

humans in the literature (see Table 1).
First, there is strong evidence to suggest that hippocampal neurogenesis occurs in humans. Postmortem tissue
from terminal skin cancer patients who were treated with
BrdU before death, displayed labeled BrdU cells in the
DG of the hippocampus [53]. NPCs have even been
discovered in the human hippocampus using proton
nuclear magnetic resonance spectroscopy and a metabolic
biomarker, as well as a novel carbon-dating technique
[54,55].
Second, angiogenesis is closely linked to hippocampal
neurogenesis [38] and exercise-induced neurogenesis is
correlated with increases in cerebral blood volume (CBV)
in mice [56]. Human participants that completed a
3-month aerobic exercise program displayed increases
in DG CBV over the 3-month period, correlating with
maximum volume of oxygen consumption (VO2max), a
measure of aerobic fitness [56].

EE in humans
Understanding the relationship between EE and neurogenesis in animals is already difficult, so an attempt to
address EE in humans is highly ambitious. With regards
to environmental enrichment, the most straightforward
disparity is that standard laboratory rodents live in a small
cage and the general human population already lives in
what most would consider an enriched environment. In
addition to the obvious differences between humans and
rodents, the tools available for us to learn about the
mechanisms and underlying cellular processes of the
human brain are limited compared to those we can use
with the laboratory rodent. For example, fMRI allows us
to compare brain regions active during behavior, but it is
difficult to interpret the data because it is an indirect
quantitative measure of blood flow changes in the brain,
which is thought to correlate with neuronal activity.
Despite these technical challenges, however, there are

Third, humans exhibit pattern separation-like behaviors

similar to mice. In a behavioral task designed to test
pattern separation, participants were presented with pictures of everyday objects and, during a testing phase, had
to determine if previously viewed objects were old,
similar, or new. fMRI revealed activation of the
DG/CA3 region only when participants recognized
similar objects and not old or new [57]. In addition,
this pattern separation ability declines in healthy human
aging [58] similar to mice [51].
Finally, and perhaps most relevant to EE, the exploration
and navigation of real and virtual environments correlate
with increases in hippocampal volume, hippocampal activity, and even the firing of place-like and grid-like cells.
Hippocampal gray matter was found to be significantly
larger in licensed London taxi drivers when compared to

Figure 1

Enrichment

Neurogenesis

Contextual Discrimination

Current Opinion in Behavioral Sciences

Schematic outlining the effects of enrichment on neurogenesis and contextual discrimination.

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Current Opinion in Behavioral Sciences 2015, 4:5662

60 Cognitive enhancement

Table 1
Similarities between animal and human studies presented in this review, in regards to environmental enrichment and neurogenesis.

Neurogenesis evidence
for the presence of
neurogenesis
Kempermann et al. [2]
VanPraag et al. [1,3]

Eriksson et al. [53]

Manganas et al. [54]
Spalding et al. [55]

Palmer et al. [38]

Pereira et al. [56]

Pereira et al. [56]

Clelland et al. [47]

Creer et al. [51]
Clemenson et al. [14]

Bakker et al. [57]

Stark et al. [58]

Freund et al. [12]

Maguire et al. [59,61]

Woollett and Maguire [60]

Harvey et al. [62]

Schmidt-Hieber and
Hausser [63]

Ekstrom et al. [64]

Jacobs et al. [65]

Angiogenesis presence
and increase of vasculature
with neurogenesis

Pattern separation
behavior dependent on the
dentate gyrus

Spatial navigation /
exploration hippocampal
involvement in the spatial
navigation and exploration
of environments
Place cells presence in the
hippocampus during the
navigation of a virtual
environment

control subjects [59]. As un-licensed taxi drivers trained to

become licensed taxi cab drivers, there was a selective
increase in hippocampal gray matter [60]. The increase in
hippocampal volume by London taxi drivers was correlated
with a spatial navigation expertise and memory of the city
of London. Similar to real world environments, the hippocampus also activates during the exploration and navigation of virtual environments in humans and animals alike
[6163]. Both place-like and grid-like cells have even been
observed in humans during a virtual-navigation task, using
single-neuron recordings from electrodes surgically
implanted in patients undergoing treatment for epilepsy
[64,65]. In the same way that exploration of a novel
environment is correlated with neurogenesis in mice
[12], the spatial exploration and navigation of real and
virtual environments correlate with structural and functional changes in the hippocampus of humans.

hippocampus-dependent behaviors like spatial navigation activate the hippocampus and that continuous exposure to large complex city environments can increase
hippocampal volume (similar to long EE exposures in
mice). In the same way that rodents use place and grid
cells to explore their environment, evidence exists to
suggest the presence of these same cell types in the
human hippocampus. In addition, although we cannot
visualize neurogenesis in humans, DG-specific processes
like pattern separation are not only observable in humans
but they also activate similar regions of the brain and are
influenced by the same environmental factors. Knowing
that these similarities exist in basic hippocampus-dependent processes may one day lead us to a way to enrich our
own lives and enhance performance on hippocampal
behaviors.

Conflict of interest
Despite the plethora of differences between humans and
the standard laboratory rodent, it is amazing to see that
Current Opinion in Behavioral Sciences 2015, 4:5662

The authors declare that they have no competing financial interests.

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Environmental enrichment and neurogenesis Clemenson, Deng and Gage 61

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