J Rehabil Med 2007; 39: 345–352
J Rehabil Med 39
© 2007 Foundation of Rehabilitation Information. ISSN 1650-1977
ENRICHED ENVIRONMENT AND ASTROCYTES IN CENTRAL NERVOUS
Michael Nilsson, MD, PhD and Milos Pekny, MD, PhD
From the Center for Brain Repair and Rehabilitation (CBR), Department of Clinical Neuroscience and Rehabilitation,
Institute for Neuroscience and Physiology at Sahlgrenska Academy, Göteborg University, Göteborg, Sweden
Rehabilitation medicine is entering a new era, based on the
knowledge that the central nervous system has a substantial
capacity for repair and regeneration. this capacity is used
in 3 distinct but overlapping situations: (i) routine house-
keeping throughout life (i.e. taking care of normal wear-and-
tear); (ii) older age, when functional reserves of various kinds
are depleted, resulting in cognitive, motor, and other deficits;
and (iii) contexts in which a neurological deficit reflects an
acute or chronic pathological process, such as neurotrauma,
stroke, or neurodegenerative disease. the positive message
here is two-fold. First, some aspects of regeneration occur
even in the adult and ageing brain and spinal cord, and we
are starting to unravel the underlying molecular mecha-
nisms. Secondly, novel therapeutic approaches and targets
are emerging that will substantially increase the efficiency
and efficacy of rehabilitation and will transform rehabilita-
tion into a discipline focusing both on its traditional domain
and on prevention, ultimately across all the age categories.
this review attempts to sum up the present knowledge about
an enriched environment, currently the single most efficient
plasticity- and regeneration-promoting paradigm. it also
summarizes research showing that astrocytes – considered
only years ago merely to nurse and support neurones – are
a novel and highly interesting target for regenerative strate-
gies in the brain and spinal cord.
Key words: enriched environment, astrocytes, astrocyte inter-
mediate filaments, plasticity, regeneration, stroke, rehabilitation,
J Rehabil Med 2007; 39: 345–352
Correspondence address: Michael Nilsson or Milos Pekny,
Center for Brain Repair and Rehabilitation (CBR), Depart-
ment of Clinical Neuroscience and Rehabilitation, Institute for
Neuroscience and Physiology, Sahlgrenska Academy, Göteborg
University, Guldhedsgatan 19, SE-413 45 Göteborg, Sweden.
Submitted March 9, 2007; accepted April 13, 2007
Stroke is a major cause of death and the primary cause of adult
disability in many countries (1). More than 60% of survivors
suffer persistent neurological deficits (2) and need compre-
hensive rehabilitation. Recovery of central nervous system
(CNS) function after injury, and stroke in particular, has long
been a primary goal of neuroscience research. Understanding
changes in the brain after an insult – and the extent to which
they influence the potential for regeneration – is of fundamental
importance in developing strategies for functional recovery. By
promoting CNS regeneration, such strategies are expected to
positively affect specific repair mechanisms involved in brain
plasticity after injury or stroke.
In contrast to the recognized regenerative capacity of neu-
rones in the peripheral nervous system (3, 4), the immature
CNS, and the CNS of lower vertebrates (5), efforts to induce
regeneration in the adult mammalian CNS have been disap-
pointing. However, after stroke, neural progenitor cells in the
subventricular zone, 1 of the 2 main neurogenic niches in the
adult brain, can proliferate, migrate into the damaged area,
and differentiate into neurones, replacing some, albeit very
few, of the neuronal cells lost to ischaemia (6–8). This is a
very encouraging message. Thus, regeneration research should
focus on re-establishing disrupted and establish compensatory
connections within the neuronal and astrocytic networks and
on replacing cells lost to pathological processes.
It is becoming increasingly clear that many CNS elements
contribute to degeneration and regeneration and that cells
other than neurones are important players – and thus potential
therapeutic targets – in these processes (9). The challenge is
to harness cellular defence mechanisms and intervene before
the environment becomes less conducive to regeneration and
to continue applying therapeutic strategies thereafter. Un-
derstanding the cellular mechanisms of damage inflicted by
cerebral ischaemia or traumatic brain injury is an essential step
in meeting this challenge. Equally important is to determine the
mechanisms that block regeneration. Both will form the basis
for devising strategies to promote neural recovery.
Functional recovery after brain injury is dependent on the
plasticity of both the cerebral cortex and unaffected parts
*This paper is based partly on a lecture given at the international
symposium ”Evidence for stroke rehabilitation – bridging into the future”,
in Göteborg, Sweden, 26–28 April, 2006.
M. Nilsson and M. Pekny
of functional neuronal and astrocyte networks (10). Neural
plasticity is an intrinsic property that enables the mammalian
brain to adapt to environmental changes during development
and adulthood. Plasticity is not static. It is an active, continuous
process throughout life (11). By design, the brain is remarkably
responsive to environmental stimuli, physiological modifica-
tions, and experiences (10), and its structure can be altered
by experience in several measurable ways. In animals and
humans, some regions in the normal adult brain, particularly
the cortex, can alter their biochemistry, structure, and function
– for example, during learning or in response to an enriched
environment (EE) (12).
First described by Donald Hebb (13), the experimental
paradigm of EE is the most widely used animal model of
experience-induced plasticity. The term refers to an environ-
ment that provides greater possibilities for physical and social
stimulation and/or interaction than standard housing conditions
(14). EE is defined as “a combination of complex inanimate
and social stimulation” (15), indicating that the interaction of
several factors is the essential feature of the EE. As Hebb’s
work and subsequent studies demonstrated, animals exposed
to EE exhibit superior performance in several tests of higher-
order cognitive ability (16, 17).
To maximize the effectiveness of rehabilitation therapies
after stroke, it is critical to determine how the brain responds
to different types of stimuli. Neural connections and corti-
cal maps are continuously remodelled by our experience.
Many studies have investigated the effects of EE on different
aspects of brain plasticity in the intact brain and after brain
injury, including stroke. Collectively, these studies show that
EE has profound effects on behaviour, induces substantial
structural and cellular changes, and specifically alters the
levels of various neuroactive compounds (18–20). In animals,
EE can induce pronounced biochemical, morphological and
functional changes in uninjured as well as in injured or dis-
eased brain. EE influences the uninjured brain in many ways
that ultimately modulate its function. EE and other forms of
complex stimulation increase brain weight and cortical and
hippocampal thickness (21), the branching, length, and spine
density of dendrites, and the size and number of discontinuous
synapses (22–24). Furthermore, EE enhances neurogenesis in
the hippocampus (25, 26). EE also increase levels of certain
neurotrophic factors (e.g. brain-derived neurotrophic factor
and nerve growth factor) that have important roles in neural
signalling and cellular plasticity (27, 28).
Enriched environment as prevention
EE has also been shown partially to prevent or reduce the
consequences of injuries or diseases in the CNS. With respect
to EE and prevention, one of the most studied animal models
is the R6/1 transgenic mouse, a model of Huntington’s disease
(HD). In these mice, EE greatly reduces the onset of the motor
symptoms (29) and delays the degenerative loss of cerebral
volume (29). In a recent epidemiological study, environmental
factors clearly modulated the clinical onset of HD (30). A simi-
lar effect has been observed in mouse models of Alzheimer’s
disease (AD) (31) and in humans with AD (32). Indeed, EE
may help to slow or prevent AD-associated cognitive decline
(32, 33), a view supported by epidemiological studies (34).
Interesting findings have also been presented on the effects of
EE on onset and progression of disease symptoms in animal
models of Parkinson’s disease and epilepsy (35, 36).
Enriched environment as a therapeutic modality
The therapeutic potential of EE has been evaluated in ani-
mal models of various neurological conditions, particularly
stroke and traumatic brain injury. For example, EE enhances
the recovery of motor function after focal brain ischaemia
induced by middle cerebral artery occlusion (22, 37). It also
has beneficial effects on cognitive functions such as memory
and learning (38, 39). Exposure to EE after experimental brain
trauma significantly improves both motor and cognitive func-
tions (40, 41). In combination with multi-modal early-onset
stimulation, EE reverses motor deficits in a model of brain
trauma (42). These results suggest that EE combined with a
“rehabilitation” program might act synergistically to enhance
functional outcome. In the clinical setting, encouraging ef-
forts have been made to provide an enriched and stimulating
environment tailored to the needs of the patient and based on
real-world experiences (43).
The morphological and biochemical correlates of EE-
induced improvements are naturally manifold. For instance,
in experimental models, EE reduces lesion size after brain
trauma, is neuroprotective and increases dendritic outgrowth
and the production of trophic factors (23, 27, 28, 36, 42).
After experimental stroke, EE normalizes the astrocyte/neurone
ratio in rats and seems to induce newly born progenitor cells
to adopt a glial fate (44, 45).
Currently, EE is providing a novel therapeutic platform from
which it is possible to derive molecular targets for the develop-
ment of “enviromimetics” – new classes of pharmacological
agents that would either mimic or enhance the positive effects
of EE. In normal mice, exposure to EE alters the expression of
genes involved in plasticity and neural signalling in different
areas of the brain (46). In post-ischaemic rats housed under
enriched conditions, we have observed large changes with a
clear temporal profile in the expression of genes involved in
cellular plasticity in the hippocampus (work in progress). Such
approaches have the potential to guide further investigation into
the function of EE-induced proteins and can ultimately be used
in combination with modern neurorehabilitation strategies.
Studies of environmentally driven plasticity in the brain have
traditionally focused on altered neuronal function, in particular
synapse function. However, astrocytes are also strongly influ-
enced by EE. Astrocyte morphology has long been known to
change in response to EE, with the changes depending both on
the duration of EE exposure and on the cortical layer in which
the astrocytes reside (9, 24, 47). The morphological plasticity
of astrocytes in response to EE appears to occur on a time-scale
similar to that of neuronal changes (48). Other results support
a close correlation between changes in astrocyte morphology
and synapse formation (48, 49), further emphasizing the synergy
J Rehabil Med 39
between neurones and astrocytes in and around the synaptic
cleft. Thus, it is not only astrocyte morphology that is changed
by EE. Rather, it seems that EE affects and refines the functional
relationship between astrocytes and neurones and that the mor-
phological changes merely reflect the altered functional state
of astrocytes. There is a body of evidence supporting the EE-
dependent enhancement of astrocyte-synapse communication,
which is of great interest in view of the fact that perisynaptic
astrocytes control synaptic transmission (50–52).
Results from different animal models point to EE as a power-
ful modality for both preventing and recovering from CNS inju-
ries and diseases. In the intact nervous system, EE has profound
effects that can be utilized to develop and improve cognitive
abilities or to resist the negative consequences of different
types of stressors. To fully translate this existing knowledge
into therapies, however, one must first consider some of the
major determinant of the outcome of any neurorehabilitation
approach, such as motivation, feeling of joy, sense of coher-
ence, social structures, extended focused physical activities,
and targeted education.
ASTROCYTES: HELPERS, DECISION-MAKERS – AND
A NEW TARGET FOR REGENERATIVE STRATEGIES?
Astrocytes, intermediate filaments, and reactive gliosis
Astrocytes, the most abundant cells in the CNS, were long con-
sidered a constituent of the brain glue (glia) and remained out of
the spotlight well into the 1980s. Even after their involvement
in CNS pathologies (e.g. trauma, ischaemia, and neurodegen-
erative diseases) was suspected, they were still perceived as
fulfilling at best a regulatory and homeostasis-supporting role.
Astrocytes were judged to be little more than providers of
nutrients and recycling units for neurotransmitters.
It was the morphological aspects of astrocytes in stroke,
neurotrauma, and neurodegenerative disease that originally
attracted the attention of neurologists and neuroscientists to
these cells and their biology. In response to any kind of CNS
injury, astrocytes change their appearance and undergo a
characteristic hypertrophy of their cellular processes referred
to as reactive gliosis or astrogliosis. The hallmark of this
phenomenon is upregulation of the intermediate filament (IF)
proteins glial fibrillary acidic protein (GFAP) and vimentin,
expression of the IF proteins nestin and (in some reactive
astrocytes) synemin, and alterations in the expression profiles
of many other proteins (53–55).
IFs, or nanofilaments, are the least understood part of the
cytoskeleton. Along with the other cytoskeletal components
– microtubules and actin filaments – they provide a structural
scaffold and serve as highly dynamic structures that integrate
diverse intracellular functions. The family of IF proteins in
vertebrates is quite large. In humans, 65 IF proteins have
been identified (56, 57). IF proteins are expressed in complex
patterns that are unique for each cell type and for different
developmental stages. IFs were at first considered to be static
structures primarily responsible for maintaining the cell shape
(58, 59). However, later studies both in vitro (60, 61) and in
vivo (62–65) revealed the rather dynamic nature of IFs and the
existence of a dynamic equilibrium between the assembled
filaments and the pool of soluble subunits (reviewed in 66).
In the absence of brain or spinal cord pathology, astro-
cytes have many functions. However, in contrast to reactive
astrocytes in the vicinity of brain lesions, their state is often
described as non-reactive. In non-reactive astrocytes, IFs con-
sist of GFAP and vimentin, while in reactive astrocytes, nestin
and synemin act as additional partners in the IF network (55,
67). In reactive astrocytes lacking both GFAP and vimentin
(GFAP–/–Vim–/–), no IFs are formed, and the nestin and synemin
proteins that are produced stay in a non-filamentous form (68).
In mature astrocytes, the major protein of the IF network is
GFAP, and the vimentin level ranges from very low to inter-
mediate, depending on the subpopulation of astrocytes (69,
70). Mature astrocytes have fine processes extending from the
main cellular processes, giving each cell a characteristic bushy
appearance (Fig. 1a). The IF network, however, is restricted
to the main processes and the soma of astrocytes (71, 72)
(Fig. 1b–e). Recently, we showed that reactive astrocytes in
denervated hippocampus or near cortical lesions increase the
thickness of their main cellular processes but access a volume
of tissue comparable to that of non-reactive astrocytes. Despite
the hypertrophy of GFAP-containing cellular processes, the
interdigitation of adjacent reactive astrocytes in denervated
hippocampus is minimal (73) (Fig. 2).
GFAP-positive astroglial cells may be involved in the base-
line neurogenesis in the adult mammalian CNS. The findings
on which this proposal was based suggested that astrocytes
positively control neurogenesis in the dentate gyrus of the
hippocampus and in the subventricular zone – the only 2 CNS
regions in which new neurones are generated in relatively
high numbers even in adults (74). Furthermore, the majority
of neural stem cells in the adult CNS may at some point be
GFAP positive and could therefore be defined as astroglial cells
(75–78). Thus, astroglial cells might control adult neurogenesis
and be the precursors of neurones added during adulthood.
Reactive gliosis, neurotrauma, and the fate of CNS transplants
To study the role of IF upregulation in reactive astrocytes in
CNS injury, several trauma models were applied to mice defi-
cient in GFAP and/or vimentin, including fine-needle injury of
the brain cortex and transection of the dorsal funiculus in the
upper thoracic spinal cord. The responses of wild-type, GFAP–/–,
and Vim–/– mice were indistinguishable. In GFAP–/–Vim–/–
mice, however, the post-traumatic glial scarring was looser
and less organized, suggesting that upregulation of IFs is an
important step in astrocyte activation. These findings also
implied that reactive astrocytes play a role in post-traumatic
healing (79). An extended healing period after CNS injury
was also reported in mice in which dividing astrocytes had
been ablated by GFAP-driven expression of herpes simplex
virus thymidine kinase and administration of ganciclovir (80,
81). After hemisectioning of the lower thoracic spinal cord,
GFAP–/–Vim–/– mice had increased axonal sprouting and better
functional recovery than wild-type controls (82).
J Rehabil Med 39
M. Nilsson and M. Pekny
Two groups have addressed the role of astrocyte IFs in neurite
outgrowth in vitro (83–85). One reported that GFAP–/–Vim–/– and
GFAP–/– astrocytes are a better substrate for the outgrowth of
neurites than wild-type astrocytes (83, 85). The other group
found comparable neurite outgrowth when neurones were
cultured on wild-type and GFAP–/– astrocytes (84). The latter
finding is consistent with the normal axonal sprouting and regen-
eration observed after dorsal hemisectioning of the spinal cord
in GFAP–/– mice (86). Recently, we reported extensive axonal
regeneration in the severed optic nerve of young GFAP–/–Vim–/–
mice overexpressing human Bcl2 in neurones (87), as well as
reduced photoreceptor degeneration after retinal detachment in
GFAP–/–Vim–/– mice (88). We suggested that the environment, in
particular astrocytes but also components the immune system,
are important modulators of CNS regeneration (89).
The involvement of astrocytes in synaptic regeneration after
neurotrauma was studied in partially deafferented hippocam-
pus after entorhinal cortex lesioning. Such lesions interrupt
axonal connections (known as the perforant path) between the
entorhinal cortex and the projection area in the outer molecular
layer of the dentate gyrus of the hippocampus (90), where
degenerating neurones trigger extensive reactive gliosis. The
distance between these 2 regions allows assessment of astro-
cyte response, degeneration, and subsequent regeneration in
the hippocampus, which is not directly affected by the surgery.
Using this model, we showed that reactive astrocytes devoid of
IFs (GFAP–/–Vim–/–) exhibited only limited hypertrophy of cell
Fig. 1. Astrocyte morphology in mammalian brain. (a) Three-dimensional reconstruction of astrocytes. Astrocytes in the adult mouse hippocampus filled
with 2 dyes. The central nervous system is divided into domains, each accessed by fine cellular processes of an astrocyte. (b) Astrocytes in the brain cortex
visualized in the most common way, by antibodies against the astrocyte-specific cytoskeletal component, glial fibrillary acidic protein (GFAP). (c–e) Reactive
astrocytes after dye filling and three-dimensional reconstruction. Note the typical bushy appearance of astrocytes with fine cellular processes that cannot
be visualized by antibodies against GFAP (compare the central astrocyte in c, d and e). Scale bar, 20 µm. Reproduced with permission from (91).
Fig. 2. The domains of non-reactive and reactive astrocytes: a concept.
(a) Interdigitation of fine cellular processes in a three-dimensional
reconstruction of dye-filled astrocytes in the dentate gyrus of the
hippocampus. The yellow zone shows the border area where cellular
processes of 2 adjacent astrocytes interdigitate. (b) Reactive astrocytes
stay within their domains, but their main cellular processes become thicker,
making them visible over a greater distance (illustrated here by the grey
circles). Reproduced from (73).
J Rehabil Med 39
processes. Many processes of GFAP–/–Vim–/– astrocytes were
shorter and less straight than those of wild-type astrocytes, al-
though the volume of CNS tissue reached by a single astrocyte
was comparable to that in wild-type mice (91). These results,
along with in vitro data on the morphology of IF-depleted as-
trocytes in primary cultures (92), show a novel role for IFs in
determining astrocyte morphology. In GFAP–/–Vim–/– mice, loss
of neuronal synapses in the outer molecular layer of the hip-
pocampal dentate gyrus was prominent 4 days after lesioning.
Of particular interest was the remarkable synaptic regeneration
10 days later (14 days after injury).
Thus, the effect of reactive astrocytes after CNS trauma
seems to be two-fold: reactive astrocytes play a beneficial role
in the acute stage but subsequently inhibit CNS regeneration.
Support for the concept of reactive gliosis as an inhibitor of
post-traumatic repair and functional recovery comes also from
studies of transgenic mice expressing an inhibitor of NF kappa
B in astrocytes (93) or deficient in EphA4 (94).
Because of their morphology and abundance in the adult
CNS, astrocytes have direct physical contact with any cell that
moves from one place to another. To assess the impact of astro-
cyte IFs on the fate of cells migrating from neural transplants,
the Chen and Pekny groups transplanted dissociated retinal
cells into the retinas of adult wild-type and GFAP–/–Vim–/– mice
and compared the efficiency of long-term integration of the
grafts (95). In wild-type hosts, few transplanted cells migrated
from the transplantation site, and few integrated into the retina.
In GFAP–/–Vim–/– hosts, however, the transplanted cells effec-
tively moved through the retina, differentiated into neurones,
and integrated into the ganglion cell layer; some even extended
neurites into the optic nerve. Six months after transplantation,
the cells were alive and well integrated (95).
These results show that the absence of IFs in astroglial cells
(astrocytes and Müller cells) of the retina increases the permis-
siveness of the retinal environment for integration of neural
transplants. The mechanism is unknown. However, IF depletion
in astroglial cells might alter their differentiation state, turning
them into cells functionally similar to more immature astro-
cytes and therefore more supportive of CNS regeneration (96).
By affecting the abundance or composition of IFs, it might be
possible to control the state of cellular differentiation and thus
many cellular functions. This would ultimately allow control
of complex processes such as the permissiveness of the CNS
for regeneration (97, 98).
INSPIRATION FOR DEVELOPING MODERN
With the development of molecular neuroscience and technolo-
gies, such as transgenic manipulation of experimental animals
and genomic and proteomic approaches, neurology develops
into a modern medical discipline based on a molecular un-
derstanding of the functions of cells and tissues in health and
disease. This forms a solid basis also for devising and refining
novel rehabilitation strategies.
This review has presented 2 rapidly developing areas with
huge potential for neurorehabilitation. One, the EE, has been
utilized in rehabilitation for centuries. Only now, however,
can its full potential be comprehensively demonstrated and
quantitatively assessed in diverse experimental systems. This
potential has not been fully realized, or implemented in ways
that can be expected to provide maximal therapeutic effects
and benefits. The application of EE is by no means limited to
rehabilitation after stroke or even to neurorehabilitation as
such. When applied in the form of tailored programs with full
emphasis on motivation, it might become a major component
of prevention programs.
The second area discussed here – astrocytes as a novel
target for regeneration promoting treatment paradigms – is
equally exciting. This concept represents a shift in the current,
admittedly largely neurocentric, thinking in neuroscience and
neurorehabilitation. Astrocytes as a cellular target for brain
and spinal cord repair are now at the centre of molecular
neuroscience and modern neuropharmacology. Their increasing
recognition within neurology is opening up new opportunities
to explore the synergy between traditional and novel neuro-
rehabilitation in the future.
The authors thank Drs Michelle Anderson, Marcela Pekna and Ulrika
Wilhelmsson for their input into this review. This work was supported
by grants from the Swedish Medical Research Council (project 20114
and 11548), The Region of Västra Götaland (RUN), Swedish Stroke
Foundation, Torsten and Ragnar Söderberg Foundations, Heart-Lung
Foundation, the Swedish Society for Medicine, W. and M. Lundgren
Foundation, John and Brit Wennerström’s Foundation for Neurological
Research, Foundation Edit Jacobson’s Donation Fund, The Rune and
Ulla Amlövs Foundation, The Axel Linders Foundation Trygg-Hansa,
Hjärnfonden, ALF Göteborg and Åhlén-stiftelsen.
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