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Exercise: A behavioral intervention to enhance brain health and plasticity

Article in Trends in Neurosciences · June 2002

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 Opinion TRENDS in Neurosciences Vol.25 No.6 June 2002 295

Exercise: a behavioral neuronal survival and resistance to brain insult [8,9],

promote brain vascularization [10,11], stimulate
neurogenesis [12], enhance learning [12,13] and

intervention to contribute to maintenance of cognitive function

during aging [14].

enhance brain health Exercise and neurotrophic factors

It is possible that some of the beneficial aspects of
exercise act directly on the molecular machinery of

and plasticity the brain itself, rather than on general health (as
was widely assumed in the early 1990s). To explore
this hypothesis, we sought a protocol for an animal
study in which exercise would be isolated as the
Carl W. Cotman and Nicole C. Berchtold central variable, and that would parallel aspects of
human exercise studies. Voluntary wheel-running
was selected because it allows rats or mice to choose
Extensive research on humans suggests that exercise could have benefits for how much to run (i.e. it avoids confounding variables
overall health and cognitive function, particularly in later life. Recent studies associated with the stress of forced treadmill
using animal models have been directed towards understanding the running and investigator handling) and it is
neurobiological bases of these benefits. It is now clear that voluntary exercise quantifiable.
can increase levels of brain-derived neurotrophic factor (BDNF) and other Several molecular systems could potentially
growth factors, stimulate neurogenesis, increase resistance to brain insult and participate in the benefits of exercise on the brain.
improve learning and mental performance. Recently, high-density Neurotrophic factors have most of the properties
oligonucleotide microarray analysis has demonstrated that, in addition to that could underlie such beneficial effects. We chose
increasing levels of BDNF, exercise mobilizes gene expression profiles that to focus initially on brain-derived neurotrophic
would be predicted to benefit brain plasticity processes. Thus, exercise could factor (BDNF) because it supports the survival and
provide a simple means to maintain brain function and promote brain growth of many neuronal subtypes, including
plasticity. glutamatergic neurons [15,16]. Subsequently, as
the neurotrophin field evolved, BDNF emerged as a
In 1890, William James first recognized that one of key mediator of synaptic efficacy, neuronal
the most important features of human behavior is the connectivity and use-dependent plasticity [17–20]
ability to carry out meaningful change [1]. He broadly (Box 1, Fig. 1).
defined this under the rubric of ‘behavioral plasticity’. We predicted that a neurotrophin-mediated
Since then, this concept of plasticity has been further response to exercise would probably be restricted to
developed to include structural change in the brain at motor–sensory systems of the brain, such as the
the cellular, molecular, and system levels, with the cerebellum, primary cortical areas or basal ganglia.
convergence of these mechanisms ultimately The findings were surprising: several days of
supporting behavioral plasticity. voluntary wheel-running increased levels of BDNF
Maintaining brain health and plasticity mRNA in the hippocampus [21], a highly plastic
throughout life is an important public health goal, structure that is normally associated with higher
and it is increasingly clear that behavioral cognitive function rather than motor activity. The
stimulation and exercise can help us to achieve it. changes in mRNA levels were found in neurons,
Such intervention is particularly crucial from middle particularly those of the dentate gyrus (DG), hilus
age onwards, when the brain faces a series of and CA3 region. They appeared within days in both
challenges that can include the pathogenesis of male [22] and female [23] rats, were sustained even
neurodegenerative diseases like Alzheimer’s disease after several weeks of exercise [24], and were
(AD). Over the past decade, a number of studies on paralleled by increased amounts of BDNF protein
humans have shown the benefits of exercise on brain (Fig. 2). In addition to the hippocampus, running
Carl W. Cotman*
Institute for Brain Aging
health and function, particularly in aging activity increased levels of BDNF mRNA in the
and Dementia, Dept of populations. Exercise participation has consistently lumbar spinal cord [25], cerebellum and cortex [22],
Neurobiology and emerged as a key indicator of improved cognitive but not in the striatum [22]. Although other trophic
Behavior and Dept of
function [2–5]. Recently, a large, five-year factors, including nerve growth factor (NGF) [22] and
Neurology, University of
California, Irvine, prospective study revealed that physical activity was fibroblast growth factor 2 (FGF-2) [26], were also
CA 92697-4540, USA. associated with lower risks of cognitive impairment, induced in the hippocampus in response to exercise,
*e-mail: cwcotman@ AD and dementia in general [6]. Furthermore, a their upregulation was transient and less robust than
uci.edu
retrospective analysis found that behavioral that of BDNF, suggesting that BDNF is a better
Nicole C. Berchtold stimulation and physical activity reduced the risk of candidate for mediating the long-term benefits of
Institute for Brain Aging
developing AD [7]. These data from humans are exercise on the brain.
and Dementia, University
of California, Irvine, supported by animal research demonstrating that Research on humans suggests that exercise and
CA 92697-4540, USA. exercise and/or behavioral enrichment can increase behavioral stimulation can maintain or improve

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296 Opinion TRENDS in Neurosciences Vol.25 No.6 June 2002

Box 1. BDNF has neurotrophic and neuroprotective properties and can affect functions that underlie brain plasticity

BDNF is neurotrophic and neuroprotective [a,b] vesicle proteins, including synapsin I, synaptophysin and
• BDNF promotes the differentiation, neurite extension and survival of a synaptotagmin.
variety of neuronal populations in culture including hippocampal,
References
cortical, striatal, septal and cerebellar neurons.
• Intraventricular BDNF infusion protects the hippocampus and cortex a Barde, Y-A. (1994) Neurotrophins: a family of proteins supporting the
from ischemic damage and protects septal cholinergic neurons from survival of neurons. Prog. Clin. Biol. Res. 390, 45–56
axotomy-induced loss. b Lindvall, O. et al. (1994) Neurotrophins and brain insults. Trends Neurosci.
17, 490–496
BDNF can enhance brain plasticity [c–f] c Schinder, A.F. and Poo, M-M. (2000) The neurotrophin hypothesis for
• BDNF gene regulation and protein release are activity-dependent. synaptic plasticity. Trends Neurosci. 23, 639–645
• BDNF enhances synaptic transmission. d Lu, B. and Chow, A. (1999) Neurotrophins and hippocampal synaptic
• Mice deficient in BDNF show impaired LTP and present learning transmission and plasticity. J. Neurosci. Res. 58, 76–87
deficits that are reversed with BDNF replacement. e McAllister, A.K. et al. (1999) Neurotrophins and synaptic plasticity. Annu.
• BDNF stimulates synaptophysin and synaptobrevin synthesis. Rev. Neurosci. 22, 295–318
• Mice deficient in BDNF signaling (trkB mutants) show f Altar, A. and DiStefano, P.S. (1998) Neurotrophin trafficking by anterotrade
decreased synaptic innervation and reduced levels of synaptic transport. Trends Neurosci. 21, 433–437

brain plasticity. Learning, a high-order of brain Roles of neuronal activity and neurotransmitters
plasticity, increases BDNF gene expression [27], Neuronal activity and neurotransmitter
and BDNF, in turn, facilitates learning [28]. interactions control BDNF gene expression patterns
This predicts that mechanisms that induce BDNF in the hippocampus, with glutamate-mediated
gene expression, such as exercise, can enhance signaling being the likely central convergence point.
learning. Indeed, running enhances LTP in the DG Several modulatory neurotransmitters that
and improves spatial learning in the water-maze converge on glutamatergic neurons, including ACh,
task [12]. GABA and monoamines, could affect BDNF
expression.
(a) The medial septum, being a source of cholinergic
BDNF
and GABAergic afferents to the hippocampus, might
participate in the upregulation of BDNF in response
to exercise. As first reported by Vanderwolf in 1969
[29], voluntary wheel-running activates a persistent
firing pattern (known as theta-rhythm) in the rat
hippocampus, and this firing pattern is dependent
on medial septal cholinergic and GABAergic
neurons [29–32]. Extensive literature supports the
Resting idea that an ACh-mediated mechanism also
Active BDNF (mRNA, protein) regulates BDNF gene expression in the
hippocampus, particularly in the basal state
(b) [33–35]. This suggests that ACh-mediated
activation of the hippocampus could underlie the
TrkB regulation of BDNF by exercise.
P Surprisingly, although septal ACh-mediated
input provides tonic regulation of baseline
P hippocampal BDNF gene expression, it is not a key
regulator in the activity-dependent state. Despite
causing complete loss of septo–hippocampal
cholinergic afferents and a reduction in basal BDNF
gene expression, selective lesions of medial septal
NMDA cholinergic neurons did not impair exercise-induced
receptor BDNF gene expression in the hippocampus [36].
activity
Key: By contrast, when partial loss of septal
cholinergic afferents was combined with loss
BDNF Glutamate
of medial septal GABAergic neurons,
TRENDS in Neurosciences
exercise-dependent BDNF regulation was
Fig. 1. Characteristics of brain-derived neurotrophic factor (BDNF) that make it a natural candidate to
disrupted, notably in the DG and hilus. Thus, there
mediate the benefits of exercise on brain health. (a) BDNF is transported retrogradely and is a strong involvement of the medial septum in
anterogradely to synapses, where it potentiates synaptic transmission, participates in gene activity-dependent regulation of BDNF gene
transcription, modifies synaptic morphology, and enhances neuronal resilience. BDNF mRNA and
expression, and it appears to involve either
protein levels increase in an activity-dependent manner. (b) Released BDNF binds to its receptor
(TrkB) presynaptically to modify transmitter release and postsynaptically to modify postsynaptic non-ACh-mediated signaling or a combination of
sensitivity, for example, via interaction with NMDA receptors [69,70]. neurotransmitter systems [36].

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 Opinion TRENDS in Neurosciences Vol.25 No.6 June 2002 297

(a) (c) (d)

300 * 360

300

BDNF (pg ml−1)

BDNF (pg ml−1)
200 240

180
(b)
100 120

60

0 0
EX SED 1 2 3 4 5
Distance (km per night)
TRENDS in Neurosciences

Fig. 2. Effects of exercise on hippocampal brain-derived neurotrophic upregulation in the hippocampus [24].
factor (BDNF) mRNA and protein levels. (a) In situ hybridization shows Noradrenaline-mediated signaling might be
that expression of BDNF mRNA in the rat dentate gyrus (DG), hilus,
CA1–CA3 regions and cortex is greater following exercise (seven days
particularly important in the modulation of BDNF
of voluntary wheel-running) than in sedentary animals (b). (c) ELISA gene expression by exercise [39].
quantification of hippocampal BDNF protein levels in the hippocampus
in sedentary (SED) and exercising (EX) animals, after five days of
Regulation by peripheral as well as central mechanisms
wheel-running (*P <0.05). (d) Rats and mice acclimate rapidly to the
running wheel and progressively increase their extent of daily running, Although CNS activity-dependent mechanisms are
in some cases up to a startling 20 kilometers (~12–13 miles) per night. pivotal in driving exercise-induced changes in levels
BDNF protein levels correlate with running distance (average over of BDNF mRNA in the brain, it is now emerging that
14 days running; R2 = 0.771).
peripheral mechanisms are also important.
Components contributing to this peripheral control
Monoamine-mediated signaling also contributes include estrogen, corticosterone and insulin-like
to BDNF gene regulation. Several antidepressants growth factor-1 (IGF-1).
that increase transmission at monoaminergic
synapses also increase BDNF gene expression Estrogen-dependent upregulation of BDNF gene
in the hippocampus [37,38]. Interestingly, expression
antidepressant treatment in combination with Steroid hormones such as estrogen influence brain
exercise enhances exercise-dependent BDNF aging, particularly in post-menopausal women.
Estrogen replacement (ER) after menopause appears
(a) *** (b) to slow age-related cognitive decline and to delay the
400
* onset of AD in human subjects [40]. Conversely,
3000 ** reduced levels of estrogen compromise neuronal
BDNF protein (pg ml−1)

300 *** * function, survival and synaptogenesis in animal

Daily distance run (m)

* * models [41], and decrease hippocampal availability of

2000
200 BDNF [23,42].
In females, the benefits of exercise appear to
100
1000 depend on the presence of estrogen [23]. After
Control
OVX two months of estrogen-deprivation, exercise no
OVX–ER longer increased either BDNF mRNA or protein
0 0
levels in the female rat hippocampus. By contrast,
)
VX )
–E EX)

X)
)

1 2 3 4 5
ED
ED
D

(E
SE

Day when exercise was combined with long-term ER,

(S
(
(S

R
l(

R
VX

–E
ro

BDNF protein levels showed a greater increase than

t

VX
O
on

VX

O
C

TRENDS in Neurosciences
O

in response to ER alone (Fig. 3a) [23]. Thus, the

presence of estrogen in females might be a
Fig. 3. Effects of estrogen deprivation on exercise-dependent increase in brain-derived
neurotrophic factor (BDNF) protein levels and running activity. (a) Exercise and estrogen increase
permissive factor necessary for exercise-induced
hippocampal BDNF protein levels; however, the effect of exercise is dependent on the presence of regulation of BDNF availability.
estrogen. BDNF levels were lower in sedentary (SED) animals that had experienced eight weeks of Interestingly, levels of voluntary physical activity
estrogen-deprivation (following ovariectomy, OVX) than in intact controls. Four weeks of also depend on estrogen status. Animals were less
estrogen-replacement (ER) increased the levels of BDNF protein in OVX (SED) animals. Exercise
(five days of voluntary wheel-running, EX) did not significantly increase BDNF levels in OVX
active in the absence of estrogen, and ER restored
animals without ER, but did lead to a significant increase in OVX–ER animals. (b) Estrogen activity to normal levels (Fig. 3b) [23]. This effect of
stimulates voluntary running activity. Following three weeks of estrogen deprivation (OVX), estrogen raises the interesting possibility that some
running activity was decreased. ER (for five days, concurrent with running-wheel exposure)
of the health benefits associated with hormone
restored running activity to normal levels. Thus, exercise and estrogen might be part of a positive
feedback loop that provides combined benefits to ensure the maintained health and functioning of replacement in women could be related to increased
the brain and body. *P <0.05, **P <0.01, ***P <0.0001. For details, see Ref. [23]. exercise participation.

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298 Opinion TRENDS in Neurosciences Vol.25 No.6 June 2002

BDNF, exon I Mitochondrial cytochrome oxidase subunits I, II, III

Zif269/Krox-24/NGFI-A Cytochrome P450 arachidonic acid epoxygenase
Synaptotagmin 5 Protein processing
Clathrin-associated protein 17 (AP17) Transcription regulation
Cyclooxygenase isoform COX-2
Integrin β5 subunit
Neuronal activity-regulated pentraxin Plasticity Metabolic
Vasoactive intestinal polypeptide (VIP) (37%) (24%)
receptor
Syndecan Complement protein C1q beta chain
Vesl Immune
Anti-aging Cyclooxygenase isoform COX-2
VGF (11%)
(15%) Other Natural killer cell protein group 2-A (NKG2A)
(10%) Major acute phase α-1 protein (MAP)
Bcl-x β
Neuronal death protein MHC class I cell surface antigen
Major hsp70-like protein hsc73 Anti-idiotype immunoglobulin M heavy chain
Klotho Mismatch repair protein MSH2

TRENDS in Neurosciences

Fig. 4. Effects of exercise on gene transcription. The majority of genes induced by exercise are increase in the brain reflects increased transport
associated with plasticity and synaptic structure. Other genes regulated by exercise include those from the periphery across the blood–brain barrier
associated with immune function, metabolism, anti-aging, protein processing and transcriptional
regulation. Abbreviations: BDNF, brain-derived neurotrophic factor; VGF, nerve-growth-factor-
[54]. Interestingly, peripheral IGF-1 appears to
inducible growth factor. For details, see Ref. [55]. participate in the neuroprotective effect of exercise,
as peripheral infusion of IGF-1-blocking antibodies
before an injury reduces the protection [9]. Because
Exercise and stress: antagonistic regulators of peripheral administration of IGF-1 induces BDNF
BDNF levels mRNA in the brain [52], BDNF is potentially a
Prolonged exposure to stress hormones downstream target that mediates some of the
(e.g. corticosteroids) is harmful for neuronal health protective effects of IGF-1. These data suggest that
and survival, particularly in the hippocampus [43]. peripheral IGF-1 initiates growth-factor cascades in
In response to acute and chronic stress, neurons the brain that can alter ongoing plasticity
undergo morphological changes, including dendritic mechanisms.
atrophy and spine reduction, which have a negative
impact on brain plasticity [44–46]. Exercise is Gene microarray expression patterns that support
commonly believed to be a behavioral strategy to brain plasticity
relieve stress, and can reduce depression and In addition to BDNF, a number of other molecular
anxiety in humans [47]. Animal studies systems that can mediate benefits to the brain are
demonstrate that corticosteroids decrease BDNF potentially regulated by exercise. To identify other
availability in the hippocampus [48], although molecular targets, the gene expression profiles of
exercise before a stressful event can counteract this ~5000 genes in the rat hippocampus were examined
downregulation. For example, one week of using high-density oligonucleotide arrays [55]. Three
voluntary wheel-running exercise before forced weeks of exercise led to changes – both increases and
swimming prevents downregulation of hippocampal decreases – in the expression of a number of genes.
BDNF mRNA and improves behavioral measures of Many of these genes are involved in synaptic function
stress [49]. The molecular mechanism(s) and plasticity, for example, being associated with
responsible for the ability of exercise to counteract membrane and neurotrophic factor trafficking,
stress is an exciting field for future research with vesicle recycling or neurite and synaptic growth
clear human relevance. (Fig. 4). The increased expression of genes encoding
several synaptic markers (e.g. synaptotagmin, Vesl
IGF-1 as a mediator of the effects of exercise and AP17) indicates a direct effect of exercise on
IGF-1, a growth factor structurally related to synaptic function [55]. It is remarkable that exercise
pro-insulin, is a potent survival factor for neurons regulates the expression of so many genes in the
and oligodendrocytes and participates in neuronal hippocampus, and the finding underscores the
growth and differentiation in the brain [50,51]. In emerging idea that exercise is a powerful effector of
addition, IGF-1 might be an upstream mediator of brain physiology.
BDNF gene regulation, neurogenesis and the ability
of exercise to protect the brain from injury [9,52]. Promotion of neurogenesis
IGF-1 levels increase in both the periphery [53] and The effect of exercise on genes encoding
brain [52] after exercise, and at least part of the neurotrophins and other proteins predicts that

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Opinion TRENDS in Neurosciences Vol.25 No.6 June 2002 299

(a)

Hippocampus
Environmental
stimuli BDNF Encoding, resistance to insult
Multiple genes promoting
synaptic plasticity

Exercise
primes encoding mechanisms

(b) Medial septum

(ACh/GABA)

Exercise Hippocampus Genomic regulation

Structural change
BDNF
− vascular
Estrogen IGF-1 Other plasticity genes
− neuronal
Glucocorticoids
− neurogenesis
Locus coeruleus (NE) Increased neuronal health
Blood−brain barrier
Raphe (5-HT)

Peripheral
factors
TRENDS in Neurosciences

Fig. 5. Mechanisms by which voluntary running primes the brain to molecule that stimulates proliferation and
encode meaningful information from the environment. (a) Exercise differentiation of hippocampal neuroprogenitor cells
might act as a gate that primes the hippocampus to respond to
environmental stimulation, while simultaneously ensuring the
[62,63], are increased in hippocampal astrocytes
viability of neurons to resist insult. These responses, in turn, feed back after exercise. Finally, microarray analysis reveals
to strengthen the brain in a use-dependent fashion. (b) Exercise- increased expression of additional neurogenesis-
mediated enhancement of the encoding of information and neural
related genes (e.g. those encoding Krox-24 and VGF)
resistance could involve factors such as brain-derived neurotrophic
factor (BDNF), a prototypical candidate molecule that can help us to [55] that are likely to act in concert with IGF-1,
understand how exercise benefits the brain. Multiple factors control BDNF and FGF-2 to modulate neurogenesis. Thus,
BDNF expression in the hippocampus. BDNF is expressed in exercise activates a number of factors that converge
glutamatergic neurons and its levels are modulated by neural activity
and neurotransmitter input from the medial septum, raphe and locus
on neurogenesis.
coeruleus. Exercise-dependent BDNF gene changes are modulated by
combined septal ACh and GABA inputs, noradrenaline (NE) and Common mechanisms underlying plasticity induced by
peripheral factors. BDNF gene expression is also dependent on steroid
exercise, behavioral enrichment and learning
hormone (estrogen and corticosterone) status and peripheral entry of
insulin-like growth factor 1 (IGF-1) into brain (which is itself modulated A robust literature documents that experience and
by exercise). behavior activate brain plasticity mechanisms and
remodel neuronal circuitry in the brain. Exercise and
behavioral enrichment paradigms, such as
exercise could regulate downstream anatomical environmental enrichment [64], rehabilitation
changes that support brain plasticity. Recently, it has training [65,66] and learning [67,68], affect common
been demonstrated that exercise increases the endpoints in the brain, including regulation of growth
number of new neurons in the DG of adult animals factors, neurogenesis and structural changes. The
[56]. Trophic factors, such as BDNF, IGF-1 and similarities between the effects of exercise and these
FGF-2, might mediate this effect. Exercise increases well-established paradigms support the hypothesis
levels of BDNF in the DG (the progenitor-cell layer of that there are common mechanisms regulating
the hippocampus) and BDNF promotes the survival behavioral plasticity.
of newly differentiated neurons [50]. Support for the
idea that BDNF is a key variable comes from the Conclusion
observation that estrogen [57], corticosteroids [58,59] Exercise is a simple and widely practised behavior
and neuronal activity [60] each regulate both BDNF that activates molecular and cellular cascades that
gene expression and neurogenesis. Exercise support and maintain brain plasticity. It induces
increases brain uptake of circulating IGF-1, a factor expression of genes associated with plasticity, such
that promotes neuronal differentiation of progenitor as that encoding BDNF, and in addition promotes
cells [50,61] and increases hippocampal BDNF gene brain vascularization, neurogenesis, functional
expression [52]. In addition, levels of FGF-2, a changes in neuronal structure and neuronal

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300 Opinion TRENDS in Neurosciences Vol.25 No.6 June 2002

resistance to injury. Significantly, these effects occur from the environment and, at the same time,
in the hippocampus, a brain region central to activates mechanisms that protect the brain from
learning and memory. BDNF availability could be damage (Fig. 5). By inducing BDNF and other
crucial for these mechanisms. Exercise-driven molecules, exercise strengthens neuronal structure
increases in the level of hippocampal BDNF are and facilitates synaptic transmission, thus, priming
controlled by neuronal activity, neurotransmitters activated cells for encoding.
and interactions with peripheral factors that include The clinical literature has recognized for years
estrogen, corticosterone and possibly IGF-1. The that exercise affects overall health and brain
peripheral influence illustrates how exercise can function. Scientific studies are now strengthening
relate overall body status to brain function. Exercise the premise that exercise can benefit brain function
recruits use-dependent plasticity mechanisms that and are encouraging additional clinical research in
prepare the brain to encode meaningful information this area.
References (Roman high-avoidance) and hyperemotional analysis by the intraseptal microinfusion of
1 James, W. (1890) The Principles of Psychology, (Roman low-avoidance) rats. Learn. Mem. 2, carbachol, atropine, and procaine. Exp. Neurol.
Holt, New York 40–48 120, 132–144
2 Berkman, L.F. et al. (1993) High, usual and 15 Barde, Y-A. (1994) Neurotrophins: a family of 31 Lee, M.G. et al. (1994) Hippocampal theta activity
impaired functioning in community-dwelling proteins supporting the survival of neurons. following selective lesion of the septal cholinergic
older men and women: findings from the Prog. Clin. Biol. Res. 390, 45–56 system. Neuroscience 62, 1033–1047
MacArthur Foundation Research Network on 16 Lindvall, O. et al. (1994) Neurotrophins and brain 32 Buzsaki, G. et al. (1985) Depth profiles of
Successful Aging. J. Clin. Epidemiol. 46, insults. Trends Neurosci. 17, 490–496 hippocampal rhythmic slow activity (‘theta
1129–1140 17 Schinder, A.F. and Poo, M-M. (2000) The rhythm’) depend on behaviour.
3 Blomquist, K.B. and Danner, F. (1987) Effects neurotrophin hypothesis for synaptic plasticity. Electroencephalogr. Clin. Neurophysiol. 61,
of physical conditioning on information- Trends Neurosci. 23, 639–645 77–88
processing efficiency. Percept. Mot. Skills 65, 18 Lu, B. and Chow, A. (1999) Neurotrophins and 33 Knipper, M. et al. (1994) Positive feedback
175–186 hippocampal synaptic transmission and between acetylcholine and the neurotrophins
4 Rogers, R.L. et al. (1990) After reaching plasticity. J. Neurosci. Res. 58, 76–87 nerve growth factor and brain-derived
retirement age physical activity sustains cerebral 19 McAllister, A.K. et al. (1999) Neurotrophins and neurotrophic factor in the rat hippocampus.
perfusion and cognition. J. Am. Geriatr. Soc. 38, synaptic plasticity. Annu. Rev. Neurosci. 22, Eur. J. Neurosci. 6, 668–671
123–128 295–318 34 Lapchak, P.A. et al. (1993) Cholinergic regulation
5 Hill, R.D. et al. (1993) The impact of long-term 20 Altar, A. and DiStefano, P.S. (1998) Neurotrophin of hippocampal brain-derived neurotrophic factor
exercise training on psychological function in trafficking by anterograde transport. Trends mRNA expression: evidence from lesion and
older adults. J. Gerontol. 48, P12–P17 Neurosci. 21, 433–437 chronic cholinergic drug treatment studies.
6 Laurin, D. et al. (2001) Physical activity and risk 21 Neeper, S.A. et al. (1995) Exercise and brain Neuroscience 52, 575–585
of cognitive impairment and dementia in elderly neurotrophins. Nature 373, 109 35 Ferencz, I. et al. (1997) Effects of cholinergic
persons. Arch. Neurol. 58, 498–504 22 Neeper, S.A. et al. (1996) Physical activity denervation on seizure development and
7 Friedland, R.P. et al. (2001) Patients with increases mRNA for brain-derived neurotrophic neurotrophin messenger RNA regulation in
Alzheimer’s disease have reduced activities in factor and nerve growth factor in rat brain. rapid hippocampal kindling. Neuroscience 80,
midlife compared with healthy control-group Brain Res. 726, 49–56 389–399
members. Proc. Natl. Acad. Sci. U. S. A. 98, 23 Berchtold, N.C. et al. (2001) Estrogen and 36 Berchtold, N.C. et al. Hippocampal BDNF is
3440–3445 exercise interact to regulate brain-derived regulated by exercise and the medial septum.
8 Stummer, W. et al. (1994) Reduced mortality neurotrophic factor mRNA and protein J. Neurosci. Res. (in press)
and brain damage after locomotor activity expression in the hippocampus. Eur. J. Neurosci. 37 Nibuya, M. et al. (1995) Regulation of
in gerbil forebrain ischemia. Stroke 25, 14, 1992–2002 BDNF and trkB mRNA in rat brain by
1862–1869 24 Russo-Neustadt, A. et al. (1999) Exercise, chronic electroconvulsive seizure and
9 Carro, E. et al. (2001) Circulating insulin-like antidepressant medications, and enhanced brain antidepressant drug treatments. J. Neurosci.
growth factor I mediates the protective effects of derived neurotrophic factor expression. 15, 7539–7547
physical exercise against brain insults of Neuropsychopharmacology 21, 679–682 38 Fujimaki, K. et al. (2000) Administration of a
different etiology and anatomy. J. Neurosci. 21, 25 Gomez-Pinilla, F. et al. (2001) Differential cAMP phosphodiesterase 4 inhibitor enhances
5678–5684 regulation by exercise of BDNF and NT-3 in rat antidepressant-induction of BDNF mRNA in rat
10 Black, J.E. et al. (1990) Learning causes spinal cord and skeletal muscle. Eur. J. Neurosci. hippocampus. Neuropsychopharmacology 22,
synaptogenesis, whereas motor activity causes 13, 1078–1084 42–51
angiogenesis, in cerebellar cortex of adult rats. 26 Gomez-Pinilla, F. et al. (1997) Physical exercise 39 Ivy, A.S. et al. (2001) The effects of NE and 5-HT
Proc. Natl. Acad. Sci. U. S. A. 87, 5568–5572 induces FGF-2 and its mRNA in the receptor antagonists on the regulation of BDNF
11 Isaacs, K.R. et al. (1992) Exercise and the brain: hippocampus. Brain Res. 764, 1–8 expression during physical activity. Soc. Neurosci.
angiogenesis in the adult rat cerebellum after 27 Kesslak, J.P. et al. (1998) Learning upregulates Abstr. 253.213
vigorous physical activity and motor skill BDNF mRNA: a mechanism to facilitate encoding 40 Garcia-Segura, L.M. et al. (2001) Neuroprotection
learning. J. Cereb. Blood Flow Metab. 12, and circuit maintenance? Behav. Neurosci. 112, by estradiol. Prog. Neurobiol. 63, 29–60
110–119 1012–1019 41 Wise, P.M. et al. (2001) Estrogens: trophic and
12 van Praag, H. et al. (1999) Running enhances 28 Tokuyama, W. et al. (2000) BDNF upregulation protective factors in the adult brain. Front.
neurogenesis, learning, and long-term during declarative memory formation in monkey Neuroendocrinol. 22, 33–66
potentiation in mice. Proc. Natl. Acad. Sci. inferior temporal cortex. Nat. Neurosci. 3, 42 Singh, M. et al. (1995) The effect of ovariectomy
U. S. A. 96, 13427–13431 1134–1142 and estradiol replacement on brain-derived
13 Young, D. et al. (1999) Environmental 29 Vanderwolf, C.H. (1969) Hippocampal electrical neurotrophic factor messenger ribonucleic
enrichment inhibits spontaneous apoptosis, activity and voluntary movement in the rat. acid expression in cortical and
prevents seizures and is neuroprotective. Nat. Electroencephalogr. Clin. Neurophysiol. 26, hippocampal brain regions of female
Med. 5, 448–453 407–418 Sprague-Dawley rats. Endocrinology 136,
14 Escorihuela, R.M. et al. (1995) Environmental 30 Lawson, V.H. and Bland, B.H. (1993) The role of 2320–2324
enrichment and postnatal handling prevent the septohippocampal pathway in the regulation 43 Sapolsky, R.M. (1996) Why stress is bad for your
spatial learning deficits in aged hypoemotional of hippocampal field activity and behavior: brain. Science 273, 749–750

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 Opinion TRENDS in Neurosciences Vol.25 No.6 June 2002 301

44 Woolley, C.S. et al. (1990) Exposure to excess 52 Carro, E. et al. (2000) Circulating insulin-like 61 Aberg, M.A. et al. (2000) Peripheral infusion of
glucocorticoids alters dendritic morphology of growth factor I mediates effects of exercise on the IGF-I selectively induces neurogenesis in the
adult hippocampal pyramidal neurons. Brain Res. brain. J. Neurosci. 20, 2926–2933 adult rat hippocampus. J. Neurosci. 20,
531, 225–231 53 Schwarz, A.J. et al. (1996) Acute effect of brief low- 2896–2903
45 Gould, E. et al. (1990) Short-term glucocorticoid and high-intensity exercise on circulating 62 Palmer, T.D. et al. (1999) Fibroblast growth factor-
manipulations affect neuronal morphology and insulin-like growth factor (IGF) I, II, and IGF- 2 activates a latent neurogenic program in neural
survival in the adult dentate gyrus. Neuroscience binding protein-3 and its proteolysis in young stem cells from diverse regions of the adult CNS.
37, 367–375 healthy men. J. Clin. Endocrinol. Metab. 81, J. Neurosci. 19, 8487–8497
46 Watanabe, Y. et al. (1992) Stress induces atrophy 3492–3497 63 Yoshimura, S. et al. (2001) FGF-2 regulation of
of apical dendrites of hippocampal CA3 pyramidal 54 Reinhardt, R.R. and Bondy, C.A. (1994) Insulin- neurogenesis in adult hippocampus after brain
neurons. Brain Res. 588, 341–345 like growth factors cross the blood–brain barrier. injury. Proc. Natl. Acad. Sci. U. S. A. 98, 5874–5879
47 Byrne, A. and Byrne, D.G. (1993) The effect of Endocrinology 135, 1753–1761 64 van Praag, H. et al. (2000) Neural consequences of
exercise on depression, anxiety and other 55 Tong, L. et al. (2001) Effects of exercise on gene- environmental enrichment. Nat. Rev. Neurosci. 1,
mood states: a review. J. Psychosom. Res. 37, expression profile in the rat hippocampus. 191–198
565–574 Neurobiol. Dis. 8, 1046–1056 65 Biernaskie, J. and Corbett, D. (2001) Enriched
48 Schaaf, M.J. et al. (2000) Corticosterone effects on 56 van Praag, H. et al. (1999) Running increases rehabilitative training promotes improved
BDNF expression in the hippocampus. cell proliferation and neurogenesis in the forelimb motor function and enhanced dendritic
Implications for memory formation. Stress 3, adult mouse dentate gyrus. Nat. Neurosci. 2, growth after focal ischemic injury. J. Neurosci. 21,
201–208 266–270 5272–5280
49 Russo-Neustadt, A. et al. (2001) Physical 57 Tanapat, P. et al. (1999) Estrogen stimulates a 66 Tillerson, J.L. et al. (2001) Forced limb-use effects
activity–antidepressant treatment combination: transient increase in the number of new neurons on the behavioral and neurochemical effects of
impact on brain-derived neurotrophic factor and in the dentate gyrus of the adult female rat. 6-hydroxydopamine. J. Neurosci. 21, 4427–4435
behavior in an animal model. Behav. Brain Res. J. Neurosci. 19, 5792–5801 67 Rampon, C. and Tsien, J.Z. (2000) Genetic
120, 87–95 58 Gould, E. et al. (1992) Adrenal hormones suppress analysis of learning behavior-induced structural
50 Arsenijevic, Y. and Weiss, S. (1998) Insulin-like cell division in the adult rat dentate gyrus. plasticity. Hippocampus 10, 605–609
growth factor-I is a differentiation factor for J. Neurosci. 12, 3642–3650 68 Geinisman, Y. (2000) Structural synaptic
postmitotic CNS stem cell-derived neuronal 59 Cameron, H.A. and Gould, E. (1994) Adult modifications associated with hippocampal LTP
precursors: distinct actions from those of brain- neurogenesis is regulated by adrenal and behavioral learning. Cereb. Cortex 10,
derived neurotrophic factor. J. Neurosci. 18, steroids in the dentate gyrus. Neuroscience 61, 952–962
2118–2128 203–209 69 Black, I.B. (1999) Trophic regulation of synaptic
51 Markowska, A.L. et al. (1998) Insulin-like 60 Cameron, H.A. et al. (1995) Regulation of adult plasticity. J. Neurobiol. 41, 108–118
growth factor-1 ameliorates age-related neurogenesis by excitatory input and NMDA 70 Kohara, K. et al. (2001) Activity-dependent
behavioral deficits. Neuroscience 87, receptor activation in the dentate gyrus. transfer of brain-derived neurotrophic factor to
559–569 J. Neurosci. 15, 4687–4692 postsynaptic neurons. Science 291, 2419–2423

‘WHO initiative’
Free access to TINS for developing countries
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The WHO and six medical journal publishers, including Elsevier Science, have launched the Access to Research
initiative, which enables ~70 developing countries to gain free access to biomedical literature through the Internet.
The science publishers were approached by the WHO and the British Medical Journal in 2001. Initially, >1000 journals,
including TINS, will be available for free or at significantly reduced prices to universities, medical schools, research and
public institutions in developing countries. The second stage will involve extending this initiative even further to more
institutions in other countries.
Gro Harlem Brundtland, director-general for the WHO, said that this initiative was ‘perhaps the biggest step ever taken
towards reducing the health information gap between rich and poor countries’.

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