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DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY REVIEW

Principles of plasticity in the developing brain

BRYAN KOLB 1,2 | ALLONNA HARKER1 | ROBBIN GIBB 1
1 Canadian Centre for Behavioural Neuroscience, University of Lethbridge, Lethbridge, AB; 2 Canadian Institute for Advanced Research, Toronto, ON, Canada.
Correspondence to Bryan Kolb, Department of Neuroscience, University of Lethbridge, Lethbridge, Alberta T1K 3M4, Canada. E-mail: kolb@uleth.ca

An early version of this paper was presented at the Early Intervention in Light of the ICF-CY Meeting held in Groningen, the Netherlands, 7–9 April 2016.

The developing brain is especially sensitive to a wide range of experiences, showing a

PUBLICATION DATA remarkable capacity for plastic changes that influence behavioural outcomes throughout the
Accepted for publication 21st June 2017. lifetime. We review the principles that regulate this plasticity in development and consider
Published online 13th September 2017. the factors that modulate the developing brain. These include early sensory, motor, and lan-
guage experience, early stress, caregiver interactions, peer interactions, psychoactive drugs,
ABBREVIATIONS diet, microbiome, and the immune system. Emphasis is given to changes in behaviour, epi-
mPFC Medial prefrontal cortex genetics, and neuronal morphology.
OFC Orbital frontal cortex
SES Socioeconomic status

Studies examining the influence of experience on brain
development originally assumed that it would require large
changes in experience, such as being raised in darkness, to
influence brain development. We now know that an unex-
pectedly large range of experiences alter brain development
and that even fairly innocuous-appearing experiences can
profoundly affect brain development. We will summarize
some of the most extensively studied effects, with an
emphasis on studies of laboratory animals, and also include
effects on functions such as language that are uniquely
human. We will not review the effects of early brain injury,
which we have reviewed elsewhere.1
Four special features of developmental plasticity are
especially important. The first feature is found in the cells
lining the subventricular zone of the lateral ventricles and
cells in the hilus of the dentate gyrus. Both regions contain
stem cells that remain active throughout life. The cells in
the subventricular zone produce both glial and neural pro-
genitor cells that can migrate into cerebral grey or white
matter, even in adulthood. In humans, the subventricular
zone cells appear mostly quiescent but can become acti-
vated, largely in response to cerebral perturbations. Stem
cells in the dentate gyrus generate new neurons at a slow
but steady pace throughout life in both rodents and
humans, although there is a decline with ageing. The func-
tional role of these cells is not totally understood, but they
do integrate with the existing neurons and likely play a
role in the formation of new memories.
A second special feature is that three types of plasticity
can be distinguished in the developing brain: experience-
independent, experience-expectant, and experience-depen-
dent. Experience-independent plasticity results from the
fact that the genome generates a rough approximation of
connectivity that is modified by both internal and external
events. Neurons that are active together increase their con-
nections, whereas those that are not coincidentally active
weaken their connections. Experience-expectant plasticity
occurs mostly during early postnatal development. For
instance, a child raised hearing Korean will thus be
exposed to different speech sounds than a child raised in
an English-speaking environment. Early in life, infants can
discriminate the speech sounds of all languages, but over
the first year the auditory system begins to change such
that the infant becomes expert in discriminating sounds in
its language environment but loses the ability to discrimi-
nate sounds that are not experienced.2 Experience-depen-
dent plasticity, a process whereby the connections of
ensembles of neurons are modified by experience, begins
in early postnatal life and continues for a lifetime. One
common example is seen in the effects of so-called ‘en-
riched experiences’.
A third special feature is the speed at which dendrites,
and especially dendritic spines, can modify their structure
to form or delete synapses in response to experience, possi-
bly in a matter of minutes.
A fourth special feature is the presence of critical peri-
ods, especially for experience-expectant plasticity. One of
the best studied models was first described by Wiesel &
Hubel3 in which they showed that if one eye of a kitten is
kept closed after birth, the open eye expands its territory
at the expense of the closed eye. When the closed eye is
eventually opened after a few months, its vision is compro-
mised, resulting in an enduring loss of spatial vision (am-
blyopia). Recent work has shown that the critical period
results from an appropriate balance of excitatory and inhi-
bitory inputs (Fig. 1). The maturation of inhibitory c-ami-
nobutryic acidergic circuits underlies the timing of onset
of the critical periods, which vary across brain regions.

1218 DOI: 10.1111/dmcn.13546 © 2017 Mac Keith Press


The critical period closes as molecular brakes dampen
plasticity, and alter the balance between excitation and
inhibition (for a review, see Takesian & Hensch4). A key
point is that it is possible to reopen the critical period by
manipulating this balance chemically.
SENSORY AND MOTOR EXPERIENCES
The simplest way to manipulate developmental sensory/
motor experiences is either to have extreme deprivation,
such as raising animals in darkness, or to provide quasi-
‘enriched’ environments where there is enhanced social,
cognitive, sensory, and/or motor experience relative to ani-
mals living in small social groups in laboratory cages. Rais-
ing animals in deprived conditions hinders development
and may lead to the permanent loss of function. Monkeys,
cats, or rats raised in the light but without patterned visual
stimulation show poor visual guidance of behaviour, even
after prolonged periods of recovery with patterned visual
input.5 The reduced vision is associated with reduced den-
dritic branching and length in both visual and posterior
cingulate cortices.
Rearing animals in enriched environments has rather dif-
ferent effects. In our studies on the effects of raising wean-
ling rats in large social groups (6–8 same-sex animals) in
complex environments leads to increased brain weight in
the order of 7% to 10%, which is associated with increases
in the number and density of blood vessels, neuron soma
size, dendritic elements, synapses, gene expression, and glia
throughout the neocortex, hippocampus, and striatum.
There is also increased production of a variety of growth
factors known to alter brain development.6 And, in con-
trast to the effects of deprivation where there is reduced
function, complex housing is generally associated with
increased motor, sensory, and cognitive functions.
Cortical maturation
PSA-NCAM
Critical period
Off
On
e.g. GABA
Figure 1: Proposed mechanism for turning on and off critical periods. Plasticity is blocked initially by factors such as polysialic acid (PSA) on neural
cell adhesion molecule (NCAM), thus limiting the parvalbumin system (PV). Critical period closes as molecular brakes (e.g. perineuronal nets) emerge to
dampen plasticity (adapted from Takesian and Hensch).4 E-I balance, balance between excitation and inhibition; GABA, c-aminobutyric acid. [Colour
figure can be viewed at wileyonlinelibrary.com].
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What this paper adds
• A discussion of the surprising range of factors influencing brain
development
• Life experiences interact resulting in a phenomenon called metaplasticity
Relatively minor modifications of visual experience can
also have the significant effects. Prusky et al.7 placed rats in
a virtual optokinetic system in which the animals stood on
a small platform and vertical lines of differing spatial fre-
quency moved past the animal. When the rats (or humans)
view the moving lines it is impossible to avoid tracking the
lines. The rats were exposed to the moving lines daily for 2
weeks beginning at eye opening (approximately postnatal
day 15). Measures of visual acuity in adulthood showed a
chronic 25% enhancement in visual acuity relative to con-
trol animals. Thus, simply being exposed to enhanced visual
input was sufficient to modify visual development.
Although it is generally assumed that the effects of com-
plex housing result from the animals physically interacting
with the environment, a series of studies by our group have
suggested that the effects of complex housing can cross
generations. For example, when male or female rats were
housed in complex environments for 28 days prior to being
mated with animals housed in standard laboratory housing,
there were similar decreases in global methylation (thus,
increased gene expression) in the offspring of both male-
and female-enriched parents, as well as changes in beha-
vioural development.8
The effects of preconception enriched housing is also
seen in the response of offspring to perinatal cerebral
injury. When the offspring of females housed in complex
environments during gestation were given perinatal medial
prefrontal lesions they showed remarkably better beha-
vioural outcomes relative to those without the gestational
E–I balance
(PV circuits)
Molecular
brakes
Age
Off
e.g. Perineuronal Nets
Review 1219

housing experience. The gestational experience increased
cortical thickness, thalamic volume, and spine density in
cortical pyramidal neurons in both the control and lesion
animals.9
LANGUAGE, COGNITIVE EXPERIENCE, AND POVERTY
Infants can discriminate the speech sounds of all languages
over the first year, but the auditory system begins to
change such that the infant becomes expert in discriminat-
ing sounds in its language environment but loses the ability
to discriminate sounds that are not experienced. Learning
more than one language in development adds another
dimension, and especially in learning how to switch rou-
tinely between languages. This mental switching has a sig-
nificant impact on cognitive abilities, and especially in
enhancing attentional and executive functions, and in
increasing cognitive reserve in ageing, presumably by some
type of plastic change in the frontal lobe.10
Although virtually all children learn a language, there
are large differences in rate of vocabulary acquisition. In a
powerful study, Hart and Risley followed children for 2
and a half years (from the age of 7–9mo to 36mo) by
observing the families at home for 1 hour each month.11
Children could be grouped into those with large vocabu-
laries at 3 years of age (~1200 words) versus those with
smaller vocabularies (~400–600 words). This difference was
related to the number of words that the children had been
exposed to in the home, which was directly related to
socioeconomic status (SES). Thus, over 1 year, children of
high SES would have been exposed to about 11 million
words and children of low SES to about 3.2 million words.
By 4 years of age the average child of lower SES would
have been exposed to about 30 million fewer words than
the child of higher SES. When the children were measured
again at 9 to 10 years, the SES-related difference actually
grew larger, suggesting that school had a negligible effect
in erasing this deficit.
The SES-related difference in cognitive abilities is
related to developmental differences in cerebral cortex.
Noble et al.12 examined the relationship between SES and
cortical surface area in over 1000 participants between the
age of 3 years and 20 years. Lower family income, inde-
pendent of ethnicity or sex, was associated with decreased
cortical surface area in widespread regions of frontal, tem-
poral, and parietal cortex, and this was correlated with
poorer performance on tests of attention, memory, vocabu-
lary, and reading. Thus, lower SES is associated with smal-
ler cortical surface area and poorer test outcomes.
PRENATAL AND POSTNATAL STRESS
The effects of stress are not only dependent upon the
hypothalamic–pituitary–adrenal axis but involve a two-way
communication between the brain and the cardiovascular,
immune, and other systems via neural and endocrine
mechanisms (for an extensive review of early stress effects,
see Kolb et al.13). One effect of stress in adults is a change
in the structure of neurons in the hippocampus, amygdala,
1220 Developmental Medicine & Child Neurology 2017, 59: 1218–1223
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and the prefrontal cortex. Studies of laboratory rodents
have shown a decrease in the dendritic arborization and
spine density in the medial prefrontal cortex (mPFC) but
an increase in these measures in orbital frontal cortex
(OFC). There are also changes in mRNA gene expression
in the mPFC, OFC, and hippocampus, with each region
showing a different pattern of altered gene expression.
Early stress predisposes individuals to a range of mal-
adaptive behaviours and psychopathologies, including
schizophrenia, depression, and drug addiction (e.g. Anda
et al.14). Perinatal stress in laboratory rodents produces a
range of behavioural abnormalities, including an elevated
and prolonged stress response, increased anxiety, impaired
learning and memory, deficits in attention, altered explora-
tory behaviour, altered social and play behaviour, and
increased preference for alcohol. These effects vary both
with precise timing and the intensity.
Evidence has accumulated to show that preconception
stress in either parent may influence the offspring by altering
behaviour, brain morphology, and epigenetics in the adult
offspring.13 For example, in our studies of the effects of pre-
conception paternal stress the offspring showed increased
anxiety and impairment in a skilled reaching task, even with
the stress being over a single sperm generation cycle. Epige-
netic analysis showed significantly decreased methylation in
frontal cortex (mPFC and adjacent motor cortex) in female
but not male offspring, and increased methylation in the
hippocampus. Furthermore, there were abnormalities in
dendritic complexity and spine density that changed signifi-
cantly across development. A parallel study showed that
preconception maternal stress led to altered dendritic
complexity and spine density in two mPFC regions.13
Studies on the effects of gestational stress have generally
found that the offspring exhibit increased anxiety, altered
play behaviour, impaired skilled reaching, and slower spa-
tial learning.13 Postmortem analyses reveal decreases in
overall brain, but not body, weight, and decreased spine
density in OFC, but increased spine density in mPFC cor-
related with changes in gene expression in these regions.
Although the anatomical pattern is different both from
preconception stress, the behavioural changes are similar.
The effects of gestational stress in humans are being
studied in a prospective study on the effects of the Quebec,
Canada ice storm of 1998. The storm hit in midwinter and
power was knocked out for up to 6 weeks, affecting
approximately 2 million people, during the coldest month
of the year. Many females were pregnant at different stages
of gestation and had varying levels of hardship, ranging
from severe to none. The offspring of pregnant females
have now been studied from the age of 2 years to 11 years
6 months. To date, the children of stressed mothers show
cognitive, linguistic, motor, and play abnormalities, and at
11 years 6 months there are dramatic differences in gene
expression (e.g. Cao-Le et al.15).
Postnatal stress also changes brain development. Short
periods of maternal separation alter the hypothalamic–pitu-
itary–adrenal axis, making it more efficient allowing better

recovery from stress.13 But there is a limit to the intensity
of maternal separation that is beneficial. Longer periods
(e.g. 3 hours daily) leads to increased anxiety in adult male
offspring, disrupted play behaviour in both sexes, decreased
brain weight, and increased dendritic complexity and spine
density in both mPFC and OFC.13 Thus, it appears that
brief periods of maternal separation are beneficial to later
adult behaviour, whereas more extended periods of separa-
tion have the opposite effect. It is likely that these con-
trasting effects are related to differential effects on gene
expression.
In sum, preconceptual, gestational, and postnatal stress
all change behaviour, epigenetics, and neuronal morphol-
ogy, although in different ways, and very differently than
stress in adulthood.
PARENT–CHILD RELATIONSHIPS
Young mammals are dependent upon their parents and
must learn to identify, remember, and prefer their care-
givers. Modifications of these relationships can significantly
alter brain development and leave effects that remain into
adulthood. For example, extensive studies on rats have
shown that the time spent in contact between the mother
and pups, including both the amount of maternal licking
and grooming correlate with a variety of somatic and beha-
vioural differences, and especially modify the development
of the hypothalamic–pituitary–adrenal axis. These changes
are correlated with changes in gene expression in the off-
spring.16 Other studies have shown changes related to
maternal–infant interactions in the mPFC, OFC, hypotha-
lamus, and amygdala.
The effects of reduced parent–child interactions in
humans have been studied in children adopted from insti-
tutions and related to the age at adoption. For example,
12- to 14-year-old children who were adopted from insti-
tutional care at a mean age of 12 months had reduced
grey-matter volumes and especially reduced prefrontal vol-
ume, which was consistent with previous studies showing
reduced prefrontal cortical thickness (e.g. Hodel et al.17).
Extensive studies of Romanian orphans adopted to various
Western countries have shown similar results, although
one additional finding is that adoption after about 18
months is associated with very poor behavioural and neu-
rological outcomes, even after over 20 years of living in
good and stable families. These children have smaller-
than-normal brains, reduced cognitive and social functions,
and abnormal brain electrical activity (e.g. Johnson
et al.18). The Romanian children are more affected than in
the US study, and this is likely related to both the severity
of caregiver deprivation and the duration of institutional-
ization in the Romanian children.
PEER RELATIONSHIPS
Although the details differ, all mammals play and the
opportunity to play is rewarding. Play can be seen as a
form of problem-solving and many forms of play have
innate rules. For example, when rats play the goal is for
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the attacking rat to nuzzle the nape of the defending rat,
who, in turn, tries to avoid the nuzzle. The roles of defen-
der and attacker are reciprocal such that the rats take turns
in each role and breaking this rule tends to end the play
bout. Kittens have a similar play pattern. Because adult rats
do not play with juveniles it is possible to house individual
juveniles with one or more adults, which provides social
interactions, but the younger animals are deprived of play.
In contrast, juveniles can be housed with one or more juve-
niles, which results in lots of play and social interaction.
Play behaviour acts to prune pyramidal neurons in
mPFC,19 which allows the neurons to be more plastic later
in life. Many developmental experiences, including gesta-
tional stress, tactile stimulation, and psychoactive drugs,
alter various aspects of play behaviour, which presumably
alters mPFC development.
PSYCHOACTIVE DRUGS
All psychoactive drugs, including prescription drugs,
change the structure of neurons, especially in prefrontal
cortex and nucleus accumbens.20 Less is known about the
effects of drug exposure during development, although it
has long been known that early exposure to alcohol is dele-
terious to brain development. As many as 20% of North
American females smoke for at least part of their preg-
nancy and nicotine easily crosses the blood–brain barrier.
Prenatal nicotine exposure increases the risk for various
neurodevelopmental disorders, including hyperactivity,
learning and memory deficits, and conduct disorders (e.g.
Button et al.21). Low doses of nicotine administered
throughout pregnancy in rats changes the structure of neu-
rons in prefrontal cortex, nucleus accumbens, and parietal
cortex of adult offspring. As with the effects of nicotine
exposure in adulthood, prenatal nicotine exposure is associ-
ated with epigenetic changes related to dendritic complex-
ity.22
Although less well studied than nicotine, there is grow-
ing evidence that prenatal exposure to a wide range of
drugs, including amphetamine, fluoxetine, valproic acid,
morphine, and marijuana alter behaviour, neuronal struc-
ture, and epigenetics in the adult offspring. Preliminary
non-invasive imaging studies in children have shown paral-
lel results in which dopamine-rich cortical (e.g. prefrontal
cortex) and subcortical (e.g. basal ganglia) reduction in
grey matter volume.23 One difficulty with many of the ani-
mal studies is that the doses are often much larger than
typically experienced by pregnant human females, which
may exaggerate the dangers of drug exposure.
DIET
Most research on nutrients in development have focused
on the effects of nutrient deficiencies, especially related to
protein-energy, iron, zinc, copper, and choline. Such nutri-
tional deficiencies can have global effects on the developing
brain or brain circuit-specific effects, depending upon the
precise timing of the nutrient deficit. A more intriguing
question is whether brain plasticity might be enhanced by
Review 1221

vitamin and/or mineral supplements, and especially a com-
bination of nutrients that would work synergistically to
enhance metabolic activity, and ultimately brain function-
ing. One promising product is EmpowerPlus. This product
is a blend of 36 vitamins, minerals, and antioxidants, and
includes a proprietary blend of herbal supplements such as
gingko biloba and the amino-acid precursors for neuro-
transmitters, choline, phenylalanine, glutamine, and
methionine. This product has been reported to improve
mood and behaviour in children, and been shown to
decrease anger, activity levels, and social withdrawal in aut-
ism while also increasing spontaneity.24 Rodent studies
have shown that using this supplement during development
leads to enhanced motor and cognitive functions and
increased dendritic arbour in mPFC. The mechanism of
dietary effects on neuronal structure may be epigenetic.
Dominguez-Salaz et al.25 studied gene methylation in the
blood of infants conceived either in the Gambian dry or
rainy season. The maternal diets are dramatically different
in the two seasons and so was the pattern of gene methyla-
tion.
GUT BACTERIA
Given that the microbiome interacts with the brain, Dinan
et al.26 proposed that the use of bacteria to alter the micro-
biome could be a novel class of psychotropic, which are
called psychobiotics. The idea is that manipulation of bac-
teria in the gut could modify brain plasticity, a conclusion
supported by several studies showing that normal gut
microbiota can affect brain and behavioural development.
For example, manipulation of gut bacteria in newborn
mice influenced motor and anxiety behaviours.27 These
behavioural changes were correlated with changes in the
turnover of noradrenaline, dopamine, and serotonin in the
striatum, as well as changes in the production of synaptic-
related proteins in cortex and striatum.
IMMUNE SYSTEM
Many proteins in the immune system are expressed in the
developing brain and some appear essential for the develop-
ment and modifications of synapses. Although there is little
direct evidence that the immune system can compromise
brain development and plasticity, epidemiological evidence
implicates maternal infection as risk factors in various
neurodevelopmental disorders, including autism, attention-
deficit–hyperactivity disorder, and schizophrenia.28
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The developing brain is responsive to a wide range of fac-
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A CK N O W L E D G E M E N T S
We wish to thank both Natural Sciences and Engineering
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Advanced Research for their long-term support for the studies
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