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Pediatr Blood Cancer

REVIEW
Brain Development, Experience, and Behavior
Bryan Kolb, PhD,* Richelle Mychasiuk, PhD, and Robbin Gibb, PhD

Brain development progresses through a series of stages beginning psychoactive drugs, parent-child relationships, peer relationships,
with neurogenesis and progressing to neural migration, maturation, intestinal flora, diet, and radiation. This sensitivity of the brain to early
synaptogenesis, pruning, and myelin formation. This review examines experiences has important implications for understanding neuro-
the literature on how early experiences alter brain development, developmental disorders as well as the effect of medical interventions
including environmental events such as sensory stimuli, early stress, in children. Pediatr Blood Cancer # 2013 Wiley Periodicals, Inc.

Key words: brain development; cerebral plasticity; environmental stimulation; epigenetics

INTRODUCTION at about 30 years [2]. The plasticity and prolonged development of


the brain provides an opportunity for continual modification of
Brain development is a prolonged process that reflects more than cognitive function but, in addition, creates a potential susceptibility
the simple unfolding of a genetic blueprint but rather reflects a to the formation of abnormal circuitry leading to compromised
complex interaction of genetic and experiential factors that shape behavioral function. The brain is especially vulnerable to
the emerging brain and ultimately behavior. Brains exposed to experiences at the onset of puberty when the frontal lobe is
different environmental events or perturbations thus may develop in massively pruning synapses. Thus, the peak age of onset for most
very different ways. The goal of the current article is to review mental disorders is estimated at 14 years [3], including anxiety
the ways the developing brain can be sculpted by a wide range of disorders, psychoses (including schizophrenia), bipolar disorder,
pre- and postnatal factors. We begin with an overview of brain depression, eating disorders, and substance abuse most commonly
development, followed by a consideration of how factors influence emerge by or during adolescence.
brain development and adult behavior. Because most of what we
know about brain plasticity and behavior in development comes
FACTORS INFLUENCING BRAIN DEVELOPMENT
from studies of the laboratory rat our discussion will focus on the rat
but will consider humans when possible. Over the past 20 years it has become clear that even fairly
innocuous-looking experiences can profoundly affect brain
development and that the range of experiences that can alter brain
BRAIN DEVELOPMENT development is much larger than had been once believed. We will
Brain development can be divided loosely into two phases. In highlight some of the most well studied effects.
most mammals the first reflects a genetically determined sequence The simplest way to manipulate experience across ages is to
of events in utero that can be modulated by maternal environment compare brain structure in animals living in standard laboratory
and pre-conceptual events. The second phase, which is both pre- caging to animals placed either in so-called enriched environments or
and postnatal in humans, is a time when the connectivity of the brain in severely impoverished environments. When animals are placed in
is very sensitive not only to the environment but also to the patterns complex environments in which there is an opportunity for animals
of brain activity produced by experiences. More importantly, to interact with a changing sensory and social environment and to
however, it is now recognized that epigenetic changes, which can be engage in far more motor activity than regular caging. There are
defined as changes in developmental outcomes, including regula- many of neural changes associated with this form of enrichment
tion of gene expression, are based upon mechanisms other than including increases in brain size, cortical thickness, neuron size,
DNA itself [1]. For example, gene expression can be altered by dendritic branching, spine density, synapses per neuron, glial
specific experiences, including pre-conceptual experiences, and numbers and complexity, and vascular arborization [4]. In contrast,
this in turn can lead to organizational changes in the nervous impoverishment produces changes in the opposite direction, as well
system. as cell loss [5].
Figure 1 outlines the general stages characteristic of brain
development in all mammals. Cells that are destined to produce the
nervous system begin to form about 3 weeks after fertilization in Canadian Centre for Behavioural Neuroscience, University of Leth-
humans. Once formed, the presumptive neurons must migrate to bridge, Lethbridge, Canada
their eventual correct location, differentiate into the appropriate
Grant sponsor: Natural Science and Engineering Research Council of
phenotype, form connections, and then are pruned based upon
Canada (B.K. and R.G.)
experience. Pruning is an important stage: the number of excitatory
synapses is 2-to-3 times greater in children than in adults and that Conflict of interest: Nothing to declare.

spine density begins to decrease during puberty, stabilizing at the Correspondence to: Bryan Kolb, Department of Neuroscience,
adult level around age 30 [2]. Canadian Centre for Behavioural Neuroscience, University of Leth-
Not all brain regions mature at the same rate. In particular, the bridge, Lethbridge, Alberta, Canada T1K 3M4. E-mail: kolb@uleth.ca
prefrontal cortex is very slow to develop, finally reaching maturity Received 14 August 2013; Accepted 25 November 2013

C 2013 Wiley Periodicals, Inc.
DOI 10.1002/pbc.24908
Published online in Wiley Online Library
(wileyonlinelibrary.com).
2 Kolb et al.

adult prefrontal cortex (e.g., [12,13]) and nucleus accumbens,


hippocampus, and other regions in the HPA-axis [14,15].
One probable mechanism for early stress effects is epigenetic.
Mychasiuk et al. [16] varied the intensity of prenatal stress on
embryonic days 12–16 (equivalent to stress in the second trimester
for humans) and used a whole genome microarray analysis to show
that over 700 genes in the frontal cortex and hippocampus were
differentially expressed following prenatal stress, with most genes
being down regulated.
Psychoactive drugs also profoundly affect brain development.
Virtually every class of psychoactive drugs, including prescription
drugs, produce large changes in the structure of cells in prefrontal
cortex and nucleus accumbens in adult rats [17]. Less is known
about the effects of early exposure to such drugs but in rats prenatal
or infant exposure to stimulants, antipsychotics, anxiolytics,
Fig. 1. Timeline of brain development in humans. Brain development antidepressants, or alcohol all significantly influence brain
begins about 3 weeks after conception and continues until about development, the largest effects being found in prefrontal cortex
30 years.  Neurogenesis is largely complete by 6 months gestation but
(e.g., [18–20]).
continues in the cerebellum up to the eighth postnatal month and in the
hippocampus and subventricular zone throughout life. In sum, exposure to both prescription drugs and drugs of
abuse has a profound effect on prefrontal development and
prefrontal-related behaviors. These effects appear to be perma-
nent and can influence brain plasticity in adulthood. The
Not only can brain development be altered by direct experience unexpected serious effects of prescription drugs on brain and
but also by indirect events such as prenatal and even preconceptual behavioral development are undoubtedly important in human
experiences. For example, Mychasiuk et al. [6] placed adult males infant brain development.
in complex housing for 28 days before pairing them in standard Mammalian infants that are born in an immature state face a
cages with females that had been housed in standard laboratory significant challenge in early life [21]. They are dependent upon
cages. Other female rats were also housed in complex environments their parents and they must learn to identify, remember, and prefer
for 28 days (7 days prior to conception and for the duration of the their caregivers. Parent-infant relationships therefore can initiate
pregnancy). Brain tissue from the frontal cortex and hippocampus long-term developmental effects that persist into adulthood [22].
was harvested for global DNA methylation analysis when the pups For example, rodent studies have shown that the time spent in
reached weaning age (day 21). Both paternally and maternally contact, the amount of maternal licking and grooming, and the time
enriching animals led to a significant decrease in gene methylation the mothers spend in a highly stimulating high-arched resting
levels in frontal cortex and hippocampus. position correlate with a variety of somatic and behavioral
The effects of early experience can also be manipulated more differences, including modifications of the hypothalalmic-adrenal
subtly. For example, when infant rats are given light tactile stress axis, changes in hippocampal structure and gene expression,
stimulation with a small brush for 15 minutes three times per day for and signaling pathways in the hypothalamus and amgydala [23–25].
10–15 days beginning at birth, there are changes in brain In addition, the amount both maternal and paternal stimulation
development and behavior that can be seen in adults (e.g., [7,8]). alters prefrontal cortex development [26–29].
Such findings speak to the importance of tactile stimulation in Peer relationships have been known to influence adult behavior
human infants. since the studies of Harlow and Harlow (e.g., [30]). One of the most
A second major influence on brain development is early stress. powerful peer relationships is play, which has been shown to be
There is a large literature collected over the past 60 years showing important for the development of adult social competence [31]. The
the effects of stress on brain and behavior in adults but it is only frontal lobe plays an essential role in play behavior and infant injury
more recently that the role of perinatal stress in infants has been to the prefrontal cortex compromises play behavior [32]. Further-
appreciated. It is now known that both gestational and infant stress more, manipulation of the intensity of play behavior alters
predisposes individuals for a variety of maladaptive behaviors and prefrontal cortex development. Bell et al. [33] placed juvenile
psychopathologies. For example, prenatal stress is a risk factor in rats with one or three adult rats or one or three other juvenile
the development of schizophrenia, attention-deficit hyperactivity animals. Adult rats do not play with juveniles so there was virtually
disorder, depression, and drug addiction [9,10]. Experimental no play with the adult animals but play behavior was increased the
studies with lab animals have confirmed these findings with the more juvenile animals that were present. Analysis of cells in the
overall results being that perinatal stress, in rodents as well as non- prefrontal cortex showed that neurons of the orbital prefrontal
human primates, is associated with behavioral abnormalities such cortex responded to the number of peers present, and not whether or
as elevated and prolonged stress response, impaired learning and not play occurred, whereas the neurons of medial prefrontal cortex
memory, deficits in attention, altered exploratory behavior, altered responded to the amount of play but not the number of conspecifics.
social and play behavior, and an increased preference for alcohol There may be an important lesson here when we consider conditions
(e.g., [11]). in which human childhood play is not normal, such as when
Although there is a rich literature on the functional effects of children are hospitalized for extended periods. The abnormalities in
early stress, less is known about how the brain is affected. In play behavior may influence prefrontal development and later adult
general, it appears that early stress leads to reduced spine density in behavior.
Pediatr Blood Cancer DOI 10.1002/pbc
Brain Development 3

One recently described experience altering brain development is CONCLUSIONS


intestinal flora. Immediately after birth, mammals are rapidly
Our understanding of the nature of normal brain development
populated buy a variety of indigenous microbes. These microbes
has advanced a long way in the past 30 years but we are just
influence development of many body functions. For example, gut
beginning to understand some of the factors that modulate this
microbiota have systemic effects on liver function [34]. Because
development. Understanding this modulation will be essential for
there is a known relation between neurodevelopmental disorders
us to begin to unravel the puzzles of neurodevelopmental disorders
such as autism and schizophrenia and microbial pathogen infections
and the effects of early medical interventions for infants and
during the perinatal period (e.g., [35,36]), Diaz Heijtz et al. [37]
children with significant health issues.
proposed that such infections could alter brain and behavioral
development. The authors compared measures of both motor
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Pediatr Blood Cancer DOI 10.1002/pbc