brain plasticity in the developing brain - occidental … brain plasticity in the developing brain 2...

CHAPTER

Brain Plasticity in theDeveloping Brain
2
Bryan Kolb1, Richelle Mychasiuk, Arif Muhammad, Robbin GibbCanadian Centre for Behavioural Neuroscience, University of Lethbridge, Lethbridge, AB, Canada

1Corresponding author: Tel.: þ1-403-329-2405; Fax: þ1-403-329-2775,

e-mail address: [email protected]

AbstractThe developing normal brain shows a remarkable capacity for plastic change in response to a

wide range of experiences including sensory and motor experience, psychoactive drugs,

parent–child relationships, peer relationships, stress, gonadal hormones, intestinal flora, diet,

and injury. The effects of injury vary with the precise age-at-injury, with the general result

being that injury during cell migration and neuronal maturation has a poor functional outcome,

whereas similar injury during synaptogenesis has a far better outcome. A variety of factors

influence functional outcome including the nature of the behavior in question and the age

at behavioral assessment as well as pre- and postinjury experiences. Here, we review the

phases of brain development, how factors influence brain, and behavioral development in both

the normal and perturbed brain, and propose mechanisms that may underlie these effects.

Keywordsbrain development, prefrontal cortex, recovery of function, types of plasticity

1 INTRODUCTIONThe development of the brain and behavior is guided not only by a basic genetic blue-

print but also by a wide range of experiences that shape the emerging brain. Brains

exposed to different environmental events such as sensory stimuli, stress, injury,

diet, drugs, and social relationships show a unique developmental trajectory. The

explosion of epigenetic studies in the past few years has also demonstrated that pre-

natal, and even preconceptual, experiences modify the organization of neural

networks. The goal of this review is to consider the manner in which the developing

brain can be modified by a range of prenatal and postnatal factors that can influence

how the brain responds to other experiences later in life. Our focus will be on the

Progress in Brain Research, Volume 207, ISSN 0079-6123, http://dx.doi.org/10.1016/B978-0-444-63327-9.00005-9

© 2013 Elsevier B.V. All rights reserved.35

http://dx.doi.org/10.1016/B978-0-444-63327-9.00005-9

36 CHAPTER 2 Brain Plasticity in the Developing Brain

neocortex of the rat because the majority of our knowledge regarding the modulation

of brain development is based on studies of neocortical development. We begin with

a brief review of the stages of brain development followed by a consideration of how

factors influence brain development and behavior.

2 STAGES OF BRAIN DEVELOPMENTThe Roman philosopher Seneca concluded that an embryo is an adult in miniature

and the purpose of development was to grow bigger. By the twentieth century, it be-

came clear that this was not the case. Today, development can broadly be divided

into two phases. In mammals, the first phase is in utero and reflects a genetically

determined sequence of events that can be modulated by the maternal environment.

The principal developmental stages here are neural generation and migration. The

second phase, which is largely postnatal in species such as the rat, but both pre-

and postnatal in species such as humans where brain development is more prolonged.

The second phase of development is a period in which the emerging connectivity of

the brain is very sensitive to both environmental stimuli but also to the patterns of

brain activity produced by previous experiences.

Table 1 summarizes seven general stages of brain development characteristic of

all mammals. The generation of neurons in rats begins on embryonic (E) day 10.5–11

when the neural tube is formed with the generative zone, called the subventricular

zone, as the primary “nursery” (for reviews, see Bayer and Altman, 1991; Semple

et al., 2013). The cerebral cortex is mainly generating cells from E15–21. Once

generated in the subventricular zone, the putative neurons migrate to their appropri-

ate locations in the developing cortical plate. The migratory process can take

2–5 days, depending upon the final location (see Fig. 1) (Bayer and Altman;,

1991; Hicks and D’Amato, 1968). There are two types of migration. Pyramidal cells

migrate from the ventricular zone along radial glia to their respective cortical layers

(Rakic, 1972). Interneurons take a tangential trajectory in what Bayer and Altman

call the lateral migratory stream as illustrated in Fig. 1. These cells are generated

more laterally in the ventricular zone in a region known as the ganglionic eminence

(Cuzon et al., 2006; Jimenz et al., 2002). Errors in the migration process, including

abnormal cell proliferation, abnormal timing or migration, or abnormal cortical

Table 1 Stages of brain development

1. Cell birth (neurogenesis, gliogenesis)2. Cell migration3. Cell differentiation4. Cell maturation (dendrite and axon growth)5. Synaptogenesis (formation of synapses)6. Cell death and synaptic pruning7. Myelogenesis (formation of myelin)

Dorsomedialneocortex

Dorsolateral

neocortex

Ventrola

teralneocortex

Piriform

cortex

2 days

3 days

4 days

5 days

Basaltelencephalon

Reservoir

Striatum

Ventricularzone

HeadLATERAL CO

RTICAL S

TRE

AM

?

FIGURE 1

A summary figure showing cell migration in the anterior and middle parts of the developing

neocortex. Neurons generated in the ventricular zone (striped layer) migrate radially to

the dorsal cortical plate in 2 days, migrate laterally to the lateral cortical plate in 3 days and

to the ventrolateral cortical plate in 4 days. Some cells generated in the ventricular zone

migrate in the lateral cortical stream for up to 4 days and accumulate in the reservoir.

Some migrate into the pyriform cortex, whereas others migrate to as yet unidentified areas in

the basal telencephalon.

From Bayer and Altman (1991), with permission.

372 Stages of Brain Development

organization, have been implicated in disorders such as epilepsy, autism, and schizo-

phrenia among others (e.g., Mochida andWalsh, 2004). Furthermore, prenatal expo-

sure to drugs, such as diazepam (a GABA agonist), can alter migration patterns

(Cuzon et al., 2006).

Once the cells reach their appropriate locations, there is a rapid differentiation

into cell types and growth of dendrites and axons, a process that peaks at 7–10 days

postnatal (P). Synapse production begins once neurons mature with a rapid increase

beginning around P10. Micheva and Ceaulieu (1996) counted the number of GABA

and non-GABA cells and found that the cell volume peaks at about P30 in


somatosensory cortex. There was no further change in synapse number at P60, which

was the oldest age that the authors examined. It is well documented that in primates

there is an overproduction and later elimination of synapses (e.g., Huttenlocher,

1984; Petanjek et al., 2011), which in humans continues well into the third decade

of life. However, the possible overproduction and pruning of synapses is not well

studied in the rat. Although Micheva and Beaulieu did not see any change up to

P60 in somatosensory cortex, it is likely that at least some regions are shedding syn-

apses after P60. Van Eden et al. (1990) showed a decline in cortical thickness in pre-

frontal cortex from P60 to P90 and Vinish et al. (2013) showed a decrease in spine

density over a similar time period in medial prefrontal cortex (mPFC). These results

imply that a more systematic analysis of synaptic formation beyond weaning is re-

quired in the rat. The need for neuronal and synaptic pruning is likely related to the

uncertainty in the number of neurons that will reach their appropriate destinations

and the appropriateness of the connections that they form.

Three features of brain development are especially important in the current con-

text. First, the cells lining the subventricular zone include stem cells that remain ac-

tive throughout life. These stem cells can produce neural or glial progenitor cells that

are able to migrate into the cerebral white or gray matter in adulthood. The role of

these cells is poorly understood as they appear to remain quiescent for extended pe-

riods but can be activated to produce neurons or glia, especially after injury

(e.g., Kolb et al., 2007). Second, cells in the dentate gyrus of the hippocampus

are generated there throughout life, although this production declines with aging.

These cells appear to play a role in functions such as memory (e.g., Spanswick

and Sutherland, 2010). Third, dendrites and spines show remarkable plasticity in re-

sponse to experience and can form synapses within hours and possibly even minutes

after some experiences (e.g., Greenough and Chang, 1989). We discuss this in the

following section.

3 GENERAL TYPES OF BRAIN PLASTICITYChanges in the brain can be shown at many levels of analysis (see Table 2) ranging

from behavior to molecules. There is no correct level of analysis, but rather the mea-

sure of plasticity must be suited to the research question being asked. Noninvasive

Table 2 Levels of analysis of plasticity

BehaviorFunctional organization (e.g., maps)Cell structure (e.g., dendritic organization)Synaptic structureMitotic activity (e.g., neurogenesis)Molecular structure (e.g., proteins)Gene expression

393 General Types of Brain Plasticity

imaging is appropriate to study experience-dependent changes in humans but is far

more difficult to use in laboratory animals. An advantage of using laboratory ani-

mals, however, is that it is possible to measure anatomical and molecular changes

in postmortem tissue of animals with different experiences. Our bias in the current

review is to emphasize the correlation between synaptic change, using Golgi-type

stains, and epigenetic analyses, looking for changes in gene methylation and/or gene

expression.

Three types of plasticity can be distinguished in the normal brain: experience-

independent, experience-expectant, and experience-dependent (Greenough et al.,

1987; Shatz, 1992). Experience-independent plasticity is largely a prenatal develop-mental process. It is impractical for the genome to specify the connectivity of every

connection in neuron development. Instead, the brain produces a rough structure in

which there is an overproduction of neurons, and later, connections, that are sculpted

in response to internal and external events. A good example of experience-

independent plasticity is the development of the eye-specific layers of the lateral ge-

niculate nucleus (LGN) of the cat (Campbell and Shatz, 1992). Axons arriving from

the retina eventually terminate in separate layers in the LGN, but retinal cells initially

also send axonal branches to the layer for the other eye. In order to segregate the

layers correctly, the retinal ganglion cells spontaneously fire so as to correlate their

firing with nearby cells but independent of those in the other eye. Cells that fire to-

gether increase their connections, whereas those out of synch weaken their connec-

tions and eventually die out. This type of plasticity, which is independent of external

sensory input, allows the nervous system more precise in connectivity without re-

quiring overwhelmingly complex genetic instructions.

Experience-expectant plasticity largely occurs during development. A good ex-

ample is the development of ocular dominance columns found in the primary visual

cortex. These alternating columns provide a mechanism for the inputs from the right

and left eyes to be combined to produce binocular vision. Wiesel and Hubel (1963)

showed in kittens that if one eye is kept closed after birth, the open eye expands its

territory, leading to shrinkage of the column related to the closed eye. When the

closed eye is eventually opened, its vision is compromised.

Finally, experience-dependent plasticity refers to a process of changing neuro-

nal ensembles that are already present. This can be seen in situations such as when

animals learn problems (e.g., Greenough and Chang, 1989), when topographic

maps expand or shrink in response to experience (e.g., Blake et al., 2002), when

animals receive intense environmental manipulations (e.g., Greenough and

Chang, 1989), injury (e.g., Kolb, 1995), or in response to abnormal experiences

such as psychoactive drugs (e.g., Robinson and Kolb, 2004). These types of expe-

riences both increase and decrease synapse numbers, often in the same animals, but

in different brain regions (see below). The key point is that the synaptic changes

reflect modifications of a basic phenotype formed in development. It is important

to note that although it is often assumed that experience-dependent plasticity

largely reflects the addition of synapses, it may be seen both in the addition

and/or pruning of synapses.

Table 3 Summary of the effects of frontal cortical injury at different ages

Age atinjury Result Basic reference

E18 Cortex develops with odd structure Kolb, Cioe, and Muirhead (1998)

Functional recovery

P1–6 Small brain, dendritic atrophy Kolb and Gibb (1993)

Poor functional outcome

P7–12 Dendrite and spine hypertrophy Kolb and Gibb (1993)

Cortical regrowth Kolb et al. (1998a,b)

Functional recovery

P25–35 Small brain Kolb and Whishaw (1981)

Partial recovery Nemati and Kolb (2012)

Dendritic hypertrophy

P55 No recovery Nemati and Kolb (2012)


4 FACTORS INFLUENCING BRAIN DEVELOPMENT IN THENORMAL BRAIN

When researchers began to study experience-dependent changes in the brain, there

was a belief that changes would be most dramatic in severely impoverished condi-

tions, such as being raised in the dark (e.g., Reisen, 1961). Such extreme experiences

did profoundly alter brain development, but it soon became clear that a wide range of

experiences, and even fairly innocuous-looking experiences, could also produce

large changes in the brain (see Table 3).

4.1 Complex housingThe simplest and most dramatic way to manipulate experience is to compare the

brain structure in animals placed in complex environments (sometimes called

enriched environments) versus that of animals housed in standard laboratory caging.

The original studies by the group at Berkley (e.g., Rozenweig et al., 1967) found

changes in cortical thickness and neurochemistry; however, it is now known that

there are changes in brain size, cortical thickness, neuron size, dendritic branching,

spine density, synapses per neuron, glial numbers and complexity, expression of neu-

rotransmitters and growth factors, and vascular arborization (e.g., Greenough and

Chang, 1989; Sirevaag and Greenough, 1988). Such changes are correlated with a

wide range of enhanced cognitive and motor abilities.

It has only been more recently that the effect of complex housing on brain devel-

opment has been investigated, especially examining the effects on the visual system

(see review by Baroncelli et al., 2010). Complex housing from birth accelerates the

maturation of visual acuity, which is associated with electrophysiological changes.

414 Factors Influencing Brain Development in the Normal Brain

Interestingly, complex housing can promote the development of the visual system

even in the absence of visual stimulation in animals housed in the dark (Bartoletti

et al., 2004). In fact, the latter study showed that the nonvisual effects of complex

housing could reverse the effects of raising animals in the dark. Although the mech-

anism of this effect is not known, one possibility is that pups raised in complex en-

vironments receive more maternal care (Sale et al., 2004), which is known to be a

strong factor in changing brain development (see below).

There are few studies of other cortical regions but one particular study showed

enhanced auditory functioning in rats raised in complex environments (Cai et al.,

2009). Early complex housing also alters the development of the parietal cortex.

Kolb et al. (2003a) placed weanling rats in complex environments and compared

the cortical changes to animals placed in the same environments as adults. Whereas

adult rats showed increased dendritic length and spine density after 90 days, juvenile

rats showed a similar increase in dendritic length but a decrease in spine density.

That is, the young animals showed a qualitatively different change in the distribution

of synapses on pyramidal neurons compared to the older animals. This result was

surprising, so the researchers wondered what earlier experience might do. In a

follow-up experiment, pregnant dams were placed in complex environments for

8 h a day beginning a week prior to their pregnancy and then throughout the 3-week

gestation. The brains of their offspring were examined in adulthood and showed a

decrease in dendritic length and an increase in spine density in parietal cortex

76

74

72

70

68

Hippocampus Frontal cortex

Control

****

Paternal enrichment

Maternal enrichment

66

Per

cent

glo

bal m

ethy

latio

n

FIGURE 2

Average global DNA methylation levels in the hippocampus and frontal cortex of offspring

of males who were housed in complex environments for 28 days prior to mating with a

control female and females who were housed in complex environments for 7 days prior to

conception and for the duration of the pregnancy.

After Mychasiuk et al. (2012).


(Gibb, 2004). Thus, complex housing has qualitatively different effects at different

developmental ages. In a parallel study, Pena et al. (2009) found enduring effects of

complex housing from weaning until adulthood on pituitary–adrenal function, social

behavior, and cognitive behavior in adulthood.

Early complex housing has also been shown to attenuate the effects of exposure to

both methylphenidate and amphetamine later in life. Alvers et al. (2012) found a re-

duction in the self-administration of low, but not high, doses of methylphenidate,

whereas Li, Robinson, and Kolb (unpublished observations) found that lifetime com-

plex housing reduced amphetamine-induced behavioral sensitization as well as the

dendritic changes in mPFC and nucleus accumbens.

Finally, Mychasiuk et al. (2012b) placed male rats in complex environments for

28 days before mating the males with control females and compared the epigenetic

effects to maternal housing as in the earlier Gibb (2004) study (Fig. 2). The offspring

of the complex-environment housed males showed a significant decrease in gene

methylation, reflecting the increased expression of about 1000 genes. More surpris-

ing, however, was that the levels of gene expression changes were remarkably sim-

ilar to those observed in the offspring of females who were housed in similar

complex environments while pregnant.

In sum, complex housing during development has profound and enduring effects

on brain development and function. A key question relates to exactly what it is about

the complex housing experience that is altering brain development.

10

9

8

7

Spi

nes

/ 10mm

6

5

AID Amygdala Cg3-basilar Cg3-apical

Tactilestimulation

Control

****

FIGURE 3

The effects of neonatal tactile stimulation on spine density in mPFC (Cg3), OFC (AID), and

amygdala. Similar results were shown for dendritic length and branching.

After Richards et al. (2012).


4.2 Sensory and motor experienceAs noted earlier, one explanation for the complex rearing effects is that there was an

increase in maternal behavior, including licking and grooming of the infants.

Schanberg and Field (1987) showed that tactile stimulation of preterm infants accel-

erated growth and led to earlier release from hospital. More recently, it has been

shown that tactile stimulation in preterm infants accelerates EEG maturation and

visual functions, as well as increasing serum levels of insulin growth factor I

(IGF-I) and growth hormone paralleling results found in rats (Field et al., 2008;

Guzzetta et al., 2009). Further studies in rats have also shown that early tactile stim-

ulation improves motor and cognitive functions in adulthood as well as increasing

dendritic length and spine density in mPFC (Fig. 3) (Richards et al., 2012) and

the expression of fibroblast growth factor-2 (FGF-2) in skin and brain (Gibb,

2004). Early tactile stimulation (either stimulation of the pregnant dam or postnatal

stimulation of the pups) attenuates the behavioral and anatomical effects of amphet-

amine in adulthood (Muhammad and Kolb, 2011a,b; Muhammad et al., 2011). And,

as discussed below, tactile stimulation dramatically improves recovery from early

cortical injury (Kolb and Gibb, 2010). There is little doubt that tactile stimulation

has an effect on cortical development that is nearly as large, although somewhat

different from, complex housing.

4.3 Psychoactive drugsAlcohol has long been associated with compromised brain development, but

only recently it has been shown that many other psychoactive drugs, including pre-

scription drugs, alter brain development. Exposure to psychoactive drugs in adult-

hood produces persistent structural changes to cells in both mPFC and orbital

prefrontal cortex (OFC) and nucleus accumbens (Robinson and Kolb, 2004). There

is now growing evidence that the prenatal administration of a wide range of psy-

choactive drugs including nicotine, diazepam, and fluoxetine chronically alters both

neuronal structure and cognitive and motor behaviors (e.g., Kolb et al., 2008;

Muhammad et al., 2013; Mychasiuk et al., 2013a,b). Similarly, administration

of amphetamine, methylphenidate, haloperidol, and olanzapine in the juvenile pe-

riod also leads to impaired behavior and dendritic aberrations in rats examined in

adulthood (Diaz Heijtz et al., 2003; Frost et al., 2010; Milstein et al., 2013; Vinish

et al., 2013).

One key question is whether early exposure to psychoactive drugs alters brain

plasticity later in life. If adult rats are given nicotine, cocaine, or amphetamine

and later placed in complex environments, neuronal plasticity is blocked

(Hamilton and Kolb, 2005; Kolb et al., 2003b). If rats are given nicotine

prenatally and placed in complex environments in adolescence, there is a complex

array of dendritic/spine changes including a partial reversal of the effects of

nicotine as well as a blockade of the effects of the complex housing

(Muhammad et al., 2013).


4.4 Parent–child relationshipsDeveloping mammals are dependent upon their parents and parent–child relation-

ships are critical for brain development. Variations in the pattern of early parent–

infant interactions can initiate long-term developmental effects that persist into

adulthood (Myers et al., 1989). This has been most extensively studied in

mother–infant interactions in rodents where the time spent in contact and the amount

of maternal licking and grooming of the infants correlate with a variety of somatic

and behavioral outcomes. For example, Meaney and his colleagues have shown that

maternal–infant interactions modulate a variety of emotional and cognitive behav-

iors in adulthood, in part through modifications of the hypothalamic–adrenal stress

response (e.g., Cameron et al., 2005) as well as changes in gene expression in

hippocampus (Weaver et al., 2005). Other studies have shown changes related to

maternal–infant interactions in the hypothalamus and amygdala (Fenoglio et al.,

2006; Moriyama et al., 2013), as well as mPFC and OFC (Muhammad and Kolb,

2011a,b).

4.5 Peer relationshipsPeer relationships, and especially play, have been known to influence the develop-

ment since the studies of Harlow (e.g., Harlow and Harlow, 1965). The prefrontal

cortex plays a central role in play behavior and, in turn, its development is strongly

influenced by play. Perinatal injury to the mPFC or OFC regions compromises play

behavior, although in different ways (e.g., Pellis et al., 2006). Similarly, the amount

of play that young rats are allowed to engage in alters the development of prefrontal

cortex. Neurons of the mPFC region respond to the amount of play but not the num-

ber of playmates, whereas the OFC responds to the number of playmates and not the

amount of play (Bell et al., 2010). Furthermore, early experiences including prenatal

stress and tactile stimulation alter play behavior and prefrontal cortex (e.g.,

Muhammad et al., 2011). Indeed, it seems likely that any treatment that alters play

behavior will alter prefrontal development and function. For example, the manipu-

lation of juvenile play behavior also changes the brain’s response to psychomotor

stimulants (Himmler et al., 2013a,b).

4.6 StressAlthough it has long been known that stress alters the brain and behavior of adults, it

is only recently that the role of perinatal stress has been appreciated. For example,

prenatal stress is now known to be a risk factor in the development of schizophrenia

attention-deficit hyperactivity disorder (ADHD), depression, and drug addiction

(Anda et al., 2006; van den Bergh and Marcoen, 2004). Studies with laboratory an-

imals have also shown that perinatal stress produces a wide range of behavioral ab-

normalities, including an elevated and prolonged stress response, impaired learning

NAc

a

b,c

a,c

a,c

a,c

a,c

control

PS

MS

a

ac a

b

a,c

a,c

b,c

a

b

8

9

10

# of

spi

nes

per

10µm

# of

syn

apse

s (x

000)

# of

syn

apse

s (x

000)

Bra

nch

orde

r

11

12

13

1.7

2.0

2.3

2.6 1.6

18

19

20

21

1.5

1.4

2. Excitatory synapses

3. Spine density

1. Dendritic branching

29

32

35

Bra

nch

orde

r38

41

44

AID Cg3B Cg3A

FIGURE 4

Mean (� SEM) total number of branch bifurcations (dendritic branching), number of

excitatory synapses, and spine density in Nucleus accumbens (NAc), OFC (AID), and mPFC

(Cg3Basilar field; Cg3Apical field). Themean branch order and number of synapses are in the

same scale shown on the right vertical axis for NAc, AID, and Cg3B but are in a different scale

for the Cg3A, which is on the left vertical axis. The letters “a” and “b” represent the

comparisons of the effects prenatal stress (PS) and maternal separation (MS), respectively,

compared to controls. The letter “c” represents comparisons between PS and MS

(ps <0.05 or better).

After Muhammad et al. (2012).



and memory, altered social and play behavior, increased anxiety, deficits in atten-

tion, and increased preference for alcohol (Weinstock, 2008).

Stress has long been known to alter the prefrontal cortex of adults (e.g., Liston

et al., 2006), but it has become apparent that the changes in the developing prefrontal

cortex are very different. For example, adult stress leads to a decrease in spine den-

sity in mPFC, but an increase in orbital cortex (Liston et al., 2006). In contrast,

Murmu et al. (2006) found that prenatal stress in degus from E16 to E21 produced

a decrease in both spine density and dendritic length in both mPFC and OFC in adult-

hood. Using a somewhat different paradigm, our laboratory exposed rats to gesta-

tional stress at E12–16 and found an increase in spine density in both mPFC and

OFC when the brains were examined at weaning or in adulthood (Muhammad

et al., 2012; Mychasiuk et al., 2012). We also compared the effects of prenatal stress

and postnatal maternal separation and found very different effects of the two

stressors (see Fig. 4). Thus, the effects of perinatal stress vary with the nature of

the stress, the precise embryonic age of the stress, and the age at which the brain

is examined.

One explanation for the difference between the Murmu results and our results

may be related to differences in epigenetic changes related to intensity of the stress.

Mychasiuk et al. (2012) found that mild gestational stress increased global methyl-

ation in prefrontal cortex (using a combined sample of mPFC and OFC), whereas

greater stress had the opposite effect. A whole-genome microarray showed that over

700 genes in the prefrontal cortex and hippocampus were differentially expressed

following prenatal stress, with most genes being downregulated.

The effects of gestational stress can be surprisingly subtle. Mychasiuk et al.

(2011a,b,c,d) housed pregnant females together for the duration of their pregnancies.

One rat received stress at E12–16 while the other (the bystander) did not. The off-

spring of both dams showed significant changes in methylation, gene expression, and

dendritic organization but the patterns of gene expression and dendritic changes were

qualitatively different (Mychasiuk et al., 2011a,b,c,d). It appears that both dams were

stressed but in different ways, which led to differential effects on the offspring brains.

One obvious question is to ask how prenatal stress affects the brain response to other

postnatal developmental experiences such as complex housing, tactile stimulation,

play, and so on.

4.7 Gonadal hormonesDuring development the most obvious effect of exposure to gonadal hormones is the

prenatal differentiation of the genitals. But the same gonadal hormone receptors are

found in the brain, so it would be surprising if there were not sex differences there

too. There are clear differences in the adult human brain (e.g., Goldstein et al., 2001)

and MRI studies of human children have shown large differences in the rate of brain

development in the two sexes (O’Hare and Sowell, 2008), with the female brain

reaching its adult volume 2–4 years earlier than the male brain. Studies in rats have

shown that neurons in the mPFC have larger dendritic fields and higher spine density


in males than females, whereas the opposite is found in OFC (e.g., Kolb and Stewart,

1991). Furthermore, there are sex differences in the effects of many perinatal expe-

riences including gestational stress, complex housing, and injury (e.g., Kolb and

Stewart, 1995; Mychasiuk et al., 2011a,b,c,d).

4.8 Intestinal floraGut microbiota have adapted to a symbiotic relationship with many animals. Soon

after birth, the gut of mammals is populated by a variety of indigenous microbes that

influence both gut and liver functions (e.g., Bjorkholm et al., 2009; Hooper and

Gordon, 2001). There are many similarities in the neurochemical organization of

the enteric and central nervous systems, so it is reasonable to speculate that gut

microbiota might influence brain function. Indeed, epidemiological studies have

shown an association between neurodevelopmental disorders including autism and

schizophrenia and microbial infections early in life (e.g., Finegold et al., 2002;

Mittal et al., 2008). Diaz Heijtz et al. (2011) manipulated gut bacteria in newborn

mice and found that gut bacteria influence motor and anxiety-like behaviors, which

were associated with changes in the production of synaptic-related proteins in cortex

and striatum. This finding is important because it provides a mechanism whereby

infections during development could influence brain development as well as a reason

why results in different laboratories could be different depending upon dietary selec-

tion and which gut microbiota are present in the respective colonies.

4.9 DietThere is an extensive literature on the effects of caloric- and/or protein-restricted

diets on brain and behavioral development (e.g., Lewis, 1990) but little research

on brain plasticity and restricted diets per se. Similarly, little is known about the

effects of enhanced diets on brain development. It is reasonable to predict that

brain development might be facilitated by vitamin and/or mineral supplements.

Dietary choline supplementation during the perinatal period leads to enhanced

spatial memory in various spatial navigation tasks (e.g., Meck and Williams,

2003; Tees and Mohammadi, 1999) and increases the levels of nerve growth fac-

tor in hippocampus and neocortex (e.g., Sandstrom et al., 2002). Halliwell and

Kolb (2003) did similar studies and found increased dendritic length in pyramidal

cells across the cerebral cortex and CA1 of the hippocampus with choline

supplementation.

Halliwell (2011) also studied the effects of a vitamin/mineral supplement to the

food of lactating rats. The same dietary supplement was reported to improve mood

and aggression in adults and adolescents with various disorders (Leung et al., 2011)

and reduced social withdrawal and anger in children with autism (Mehl-Madrona

et al., 2010). Analysis of the adult offspring of lactating rats fed the same supplement

found an increase in dendritic length in pyramidal neurons in mPFC and parietal


cortex but not in OFC. Furthermore, the same diet facilitated recovery from perinatal

mPFC lesions in rats.

5 BRAIN DEVELOPMENT AFTER EARLY BRAIN INJURYThe first systematic studies on the effect of brain injury in development were

done by Margaret Kennard, beginning in the 1930s (e.g., Kennard, 1942). She

made unilateral motor cortex lesions in infant and adult monkeys and found

milder impairments in her young animals. This led her to suggest that there

was some change in the cortical organization of the infants that supported more

normal behavior (Kennard, 1942). Although Kennard was aware that her monkeys

still had deficits, she is credited with the general idea that “earlier is better,” a

conclusion that Teuber (1975) referred to as the Kennard Principle. Hebb

(1945, 1949) reached a different conclusion, however. He was studying the

effects of early frontal lobe injury in children and concluded that these children

had worse outcomes than adults with similar injuries. He suggested that the early

frontal injury was interfering with the normal development of neural networks

needed to support many adult behaviors (see also Stiles, 2012). The conclusions

of Kennard and Hebb would appear to be at odds, but over the past 30 years’ ex-

tensive studies of monkeys, cats, and rats with cortical injuries have shown that

both views are partially correct. The outcomes depend upon the precise age at

injury, the behavioral measurements used, the age at assessment, and whether

the injury is unilateral or bilateral.

5.1 Age at injuryAge at injury refers not to the actual postnatal age of animals but to their develop-

mental age. Rodents and carnivores are born less mature than primates, so birth date

is not helpful in comparing across species. We will consider the effects of cortical

lesions in rats first, with an emphasis on frontal lesions because as in monkeys

and cats, this is where most of the studies are focused. Although it is common in

the perinatal ischemia literature to make lesions on postnatal day 7 (P7) with rats

to mimic birth asphyxia in humans, this age misses much of the story.

It has become clear that in rats and mice, damage on days 1–5 has devastating

consequences on behavior, with the effect generally being worse the earlier the post-

natal injury, regardless of which cortical region is damaged. In contrast, similar dam-

age on days 7–12 permits much better functional outcome, and depending upon the

behavioral measure, there can be surprisingly normal behavior, despite the fact that

the brain is significantly smaller than normal (see Table 2). There is still a better out-

come than observed in adults when mPFC lesions are incurred in early adolescence.

We are aware of only one study of prenatal cortical lesions in rats and there was re-

markably normal behavior, in spite of a highly abnormal brain (Kolb et al., 1994a,b).

495 Brain Development After Early Brain Injury

There were, however, a series of studies by SamHicks in the 1950s in which ionizing

radiation was used to alter brain development, which in some cases led to surpris-

ingly good outcomes in spite of abnormal brains, provided there was no hydroceph-

alus (e.g., Hicks and D’Amato, 1961).

In sum, functional outcome is good if injury is during the latter part of neurogen-

esis (E18) but poor if it is during migration and the beginning of synaptogenesis. It is

better again after migration is done and synaptogenesis is burgeoning. We must note

that although we have focused on mPFC lesions, a similar pattern is seen after OFC,

motor cortex, posterior cingulate cortex, posterior parietal cortex, visual cortex, and

auditory cortex lesions (see review by Kolb et al., 2010). As might be expected, how-

ever, recovery is not equivalent across all regions, with posterior injury allowing less

recovery than anterior lesions.

Results from studies of cats and monkeys present a similar pattern, although the

dates vary because of differences in gestational rate. Villablanca and his colleagues

conducted an extensive series of studies on the behavior of cats with frontal or pre-

frontal injuries (e.g., Villablanca et al., 1993). Cats are an interesting comparison to

the rat and monkey because they are embryologically older than rats at birth with a

gestation period of about 65 days, but they are much younger at birth than monkeys.

Overall, Villablanca has found that although cats with prefrontal lesions shortly after

FIGURE 5

Photographs of brains of animals given midline frontal cortrex lersions on postnatal day 10

and then sacrificed on postoperative days 1, 3, 8, or 23. The lesion cavity is evident at day 1 but

by day 23 is only visible as a scar. By day 90 (not shown) the scar is no longer visible.

After Kolb et al. (1998a,b).


birth show good recovery relative to animals with lesions later in life, cats with pre-

natal lesions have severe behavioral impairments. Thus, the newborn cats appear

similar to P10 rats, whereas the prenatal cats are similar to P1–6 rats.

Monkeys are different again. They are born much older than rats, cats, or even

humans. Although Kennard reported better outcomes with infant lesions, as did

Harlow et al. (1964), the bulk of the later evidence largely by Goldman and col-

leagues did not report this (see reviews by Goldman, 1974; Goldman et al.,

1983). In contrast, however, prenatal lesions in monkeys allow substantial recovery

(Goldman and Galkin, 1978). The prenatal lesions are more similar in embryological

time to newborn cats and P10 rats. We can predict that if Goldman and Galkin had

made their prenatal lesions even earlier, the outcome would be similar to the prenatal

lesions in cats and lesions in newborn rats.

But what are the anatomical correlates of this recovery? Studies of unilateral mo-

tor cortex lesions (e.g., Hicks and D’Amato, 1975) found anomalous projections

from the intact hemisphere to the spinal cord, leading to the presumption that these

projections supported the functional recovery. They likely did. Similarly, there are

anomalous projections in the cat visual system that are associated with functional

recovery (Payne and Lomber, 2001) as well as extensive anomalous connections af-

ter neonatal hemidecortication in both rats and cats that are correlated with recovery.

But anomalous projections are also associated with poor outcomes. For example,

whereas rats with P1 mPFC lesions have significant abnormal connections, P10 an-

imals do not (Kolb et al., 1994a) but it is the P10 animals that show recovery, not the

rats with the rewired brain. There are several other types of anatomical changes that

support recovery in P10 rats. For example, there is widespread dendritic hypertrophy

of cortical pyramidal neurons as well as increased spine density. Furthermore,

there is evidence that for at least some types of P10 lesions, namely mPFC and pos-

terior cingulate, there is spontaneous neurogenesis that fills the lesion cavity (Fig. 5)

(Kolb et al., 1998a,b). The neurons that reform the frontal region establish connec-

tions with subcortical regions such as the striatum and have electrical activity that is

nearly normal (Driscoll et al., 2007). In the process of studying the apparent regen-

eration of the lost cortex, we discovered serendipitously that injections of the mitotic

marker, bromodeoxyuridine (BrdU), on E12–14 disrupt the postnatal activity of stem

cells (Kolb et al., 1999) and completely block the postinjury neurogenesis (Kolb

et al., 1998a,b, 2012). Not surprisingly there is no functional recovery if there is

no neurogenesis.

Finally, one other mechanism appears to be the survival of neurons in the thal-

amus that should have degenerated after the injuries. Normally, if cortical regions are

damaged, the thalamocortical projection cells die. This is true after neonatal visual

cortex lesions but not after prefrontal lesions. Cells in the dorsal medial thalamus,

which projects to prefrontal cortex, survive and form connections with remaining

frontal regions in both monkeys and rats (Goldman and Galkin, 1978) and rats

(Kolb and Nonneman, 1978), although this likely depends on the age at injury.

Van Eden et al. (1998) used unbiased stereology to count neurons after P6 mPFC

515 Brain Development After Early Brain Injury

lesions and found no difference from adults with similar lesions. This study should be

repeated with P10 lesions.

5.2 Behavior specificityAs a rule of thumb, cognitive functions show better functional recovery than motor

functions, which in turn show better recovery than species-typical behaviors, which

show virtually no recovery regardless of the age at injury (e.g., Kolb and Whishaw,

1981). It appears that it is easier for the brain to form new neuronal ensembles to

solve cognitive tasks than motor tasks and the neural circuits underlying species-

typical behaviors are relatively hard-wired and not easily replaced.

One surprising effect of early lesions is seen in spatial behaviors. Rats with P1–5

show poor recovery, which is not surprising given that adult rats with similar lesions

are also impaired. What is unexpected, however, is that lesions elsewhere in the ce-

rebral cortex at P1–5 also produce deficits in spatial behaviors even though similar

adult lesions do not. This effect is not unique to rats, however, as children with early

cortical lesions in either hemisphere show the same result (e.g., Akshoomoff et al.,

2002). This is in marked contrast to the recovery of language in children with peri-

natal injuries to the speech areas, although the recovery of language is less complete

than was originally believed (Thai et al., 1991).

5.3 Age at assessmentOne of challenges in assessing the effects of early brain injury is the problem of

knowing when to investigate the behavior. This is nicely illustrated by the early stud-

ies of Goldman (e.g., Goldman, 1974). She was initially impressed with apparent re-

covery of functions after frontal lobe injuries in infant monkeys but as she continued

her studies it became clear that she, and others before her, had overestimated the ex-

tent of recovery because the animals were tested when they were still young. Thus,

she found that animals with dorsolateral prefrontal lesions became progressively

more impaired at cognitive tasks such as delayed alternation as the brain developed

(Goldman et al., 1983).

She tested the idea that age was important directly by studying the behavioral

effect of reversibly cooling the otherwise normal prefrontal cortex of monkeys at

different ages. On a task that monkeys with adult lesions are impaired at (delayed

response), she found that when she cooled the cortex at 9–16 months of age the an-

imals performed as well as they did in the uncooled state. However, when tested at

19–31 months the animals were impaired, and this impairment grew progressively

larger as they grew older. Thus, she was able to show that animals with early cortical

lesions “grow into their deficits,” an observation also made in children with congen-

ital brain injuries (Banich et al., 1990) and hamsters with mPFC lesions on P2 (Kolb

and Whishaw, 1985).


But age at assessment can work in reverse as well. When rats were given mPFC

lesions on P1 or P10 and then behaviorally tested at P22–25, both groups were

severely impaired relative to controls (Kolb and Gibb, 1993). However, when the

rats were tested at P52–55, the P10 rats were no longer impaired whereas the P1 rats

were. The recovery of the P10 rats was correlated with hypertrophy of cortical

pyramidal neurons that was not present in the brains of P25 animals. Thus, not only

can animals grow into deficits but out of them too.

Ipsilateral forelimb

Contralateral forelimb

Neonate80

70

60

50

40

30

20

10

0

Hit

perc

ent

80

70

60

50

40

30

20

Control Small Med Large Hemi

10

0

Hit

perc

ent

Adult

*

*

**

FIGURE 6

Performance on a skilled reaching task by rats with adult or P5 unilateral lesions of

varying sizes (small, medium, and large) of the motor cortex or the entire neocortex

(hemidecorticate). Reaching was affected bilaterally, although more severely in the

contralateral forepaw and increased with lesion size. Rats with neonatal lesions showed

significantly better reaching with the contralateral paw than the adults.

After Whishaw and Kolb (1988).

536 Unilateral Versus Bilateral Injury

6 UNILATERAL VERSUS BILATERAL INJURYAn obvious difference between the unilateral and bilateral injuries is that in the for-

mer case there is an intact region homologous to the injured region, whereas in the

bilateral case there is not. Two predictions from this difference are that we would

expect better recovery from unilateral injury and the postinjury sequelae of brain

changes are likely different. Both predictions are borne out.

Hicks and D’Amato (1975) were the first to show that when infant rats sustained

unilateral lesions of the corticospinal projection neurons, they were subsequently

found to have an anomalous ipsilateral pathway from the intact hemisphere to the

spinal cord. They presumed that this pathway was responsible for the improved mo-

tor outcomes of the infants relative to adults with similar injuries. One prediction

from their study is that rats with bilateral lesions in infancy (P1) should not show

recovery because they would not have a normal hemisphere to project to the spinal

cord. This is the case (Kolb et al., 2000a,b). Furthermore, in contrast to unilateral

operates, the bilateral operates are impaired at tests of spatial navigation, in contrast

to rats with adult lesions. This spatial deficit may be related to anomalous connec-

tions from the posterior cortical regions to the spinal cord, connections that likely

were present at birth and failed to die after the early motor cortex lesions (e.g.,

O’Leary, 1989).

Although unilateral focal lesions provide an advantage in recovery, this advan-

tage is reduced as the size of the lesion increases (Whishaw and Kolb, 1988). Fur-

thermore, the larger the lesion, the greater is the impairment not only of the

contralateral limb but also of the ipsilateral limb (Fig. 6).

Table 4 Summary of the effects treatments on recovery from early brain injury

Treatment Outcome Basic reference

Behavioral therapy

Complex housing Improved behavior Kolb and Elliott (1987)

Tactile stimulation Improved behavior Kolb and Gibb (2010)

Chemical therapy

FGF-2 (P3 mPFC) Improved behavior Comeau et al. (2007a,b)

FGF-2 (P10 Motor) Nearly normal behavior Monfils et al. (2006)

Manipulation of gonadalhormones

Impaired recovery Kolb and Stewart (1995)

Prenatal experiences

FGF-2 Improved behavior Comeau et al. (2007a,b)

Tactile stimulation Improved behavior Gibb (2004)

Diazepam Improved behavior Kolb et al. (2008)

Fluoxetine Blocked recovery kolb et al. (2008)

Excessive exercise Reduced recovery Gibb (2004)

Gestational stress Blocked recovery Halliwell (2011)


The extreme form of a unilateral lesion is hemidecortication or hemispherec-

tomy. As shown in Fig. 3, hemidecorticates are severely impaired with both limbs,

but the neonatal (P2) hemidecorticates are significantly better with their contralateral

limb than the adult decorticates. This is correlated both with considerable rewiring of

the normal hemisphere and also with hypertrophy of pyramidal neurons throughout

the intact hemisphere (Kolb et al., 1992). Curiously, whereas rats with bilateral focal

lesions on P10 are always functionally advantaged relative to those with lesions at

P1–6, this is not true with hemidecortication (Kolb and Tomie, 1988). In contrast, the

early operates fare better and have more extensive anatomical remodeling. The dif-

ference between age-related differences between focal lesions and hemidecortication

begs for more study.

7 FACTORS INFLUENCING BRAIN DEVELOPMENT IN THEINJURED BRAIN

The obvious place to look for beneficial modulating effects on the early-injured brain

is at the animals with the earliest focal lesions. After all, these are the animals with

the worst functional outcomes in the absence of treatment. Because most of the stud-

ies on modulating factors have been using rats with medial frontal lesions, our dis-

cussion will focus on this preparation, with reference to other lesions where

appropriate. We have grouped the factors into (1) behavioral therapy, (2) pharmaco-

logical therapy, and (3) prenatal therapy (see Table 4). We discuss each in turn.

7.1 Behavioral therapyAlthough behavioral therapy would seem to be the most obvious type of treatment to

study, there are surprisingly few studies in either laboratory animals or human chil-

dren and virtually no evidence regarding when the optimal time might be or how

intense it ought to be. We began our studies by looking at complex housing. Placing

animals with bilateral P1–7 mPFC lesions in complex housing for 90 days beginning

at weaning stimulates significant functional improvement on tests of both cognitive

and motor behaviors and this is correlated with increased cortical thickness, brain

weight, and dendritic length (Kolb and Elliott, 1987). In contrast, placing the animals

in the complex environments as adults was ineffective (Comeau et al., 2008), unless

the lesions are unilateral (Williams et al., 2006).

Tactile stimulation is also an effective treatment. Rats were given mPFC on P3

and then beginning on P4 they received two weeks of tactile stimulation for 15 min

3� per day (Kolb and Gibb, 2010). The improvement on both spatial learning and

skilled motor function was remarkable (Fig. 4) and was correlated with increased

spine density in the tactile-stimulated mPFC rats. One possible mechanism for the

effect of tactile stimulation is that the tactile stimulation increases the expression

of FGF-2 in both skin and brain providing a possible mechanism for the therapeutic

FIGURE 7

Sagittal brain sections illustrating normal motor cortex (A), a P10 motor cortex lesion

(B), and a P10 motor cortex lesion and FGF-2 treatment (C). Compared to control cortex,

the FGF-2 stimulated regrowth does not illustrate a laminar distribution. Scale bars in

(A), (B), and (C) are 550 mm. Scale bars in (D) and (E) are 250 mm.

After Monfils et al. (2008).

557 Factors Influencing Brain Development in the Injured Brain

abilities of tactile stimulation (Gibb, 2004). We note parenthetically that complex

housing also increases FGF-2 expression in cortex (Kolb et al., 1998).

7.2 Chemical therapyIn view of the apparent role of FGF-2 in recovery, we subcutaneously administered

FGF-2 directly as a therapy after P4 mPFC lesions and found significant functional

improvement (Comeau et al., 2007a,b, 2008). In parallel studies, we administered

FGF-2 to rats with P3 or P10 motor cortex lesions. The FGF-2 essentially reversed

all of the motor deficits in the P10, but not the P3 lesion animals, but more impor-

tantly, the lost motor cortex tissue regenerated and formed corticospinal connections

(Monfils et al., 2006, 2008) (Fig. 7). Pretreating the rats with BrdU on E12 blocked

the FGF-2-mediated regeneration and prevented functional recovery, just as it did

after the spontaneous regeneration after P10 mPFC lesions (see above).

Not all chemical treatments are beneficial, however. Perinatal depletion of nor-

adrenaline on P1–3, administration of testosterone to female rats on P1, or blockade

of gonadal hormones by gonadectomy on P1 both block recovery and the associated

dendritic changes following P7 mPFC lesions (Kolb and Stewart, 1995; Kolb and

Sutherland, 1992). Furthermore, even FGF-2 can be detrimental. In one study


performed in our laboratory, we gave FGF-2 and placed animals in complex housing

at weaning (Hastings, 2003). This combination made the animals worse, possibly

because the combined treatments raised FGF-2 to a toxic level.

7.3 Prenatal therapyGiven that prenatal events such as gestational stress alter brain development, we

wondered if prenatal events might influence recovery from perinatal injury. They

do. Prenatal tactile stimulation (i.e., of the pregnant mom), prenatal diazepam,

and prenatal FGF-2 all enhance recovery from P3 mPFC lesions (Comeau et al.,

2008; Gibb, 2004; Kolb et al., 2008). In contrast, prenatal administration of fluox-

etine, prenatal stress, or excessive maternal exercise block recovery of rats with

P7 mPFC lesions (Day et al., 2003; Gibb, 2004; Halliwell, 2011). The powerful ef-

fects of prenatal events, both positive and negative, demand further study as they

likely can account for some of the variance in outcomes observed in children with

perinatal perturbations such as ischemia.

8 SUMMARYWe have shown that the developing normal and injured brain shows a remarkable ca-

pacity for plastic change, both for better and worse. A key remaining question is how

this happens. Althoughwe have not discussed it here one consistent observation in both

the normal and injured brain is a sex difference in experience-dependent plasticity. It is

not simply that one sex is more plastic but rather that there is a sexual dimorphism in

both the functional and anatomical effects of experiences. One clear example is the

effect of prenatal stress on gene expression (Mychasiuk et al., 2011b). Although there

are large changes in gene expression in the prefrontal cortex of each sex, there are few

overlapping gene expression changes. But both sexes show a marked alteration in den-

dritic organization, suggesting that there are multiple mechanisms underlying the ob-

served plastic changes. This is clearly grist for future studies.

AcknowledgmentsThis research was supported by NSERC of Canada grants to B. K. and R. G.

ReferencesAkshoomoff, N., Feroleto, C., Doyle, R., Stiles, J., 2002. The impact of early unilateral brain

injury on perceptual organization and visual memory. Neuropsychologia 40, 539–546.

Alvers, K., Marusich, J.A., Gipson, C.D., Beckmann, J., Bardo, M., 2012. Environmental en-

richment during development decreases intravenous self-administration of methylpheni-

date at low unit doses in rats. Behav. Pharmacol. 23, 650–657.

http://refhub.elsevier.com/B978-0-444-63327-9.00005-9/rf0005





57References

Anda, R., Felitti, V., Bremner, J., Walker, J., Whitfield, C., Perry, B., Dube, S., Giles, W.,

2006. The enduring effects of abuse and related adverse childhood experiences in child-

hood. A convergence of evidence from neurobiology and epidemiology. Eur. Arch. Psy-

chiatry Clin. Neurosci. 256, 174–186.

Banich, M., Cohen-Levine, S., Kim, H., Huttnlocher, P., 1990. The effects of developmental

factors on IQ in hemiplegic children. Neuropsychologia 28, 35–47.

Baroncelli, L., Braschi, C., Spolidoro, M., Begenisic, T., Sale, A., Maffei, L., 2010.

Nurturing brain plasticity: Impact of environmental enrichment. Cell Death Differ. 17,

1092–1103.

Bartoletti, A., Medini, P., Berardi, N., Maffei, L., 2004. Environmental enrichment prevents

effects of dark-rearing in the rat visual cortex. Nat. Neurosci. 7, 215–216.

Bayer, S., Altman, J., 1991. Neocortical Development. Raven Press, New York, NY.

Bell, H., Pellis, S., Kolb, B., 2010. Juvenile peer play experience and the development of the

orbitofrontal and medial prefrontal cortices. Behav. Brain Res. 207, 7–13.

Bjorkholm, B., Bok, C.M., Lundin, A., Rafter, J., Hibberd, M., Pettersson, S., 2009. Intestinal

microbiota regulates xenobiotic metabolism in the liver. PLoS One 4, e6958.

Blake, D., Strata, F., Churchland, A., Merzenich, M.M., 2002. Neural correlates of instrumen-

tal learning in primary auditory cortex. Proc. Natl. Acad. Sci. U. S. A. 99, 10114–10119.

Cai, R., Fuo, F., Zhang, J., Xui, J., Cui, Y., Sun, X., 2009. Environmental enrichment improves

behavioral performance and auditory spatial representation of primary auditory cortical

neurons in rat. Neurobiol. Learn. Mem. 91, 366–376.

Cameron, N., Champagne, F., Carine, P., Fish, E., Ozaki-Kurodoa, K., Meaney, M., 2005.

The programming of individual differences in defensive responses and reproductive

strategies in a rat through variations in maternal care. Neurosci. Biobehav. Rev. 29,

843–865.

Campbell, G., Shatz, C., 1992. Synapses formed by identified retinogeniculate axons during

the segregation of eye input. J. Neurosci. 12, 1847–1858.

Comeau, W., Hastings, E., Kolb, B., 2007a. Differential effects of pre and postnatal FGF-2

following medial prefrontal cortical injury. Behav. Brain Res. 180, 18–27.

Comeau, W., Hastings, E., Kolb, B., 2007b. Pre- and postnatal FGF-2 both facilitate recovery

and alter cortical morphology following early medial prefrontal cortical injury. Behav.

Brain Res. 180, 18–27.

Comeau, W., Gibb, R., Hastings, E., Cioe, J., Kolb, B., 2008. Therapeutic effects of complex

rearing or bFGF after perinatal frontal lesions. Dev. Psychobiol. 50, 134–146.

Cuzon, V., Yeh, P., Cheng, Q., Yeh, H., 2006. Ambient CAGA promotes cortical entry of tan-

gentially migrating cells derived from the medial ganglionic eminence. Cereb. Cortex 16,

1377–1388.

Day, M., Gibb, R., Kolb, B., 2003. Prenatal fluoxetine impairs functional recovery and neu-

roplasticity after perinatal frontal cortex lesions in rats. Soc. Neurosci. Abstr. 29, 459.10.

Diaz Heijtz, R., Kolb, B., Forssberg, H., 2003. Can a therapeutic dose of amphetamine during

pre-adolescence modify the pattern of synaptic organization in the brain? Eur. J. Neurosci.

18, 3394–3399.

Diaz Heijtz, R., Wang, S., Anuar, F., Qian, Y., Bjorkholm, B., Samuelsson, A., Hibberd, M.,

Forssberg, H., Pettersson, S., 2011. Normal gut microbiota modulates brain development

and behavior. Proc. Natl. Acad. Sci. U. S. A. 108, 3047–3052.

Driscoll, I., Monfils, H., Flynn, C., Teskey, G.C., Kolb, B., 2007. Neurophysiological prop-

erties of cells filling the neonatal medial prefrontal cortex lesion cavity. Brain Res.

1178, 1209–1218.


















































Fenoglio, K., Chen, Y., Baram, T., 2006. Neuroplasticity of the hypothalic-pituitary-adrenal

axis early in life requires recurrent recruitment of stress-regulating brain regions.

J. Neurosci 26, 2434–2442.

Field, T., Diego, M., Hernandez-Reif, M., Dieter, J., Kumar, A., Schanberg, S., Kuhn, C.,

2008. Insulin and insulin-like growth factor-1 increased in preterm neonates following

massage therapy. J. Dev. Behav. Pediatr. 29, 463–466.

Finegold, S., Molitoris, D., Song, Y., Liu, C., Vaisanen, M., Bolte, E., Kaul, A., 2002. Gastro-

instinal microflora studies in late onset autism. Clin. Infect. Dis. 35, S6–S16.

Frost, D., Cerceo Page, S., Carroll, C., Kolb, B., 2010. Early exposure to haloperidol or

olanzapine induces long-term alterations of dendritic form. Synapse 64, 191–199.

Gibb, R., 2004. Perinatal experience and recovery from brain injury. Unpublished PhD Thesis,

University of Lethbridge.

Goldman, P.S., 1974. An alternative to developmental plasticity: heterology of CNS

structures in infants and adults. In: Stein, D.G., Rosen, J., Butters, N. (Eds.), Plasticity

and Recovery of Function in the Central Nervous System. Academic Press, New York,

NY, pp. 149–174.

Goldman, P.S., Galkin, T.W., 1978. Prenatal removal of frontal association neocortex in the

fetal rhesus monkey: anatomical and functional consequences. Brain Res. 152, 451–485.

Goldman, P.S., Isseroff, A., Schwrtz, M., Bugbee, N., 1983. The neurobiology of cognitive

development. In: Mussen, P.H. (Ed.), Handbook of Child Psychology: Biology and In-

fancy Development. Wiley, New York, NY, pp. 311–344.

Goldstein, J.S., Seidman, L., Horton, N., Makris, N., Kennedy, D., Caviness, V., Faraone, S.,

Tsuang, M., 2001. Normal sexual dimorphism of the adult human brain assessed by in vivo

magnetic resonance imaging. Cereb. Cortex 11, 490–497.

Greenough, W., Chang, F., 1989. Plasticity of synapse structure and pattern in the cerebral

cortex. In: Peters, A., Jones, E. (Eds.), Cerebral Cortex. Plenum Press, New York, NY,

pp. 391–440.

Greenough, W., Black, J., Wallace, C., 1987. Experience and brain development. Child Dev.

58, 539–559.

Guzzetta, A., Baldini, S., Bancale, A., Baroncelli, L., Ciucci, F., Ghirri, P., Putignano, E.,

Sale, A., Viegi, A., Berardi, N., Boldrini, A., Cioni, G., Maffei, L., 2009. Massage accel-

erates brain development and the maturation of visual function. J. Neurosci. 29,

6042–6051.

Halliwell, C., 2011. Treatment interventions following prenatal stress and neonatal cortical

injury. Unpublished PhD Thesis, University of Lethbridge, Lethbridge, AB.

Halliwell, C., Kolb, B., 2003. Vitamin/mineral supplements enhance recovery from perinatal

cortical lesions in rats. Soc. Neurosci. Abstr. 459, 11.

Hamilton, D.A., Kolb, B., 2005. Differential effects of nicotine and complex housing on sub-

sequent experience-dependent structural plasticity in the nucleas accumbens. Behav. Neu-

rosci. 119, 355–365.

Harlow, H., Harlow,M., 1965. The affectional systems. In: Schier, A., Harlow, H., Stollnitz, F.

(Eds.), Behaviour of Nonhuman Primates. Academic Press, New York, NY.

Harlow, H., Akert, K., Schiltz, K., 1964. The effects of bilateral prefrontal lesions on learned

behavior of neonatal, infant, and preadolescent monkeys. In: Warren, J., Akert, K. (Eds.),

The Frontal Granular Cortex and Behaviour. McGraw-Hill, New York, NY, pp. 126–148.

Hastings, E., 2003. Environmental and pharmacological intervention following cortical brain

injury. Unpublished Thesis, University of Lethbridge, Lethbridge, AB.
















































59References

Hebb, D.O., 1945. Organization of behavior. McGraw-Hill, New York, NY.

Hebb, D.O., 1949. The Organization of Behavior. Wiley Publishing, New York, NY.

Hicks, S., D’Amato, C., 1961. How to design and build abnormal brains using radiation during

development? In: Fields, S., Desmond, M. (Eds.), Disorders of the Developing Nervous

System. Thomas, Springfield, IL, pp. 60–79.

Hicks, S., D’Amato, C., 1968. Cell migrations to the isocortex of the rat. Anat. Rec. 160,

619–634.

Hicks, S., D’Amato, C., 1975. Motor-sensory corticospinal system and developing locomotion

placing in rats. Am. J. Anat. 143, 1–42.

Himmler, B., Nakahashi, A., Snow, E., McMickle, A., Muhammad, A., Biondolillo, K.D.,

Pellis, S., Kolb, B., 2013a. Juvenile play experience attenuates the initial response to nic-

otine sensitization and voluntary consumption of nicotine in adult rats. Manuscript in

Submission.

Himmler, B., Pellis, S.M., Kolb, B., 2013b. Juvenile play experience primes neurons in the

medial prefrontal cortex to be more responsive to later experiences. Neuroscience Letters,

in press.

Hooper, L., Gordon, J., 2001. Commensal host-bacterial relationships in the gut. Science 292,

1115–1118.

Huttenlocher, P.R., 1984. Synapse elimination and plasticity in developing human cerebral

cortex. Am. J. Ment. Defic. 88, 488–496.

Jimenz, D., Lopez-Mascaraque, L., de Carlos, J., Valverde, F., 2002. Further studies on

cortical tangential migration in wild typeand Pax-6 mutant mice. J. Neurocytol. 31,

719–728.

Kennard, M., 1942. Cortical reorganization of motor function. Arch. Neurol. 48, 227–240.

Kolb, B., Nonneman, A.J., 1978. Sparing of function in rats with early prefrontal cortex le-

sions. Brain Res. 151, 135–148.

Kolb, B., 1995. Brain Plasticity and Behavior. Lawrence Erlbaum, Hillsdale, NJ.

Kolb, B., Elliott, W., 1987. Recovery from early cortical damage in rats. II. Effects of expe-

rience on anatomy and behavior following frontal lesions at 1 or 5 days of age. Behav.

Brain Res. 26, 47–56.

Kolb, B., Gibb, R., 1993. Possible anatomical basis of recovery of spatial learning after neo-

natal prefrontal lesion in rats. Behav. Neurosci. 107, 799–811.

Kolb, B., Forgie, M., Gibb, R., Gorny, G., Rowntree, S., 1998. Age, experience, and the chang-

ing brain. Neurosci. Biobehav. Rev. 22, 143–159.

Kolb, B., Gibb, R., 2010. Tactile stimulation after frontal or parietal cortical injury in infant

rats facilitates functional recovery and produces synaptic changes in adjacent cortex.

Behav. Brain Res. 214, 115–120.

Kolb, B., Stewart, J., 1991. Sex-related differences in dendritic branching of cells in the pre-

frontal cortex of rats. J. Neuroendocrinol. 3, 95–99.

Kolb, B., Stewart, J., 1995. Changes in the neonatal gonadal hormonal environment prevent

behavioral sparing and alter cortical morphogenesis after early frontal cortex lesions in

male and female rats. Behav. Neurosci. 109, 285–294.

Kolb, B., Sutherland, R., 1992. Noradrenaline depletion blocks behavioral sparing and alters

cortical morphogenesis after neonatal frontal cortex damage in rats. J. Neurosci. 12,

2221–2330.

Kolb, B., Tomie, J., 1988. Recovery from early cortical damage in rats. IV. Effects of hemi-

decortication at 1, 5, or 10 days of age. Behav. Brain Res. 28, 25–274.










































Kolb, B., Whishaw, I., 1981. Neonatal frontal lesions in the rat: sparing of learned but not

species-typical behavior in the presence of reduced brain weight and cortical thickness.

J. Comp. Physiol. Psychol. 95, 863–879.

Kolb, B., Whishaw, I., 1985. Neonatal frontal lesions in hamsters impair species-typical be-

haviors and reduce brain weight and cortical thickness. Behav. Neurosci. 99, 691–704.

Kolb, B., Gibb, R., van der Kooy, D., 1992. Neonatal hemidecortication alters cortical and

striatal structure and connectivity. J. Comp. Neurol. 322, 311–324.

Kolb, B., Gibb, R., Van der Kooy, D., 1994a. Neonatal frontal cortical lesions in rats alter cor-

tical structure and connectivity. Brain Res. 645, 85–97.

Kolb, B., Murihead, D., Cioe, J., 1994b. Neonatal frontal cortex grafts fail to attenuate behav-

ioral deficits or abnormal cortical morphogenesis. Brain Res. 647, 15–22.

Kolb, B., Cioe, J., Muirhead, D., 1998. Cerebral morphology and functional sparing after pre-

natal frontal cortex lesions in rats. Behav. Brain Res. 91, 143–155.

Kolb, B., Forgie, M., Gibb, R., Gorny, G., Rowntree, S., 1998a. Age, experience and the

changing brain. Neurosci. Biobehav. Rev. 22, 143–159.

Kolb, B., Gibb, R., Gorny, G., Whishaw, I., 1998b. Possible brain regrowth after cortical

lesions in rats. Behav. Brain Res. 91, 127–141.

Kolb, B., Pedersen, B., Ballerman, M., Gibb, R., Whishaw, I., 1999. Embryoinc exposure

to BrdU produces chronic changes in brain and behavior of rats. J. Neurosci. 19,

2337–2349.

Kolb, B., Cioe, J., Whishaw, I., 2000a. Is there an optimal age for recovery from motor cortex

lesions? I. Behavioural and anatomical sequelae of bilateral motor cortex lesions in rats on

postnatal days 1, 10, and in adulthood. Brain Res. 882, 62–74.

Kolb, B., Cioe, J., Whishaw, I., 2000b. Is there an optimal age for recovery from

unilateral motor cortex lesions? Behavioural and anatomical sequelae of unilateral motor

cortex lesions in rats on postnatal day 1, 10, and in adulthood. Restor. Neurol. Neurosci.

17, 61–70.

Kolb, B., Gibb, R., Gorny, G., 2003a. Experience-dependent changes in dendritic arbor and

spine density in neocortex vary with age and sex. Neurobiol. Learn. Mem. 79, 1–10.

Kolb, B., Gorny, G., Li, Y., Samaha, A., Robinson, T., 2003b. Amphetamine or cocaine limits

the ability of later experience to promote structural plasticity in the neocortex and nucleus

accumbens. Proc. Natl. Acad. Sci. 100, 10523–10528.

Kolb, B., Morshead, C., Gonzalez, C., Kim, N., Shingo, T., Weiss, S.M., 2007. Growth factor-

stimulated generation of new cortical tissue and functional recovery after stroke damage to

the motor cortex of rats. J. Cereb. Blood Flow Metab. 27, 983–997.

Kolb, B., Gibb, R., Pearce, S., Tanguay, R., 2008. Prenatal exposure to prescription medica-

tions alters recovery following early brain injury in rats. Soci. Neurosci. Abstr. 349, 5.

Kolb, B., Halliwell, C., Gibb, R., 2010. Factors influencing neocortical development in the

normal and injured brain. In: Blumberg, M.S., Freeman, W.M., Robinson, S. (Eds.),

Developmental and Comparative Neuroscience: Epigenetics, Evolution and Behavior.

Oxford University Press, New York, NY.

Kolb, B., Pedersen, B., Gibb, R., 2012. Embryonic pretreatment with bromodeoyuridine

blocks neurogenesis and functional recovery from perinatal frontal lesions. Dev. Neurosci.

34, 228–239.

Leung, B.,Wiens, K., Kaplan, B., 2011. Does prenatal micronutrient supplementation improve

children’s mental development? A systematic review. BMC Pregnancy Childbirth 11,

1–12.
















































61References

Lewis, P., 1990. Nutrition and anatomical development of the brain. In: van Gelder, N.M.,

Butterworth, R.F., Drujan, B. (Eds.), (Mal)Nutrition and the Infant Brain. Wiley-Liss,

New York, NY.

Liston, C., Miller, M., Goldwater, D., Radley, J., Rocher, A., Hof, P., Morrison, J.,

McEwen, B., 2006. Stress-induced alterations in prefrontal cortical dendritic morphology

predict selective impairments in perceptual attentional set-shifting. J. Neurosci. 26,

7870–7874.

Meck, W., Williams, C., 2003. Metabolic imprinting of choline by its availability during ges-

tation: Implications for memory and attentional processing across the lifespan. Neurosci.

Biobehav. Rev. 27, 385–399.

Mehl-Madrona, L., Leung, B., Kennedy, C., Paul, S., Kaplan, B., 2010. Micronutrients versus

standard medication management in autism: a naturalistic case–control study. J. Child

Adolesc. Psychopharmacol. 20, 95–103.

Micheva, K., Ceaulieu, C., 1996. Quantitative aspects of synaptogenesis in the rat barrel field

cortex with special reference to GABA circuitry. J. Comp. Neurol. 373, 340–354.

Milstein, J., Elnabawi, A., Swanson, T., Enos, J., Bailey, A., Kolb, B., Frost, D., 2013.

Olanzapine treatment of adolescent rats causes enduring specific memory impairments

and alters cortical development and function. PLoS One 8, e57308.

Mittal, V., Ellman, L., Cannon, T., 2008. Gene environment interaction and covariation in

schizophrenia: the role of obstetric complications. Schizophr. Bull. 34, 1083–1094.

Mochida, G., Walsh, C., 2004. Genetic basis of developmental malformations of the cerebral

cortex. Arch. Neurol. 61, 637–640.

Monfils, M.H., Driscoll, I., Kamitakahara, H., Wilson, B., Flynn, C., Teskey, G.C., Kleim, J.,

Kolb, B., 2006. FGF-2 induced cell proliferation stimulates anatomical neuro-

physiological and functional recovery from neonatal motor cortex injury. Eur. J. Neurosci.

24, 739–749.

Monfils, H., Driscoll, I., Vavrek, R., Kolb, B., Fouad, K., 2008. FGF-2 induced functional im-

provement from neonatal motor cortex injury via corticospinal projections. Exp. Brain

Res. 185, 453–460.

Moriyama, C., Galic, M., Mychasiuk, R., Pittman, Q.J., Perrot, T., Currie, R.W., Esser, M.J.,

2013. Prenatal transport stress, postnatal maternal behavior, and offspring sex differen-

tially affect seizure susceptibility in young rats. Epilepsy Behav. 29, 19–27.

Muhammad, A., Kolb, B., 2011a. Maternal seperation during development alters

dendritic morphology in the nucleus accumbens and prefrontal cortex. Neuroscience

216, 103–109.

Muhammad, A., Kolb, B., 2011b. Prenatal tactile stimulation attenuates drug-induced behav-

ioral sensitization, modifies behavior, and alters brain architecture. Brain Res. 1400,

53–65.

Muhammad, A., Hossain, S., Pellis, S., Kolb, B., 2011. Tactile stimulation during development

attenuates amphetamine sensitization and structurally reorganizes prefrontal cortex and

striatum in a sex-dependent manner. Behav. Neurosci. 125, 161–174.

Muhammad, A., Carroll, C., Kolb, B., 2012. Stress during development alters dendritic

morphology in the nucleus accumbens and prefrontal cortex. Neuroscience 216, 103–109.

Muhammad, A., Mychasiuk, R., Hosain, R., Nakahashi, A., Carroll, C., Gibb, R., Kolb, B.,

2013. Training on motor and visual spatial learning tasks in early adulthood produces large

cahnges in dendritic organization of prefrontal cortex and nucleus accumbens of rats given

nicotine prenatally. Neuroscience 252, 178–189.

















































Murmu, M., Salomon, S., Biala, Y., Weinstock, M., Braun, K., Bock, J., 2006. Changes in

spine density and dendritic complexity in the prefrontal cortex in offspring of mothers ex-

posed to stress during pregnancy. Eur. J. Neurosci. 24, 1477–1487.

Mychasiuk, R., Gibb, R., Kolb, B., 2011a. Prenatal bystander stress induces neuroanatomical

changes in the prefrontal cortex and hippocampus of developing rat offspring. Brain Res.

1412, 55–62.

Mychasiuk, R., Gibb, R., Kolb, B., 2011b. Prenatal stress produces sexually dimorphic and

regionally-specific changes in gene expression in hippocampus and frontal cortex of de-

veloping rat offspring. Dev. Neurosci. 33, 531–538.

Mychasiuk, R., Ilnystkyy, S., Kovalchuk, O., Kolb, B., Gibb, R., 2011c. Intensity matters:

brain, behaviour, and the epigenome of prenatally stressed rats. Neuroscience 180,

105–110.

Mychasiuk, R., Schmold, N., Ilnystkyy, S., Kovalchuk, O., Kolb, B., Gibb, R., 2011d. Prenatal

bystander stress alters brain, behavior, and the epigenome of developing rat offspring.

Dev. Neurosci. 33, 159–169.

Mychasiuk, R., Zahir, S., Schmold, N., Ilnystkyy, S., Kovalchuk, O., Gibb, R., 2012. Parental

enrichment and offspring development: Modifications to brain, behavior, and the epigen-

ome. Behav. Brain Res. 228, 294–298.

Mychasiuk, R., Muhammad, A., Gibb, R., Kolb, B., 2013a. Long-term alterations to dendritic

morphology and spine density associated with prenatal exposure to nicotine. Brain Res.

1499, 53–60.

Mychasiuk, R., Muhammad, A., Kolb, B., 2013b. Environmental enrichment alters structural

plasticity of the adolescent brain but does not remediate the effects of prenatal nicotine

exposure. Synapse, in press.

Myers, M., Brunelli, S., Squire, J., Shindledecker, R., Hofer, M., 1989. Maternal behaviour of

SHR rats in its relationship to offspring blood pressure. Dev. Psychobiol. 22, 29–53.

Nemati, F., Kolb, B., 2012. Recovery frommedial prefrontal cortex injury during adolescence:

implications for age-dependent plasticity. Behav. Brain Res. 229, 168–175.

O’Hare, E., Sowell, E.R., 2008. Imaging developmental changes in gray and white matter in

the human brain. In: Nelson, C., Luciana, M. (Eds.), Handbook of Developmental Cogni-

tive Neuroscience. MIT Press, Cambridge, MA.

O’Leary, D., 1989. Do cortical areas emerge from a protocortex? Trends Neurosci. 12,

400–406.

Payne, B., Lomber, S., 2001. Reconstructing function systems after lesions of cerebral cortex.

Nat. Rev. Neurosci. 2, 911–919.

Pellis, S., Hastings, E., Shimizu, T., Kamitakahara, H., Komorowska, J., Forgie, M., Kolb, B.,

2006. The effects of orbital frontal cortex damage on the modulation of defensive

responses by rats in playful and nonplayful social contexts. Behav. Neurosci. 120, 72–84.

Pena, Y., Prunell, M., Rotilant, D., Armario, A., Escorihuela, R.M., 2009. Enduring effects of

environmental enrichment from weaning to adulthood on pituitary-adrenal function,

pre-pulse inhibition and learning in male and female rats. Psychoneuroendocrinology

34, 1390–1394.

Petanjek, Z., Judas, M., Simic, G., Rain, M., Uylings, H.B., Rakic, P., Kostovic, I., 2011.

Extraordinary neonty of synaptic spines in the human prefrontal cortex. Proc. Natl. Acad.

Sci. U. S. A. 108, 13281–13286.

Rakic, P., 1972. Mode of cell migration to the superficial layers of fetal monkey neocortex.

J. Comp. Neurol. 145, 13281–13286.













































63References

Reisen, A., 1961. Studying preceptual development using the technique of sensory depriva-

tion. J. Nerv. Ment. Dis. 132, 21–25.

Richards, S., Mychasiuk, R., Kolb, B., Gibb, R., 2012. Tactile stimulation during development

alters behaviour and neuroanatomical organization of normal rats. Behav. Brain Res. 231,

86–91.

Robinson, T.E., Kolb, B., 2004. Structural plasticity associated with exposure to drugs of

abuse. Neuropharmacology 47, 33–46.

Rozenweig, M.R., Bennett, E.L., Diamond, M.C., 1967. Effects of differential environments

on brain anatomy and brain chemistry. Proc. Annu. Meet. Am. Psychopathol. Assoc. 56,

45–56.

Sale, A., Putignano, E., Cancedda, L., Landi, S., Circulli, A., Berardi, N., Maffei, L., 2004.

Enriched environment and acceleration of visual system development. Neuropharmacol-

ogy 47, 649–660.

Sandstrom, N., Loy, R., Williams, C., 2002. Prenatal choline supplementation increases NGF

levels in the hippocampus and frontal cortex of young and adult rats. Brain Res. 947, 9–16.

Schanberg, S., Field, T., 1987. Sensory deprivation stress and supplemental stimulation in the

rat pup and preterm neonate. Child Dev. 58, 1431–1447.

Semple, B., Blomgren, K., Gimlin, K., Ferriero, D.N., Noble-Haeusslein, H.L., 2013. Brain

development in rodents and humans: identifying benchmarks of maturation and vulnera-

bility to injury across species. Prog. Neurobiol. 106–107, 1–16.

Shatz, C., 1992. The developing brain. Sci. Am. 267, 60–67.

Sirevaag, A., Greenough, W., 1988. A multivariate statistical summary of synaptic plasticity

measures in rats exposed to complex, social, and individual environments. Brain Res. 441,

386–392.

Spanswick, S., Sutherland, R., 2010. Object/context-specific memory deficits associated with

loss of hippocampal granule cells after adrenalectomy in rats. Learn. Mem. 17, 241–245.

Stiles, J., 2012. The effects of injury to dynamic neural networks in the mature and developing

brain. Dev. Psychobiol. 54, 343–349.

Tees, R., Mohammadi, E., 1999. The effects of neonatal choline dietary supplementation on

adult spatial and configural learning and memory in rats. Dev. Psychobiol. 35, 226–240.

Teuber, H., 1975. Recovery of function after brain injury inman. In: Outcome of SevereDamage

to the Nervous System. Ciba Foundation Symposium. Elsevier, North Holland, Amsterdam.

Thai, D., Marchman, V., Stiles, J., Aram, D., Trauner, D., Nass, R., Bates, E., 1991. Early lex-

ical development with focal brain injury. Brain Lang. 40, 491–527.

van den Bergh, B., Marcoen, A., 2004. High antenatal maternal anxiety is related to ADHD

symptoms, externalizing problems and anxiety in 8- and 9-year-olds. Child Dev. 75,

1085–1097.

Van Eden, C.G., Mrzljak, L., Voorn, P., Uylings, H.B., 1990. The development of the rat pre-

frontal cortex: Its size and development of connections with thalamus, spinal cord, and

other cortical areas. Prog. Brain Res. 85, 169–183.

Van Eden, C.G., Rinkens, A., Uylings, H.B., 1998. Retorgrade degeneration of the thalamic

neurons in themediodorsal nucleus after neonatal and adult aspiration lesions in themedial

prefrontal cortex in the rat. Implications for mechanisms of functional recovery. Eur.

J. Neurosci. 10, 1581–1589.

Villablanca, J., Hovda, D., Jackson, G., Infante, C., 1993. Neurological and behavioral effects

of a unilateral frontal cortical lesion in fetal kittens, II. Visual system tests and proposing a

’critical period’ for lesion effects. Behav. Brain Res. 57, 72–92.

















































Vinish, M., Elnabawi, A., Milstein, J., Burke, J., Kallevang, J., Turek, K., Merchenthaler, I.,

Bailey, A., Kolb, B., Cheer, J., Frost, D., 2013. Olanzapine treatment of adolescent rats

alters adult reward behaviour and nucleus accumbens function. Int. J. Neuropsychophar-

macol. 25, 1–11.

Weaver, I., Champange, F., Brown, S., Dymov, S., Sharma, S., Meaney, M., Szyf, M., 2005.

Reversal of maternal programming of stress response in adult offspring through methyl

supplementation: altering epigenetic marking later in life. J. Neurosci. 25, 11045–11054.

Weinstock, M., 2008. The long-term behavioral consequences of prenatal stress. Neurosci.

Biobehav. Rev. 32, 1073–1086.

Whishaw, I., Kolb, B., 1988. Sparing of skilled forelimb reaching and corticospinal projections

after neonatal motor cortex removal or hemidecortication in the rat: Support for the

Kennard Doctrine. Brain Res. 451, 97–114.

Wiesel, T., Hubel, D., 1963. Effects of visual deprivation on morphology and physiology of

cells in the cat’s lateral geniculate body. J. Neurophysiol. 26, 6.

Williams, P., Gharbawie, O., Kolb, B., Kleim, J., 2006. Experience-dependent amelioration of

motor impairments in adulthood following neonatal medial frontal cortex injury in rats

accompanied by motor map expansion. Dev. Neurosci. 141, 1315–1326.


















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