Download Development of the Cell Population in the Brain

Cerebral Cortex January 2016;26:89–95
doi:10.1093/cercor/bhu178
Advance Access publication August 13, 2014
Development of the Cell Population in the Brain White Matter of Young Children
Rasmus Krarup Sigaard, Majken Kjær and Bente Pakkenberg
Research Laboratory for Stereology and Neuroscience, Bispebjerg and Frederiksberg Hospitals, Denmark
Address correspondence to Bente Pakkenberg, Research Laboratory for Stereology and Neuroscience, Bispebjerg and Frederiksberg Hospitals,
Bispebjerg Bakke 23, opg. 11B, DK-2400 Copenhagen NV, Denmark. Email: [email protected], [email protected]
While brain gray matter is primarily associated with sensorimotor processing and cognition, white matter modulates the distribution of
action potentials, coordinates communication between different brain
regions, and acts as a relay for input/output signals. Previous studies
have described morphological changes in gray and white matter
during childhood and adolescence, which are consistent with cellular
genesis and maturation, but corresponding events in infants are poorly
documented. In the present study, we estimated the total number of
cells (neurons, oligodendrocytes, astrocytes, and microglia) in the
cerebral white matter of 9 infants aged 0–33 months, using designbased stereological methods to obtain quantitative data about brain
development. There were linear increases with age in the numbers of
oligodendrocytes (7–28 billion) and astrocytes (1.5–6.7 billion) during
the first 3 years of life, thus attaining two-thirds of the corresponding
numbers in adults. The numbers of neurons (0.7 billion) and microglia
(0.2 billion) in the white matter did not increase during the first 3 years
of life, but showed large biological variation.
Keywords: brain development, humans, neuroanatomy, stereology,
subcortical white matter
Introduction
Quantitative stereological studies of the normal human brain
have hitherto focused largely on cell population in gray matter
of the adult (Pakkenberg and Gundersen 1997; Pelvig et al.
2008), and on development of the fetal brain (Samuelsen et al.
2003). Less attention has been given proliferation of cell populations during the early postnatal period, and development of
the subcortical white matter is in particular need of documentation. The human brain is only 30% of its adult size at birth
versus approximately 65% in the macaque monkey and approximately 45% in chimpanzee, and attains approximately
80% of its adult weight during the first 2–3 postnatal years
(Prechtl 1986; Jensen 1996). Thus, man is an extreme case for
perinatal brain development, with the period of maximal brain
growth extending from the last half of gestation into the first
year of life (Dobbing and Sands 1973). Approximately half of
the mass of the neonate human brain is white matter, in which
the predominant cell type consists of glia, that is oligodendroglia
and astrocytes, which together provide the myelin for neuronal
fibers and maintain a cellular and extracellular environment necessary for neuronal functioning. There is a growing recognition
that glia, possibly through a glial network, may undertake intracellular communication, complementing that of the neurons
themselves (Baumann and Pham-Dinh 2001). Although oligodendrocytes are well known for their production of myelin, the
full range of their functions remains a puzzle; satellite oligodendrocytes without any connection of the myelin sheath have been
described (Baumann and Pham-Dinh 2001). The development
of the non-neuronal elements of the human brain has been a
neglected topic.
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The human forebrain develops from the cranial part of the
neural tube (Stiles and Jernigan 2010), and the future brain
cells originate from proliferating progenitor cells situated in
the areas surrounding the telencephalic ventricles, that is the
ventricular zone, the subventricular zone, and the ganglionic
eminence. From these regions, the newly generated and differentiated neurons migrate radially along a scaffold provided by
radial glial cells, or tangentially toward the cortical plate (Rakic
1988; Kornack 2000; Parnavelas et al. 2000). Some neurons
stop their migration in the subplate, a transient zone identified
in the fetus, which gradually dissolves during early infancy,
and merges with the intermediate zone to become the white
matter of the adult brain (Kostovic and Rakic 1980, 1990; Judas
et al. 2010). The subventricular zone, which is present in the
late gestational and early postnatal mammalian brain, is the
major source of astrocytes and oligodendrocytes; maturation of
these cells occurs in early postnatal life, where there is a large
expansion of the fiber network. In the late prenatal and early
postnatal period, when the majority of subplate neurons die,
the remaining cells come to comprise the interstitial neurons
of the adult white matter (Kostovic and Rakic 1980, 1990;
Chun and Shatz 1989; Ghosh and Shatz 1992). Although oligodendrocyte proliferation occurs early, myelination takes place
late in development; in general, the pattern of myelination proceeds from proximal to distal structures in the long tracts, from
the phylogenetically older to newer structures, that is in a
caudo-cephalic direction in the cerebral while matter. First
myelination begins in the spinal cord at as early as 22 weeks of
gestation, but commences gradually in the hemispheric white
matter during the first 2 postnatal years, and continues to
develop until late adolescence (Friede 1989). Thus, even at
term, the hemispheres are almost totally devoid of myelin, and
the high water content of the white matter probably contributes for the extreme fragility of the immature brain (Larroche
1998). The primary sensory pathways are myelinated first,
while the associative areas myelinate later, and last of all the
anterior frontal and anterior temporal cortices. Myelin plays an
inhibitory role to growing axons, and contributes to the anatomic stability of the mature, intact nervous system, by preventing random regrowth of axon sprouts once pathways have
been established and myelinated. High-speed salutatory conduction, fidelity of signaling for long distances, and space
economy are the 3 major advantages conferred to the vertebrate nervous system by the myelin sheath. The importance of
myelin in maintaining normal human brain function is highlighted by its involvement in an array of different neurological
diseases, such as leukodystrophies and multiple sclerosis in
the central nervous system and peripheral neuropathies in the
peripheral nervous system (Baumann and Pham-Dinh 2001).
Structural MRI and molecular biological studies have shown
morphological and quantitative changes in gray and white
matter during human childhood and adolescence, consistent
with ongoing cellular maturation and the formation of new
cells (Winick 1968; Dobbing and Sands 1973; Toft et al. 1995;
Giedd et al. 2010; Sanchez et al. 2012). Glial progenitors in the
cortex and white matter continue to proliferate in infancy,
throughout childhood and into adulthood (Miller 2002), in
concert with forebrain myelination (Aubert-Broche et al.
2008). Increasing cell size, glial proliferation, and marked myelination all contribute to the substantial brain growth in the
first 3 years of life (Voigt and Pakkenberg 1983; Jernigan et al.
2011). Despite this knowledge about the developing brain,
there is no quantitative data on the proliferation of cell populations in white matter during the postnatal period. In this study,
we aimed to quantify the total number of neurons and glial
cells in the subcortical white matter of 9 infant brains, ranging
in age from newborn to 3 years of age. To this end, we used
modern stereological cell counting methods for unbiased estimation of cell populations. The project took advantage of a
unique collection of postmortem brain specimens from infants
who died without primary neurological deficits that were collected and preserved at the brain bank at Bispebjerg Hospital.
Materials and Methods
Subject Characteristics
The study was based on hemispheres from the brains of 9 infants (age
range 0–33 months) obtained postmortem from 1983 to 1991, all in
accordance with Danish law regarding autopsied human tissue. The
brains were selected from a larger sample of infant brains, but limited
to those individuals without disease of the central nervous system,
with the single except of the 23-month-old infant who died from diatesis hemorrhagica and with meningococcal meningitis. Table 1 details
the clinical information on cause of death, brain weight, and storage
time in fixative. None of the brains had tumors or hemorrhages, and
none showed signs of cortical spongiosis, vasculitis, or encephalitis.
The brains had been stored in different fixatives for various periods of
time, so the brain weights are not directly comparable; despite this
caveat brain weights were all within the normal range (Voigt and
Pakkenberg 1983), except for a 19-month-old infant’s brain, that had
been fixed in picric acid for 28 years. The material was limited to 9
brains as a consequence of our strict inclusion criteria.
Tissue Processing
All brains had been fixed for at least 10 years in 0.1 M sodium
phosphate-buffered 4% formaldehyde ( pH 7.2) at room temperature.
Brains that were very soft were transferred to a solution of 50% formaldehyde (Merck 37%, Germany, 1.04003), 25% saturated picrid acid
(Prolabo), and 25% demineralized water. Thus, differing fixation histories influenced their volume shrinkage. After fixation, the cerebrum
Table 1
Subject characteristics
Age of
subjects
Sex
Cause of death
Brain
weight (g)
Newborn
(6 min)
14 days
4 months
F
Asphyxia
420
11
F
M
318
548
20
25
8 months
9 months
15 months
M
M
M
615
647
1034
26
26
20
19 months
23 months
F
M
696
1274
28
26
33 months
F
Asphyxia, pneumonia
Complications during surgery for truncus
arteriosus persistens
Mb. Cordis congenitalis
Mb. Cordis congenitalis
Complications during diaphragmatic hernia
surgery
Mb. Cordis congenitalis
Diatesis hemorrhagica caused by severe
tracheobronchitis mucopurulenta
Sequelae to multiple dog bites
933
25
90 Development of the Cell Population in the Brain White Matter
•
Time in
fixative
(years)
Sigaard et al.
was detached from the brainstem at the level of the third cranial nerve,
and the meninges were removed. One hemisphere from each brain
was used for stereology (5 left and 4 right hemispheres). The right or
the left hemisphere was selected following the rules of systematic
uniform random sampling (SURS; Gundersen et al. 1999). The entire
hemisphere was coronally cut into 2.5-cm slabs, dehydrated, and embedded in paraffin in a LeicaASP300 tissue processor, followed by
coronal sectioning on a Leica SM2400 sliding microtome set at 40 µm
thickness. Exhaustive sectioning resulted in a total of 2100–3800 sections from each hemisphere, which were sampled with a known and
predetermined interval. A wetted filter paper was placed on the paraffin block to allow collection of the sampled section without the use of
water baths. When the section adhered to the filter paper, it was
mounted on a double-silane-coated microscope slide by placing the
paper with the section facing down on the slide and pressing gently
with a printing roller. This procedure resulted in an almost complete
absence of tissue deformation artifacts, such as usually arise from the
use of water baths. Specifically, there was no shrinkage in the z-axis,
and the final tissue section height after processing remained about
40 μm as in Eriksen and Pakkenberg (2007).
Upon slide mounting, the sampled sections were dried at 40 °C for
24 h, followed by heating to 60 °C for 60 min. They were then
dewaxed in xylene for 2 × 30 min, followed by 2 × 20 min in 99%
ethanol, 2 × 10 min in 96% ethanol, 5 min in 70% ethanol, 5 min in 35%
ethanol, 5 min in 17% ethanol, and 5–10 min in distilled water. The
rehydrated sections were stained for 45 min using a modified Giemsa
stain containing 200 mL of Giemsa stock solution (Merck, Germany,
product 1.09204) and 800 mL of potassium hydrogen phosphate
(67 mmol/L, pH 4.4), which was filtered before use. Finally, the sections were differentiated with 0.5% acetic acid and dehydrated by
passage through 96% ethanol, 99% ethanol for 2 × 2.5 min, and xylene
for 2 × 15 min.
Criteria for Visually Determining Cell Type
As previously described (Pelvig et al. 2003, 2008; Fabricius et al. 2013),
determination of cell type was performed based on morphology. The
cells were identified as neurons if they had a single large nucleolus free
of any surrounding heterochromatin, a typical pale chromatin pattern
in a triangularly rounded nucleus, and visible cytoplasm surrounding
the nucleus (Duffy 1983; Berry and Butt 1997; Fig. 1). Oligodendrocytes are often found in clusters and are characterized by a small
rounded or oval nucleus with dense chromatin structure and a perinuclear halo (Fuller and Burger 1997; Baumann and Pham-Dinh
2001). Astrocytes are defined as cells with a round and pale nucleus
with heterochromatin concentrated in granules in a rim below the
nuclear membrane and a relatively translucent cytoplasm. A small nucleolus is not always identified, but when present, it often shows eccentric localization. Astrocytes are often found in isolation, and their
nuclear membrane has a sharp profile. Microglia cells are defined by a
small elongated or comma-shaped nucleus with dense peripheral chromatin (Pelvig et al. 2003). Endothelial cells were not included in the
study.
Stereological Design
For white matter volume estimations, the section sampling fraction was
1/100 for all brains, providing 19–35 sections per brain. For the estimation of cell densities in the subcortical white matter, the sampling fraction was 1/200–1/400, yielding 9–11 sections per hemisphere. For
precision of estimates see, for example, Pakkenberg and Gundersen
(1988) and Slomianka and West (2005). The sections were selected following the rules of SURS (Gundersen et al. 1999) to ensure that all
parts of the subcortical white matter had an equal probability of being
sampled. Estimations of white matter regions included the subcortical
white matter, corpus callosum, internal and external capsules, and
anterior and posterior commissures.
Volume Estimation
Estimates of subcortical white matter volume were obtained by
employing Cavalieri’s principle using point probes that were
focus with visible nucleoli inside the counting frame. When the
number of cells in all disectors, ΣQ −, had been counted for 1 brain, the
numerical density, NV, was estimated as described previously (Pelvig
et al. 2008). The total number of particles was estimated as the product
of the reference volume and the numerical density in the samples,
multiplied by 2, to provide bilateral data. Cells that could not be clearly
identified were separately classified as unidentified cells. They only
constituted a negligible fraction of the total cell counts. Epithelial cells
were not included in the counts.
Figure 1. Representative images of (a) a neuron, (b) an oligodendrocytes, (c) an
astrocyte, and (d) a section of a brain. Neurons have a combination of a single large
nucleolus, typically a triangularly rounded nucleus, which are surrounded by a visible
cytoplasm; oligodendrocytes are characterized by a small rounded or oval nucleus with
a dense chromatin structure and a perinuclear halo; astrocytes have a round or
triangular and pale nucleus with the heterochromatin concentrated in small granules
and sometimes small nucleoli, often situated eccentrically; microglia (not shown) have
small elongated or comma-shaped nucleus with a dense peripheral chromatin. The bar
in a, b, and c = 10 μm; the bar in d = 1 cm.
systematically and randomly applied to each cross-sectional area. The
Cavalieri volume was estimated by multiplying the average distance
between the sections, T = t × k, where t is the average section thickness
(∼40 µm) and k is the inverse sampling fraction of the sections (100).
T was multiplied by the total cross-sectional area of the white matter,
which was obtained by multiplying the total number of counted
points in the region of interest by the area per test point (Gundersen,
Bendtsen, et al. 1988; Gundersen et al. 1999).
When tissue is embedded in paraffin, substantial tissue shrinkage is
inevitable. Normally, this can be accommodated by multiplying the
volume by a shrinkage correction factor. However, this was not possible in this study due to the differences in shrinkage artifacts caused
by the variety of fixative compositions and durations for the 9 samples.
Accordingly, estimated cell densities cannot be compared directly, as
they are influenced to differing extents by shrinkage. Nonetheless, the
product of the density and the volume after final processing gives an
unbiased estimate of the total cell numbers, and as such, can be compared among the brains, irrespective of shrinkage.
Cell Density and Number Estimation
The numerical cell densities of neurons and glial cells were estimated
by applying the optical disector (Gundersen, Bagger, et al. 1988). The
sections were analyzed on a BX-50 Olympus microscope equipped
with a Heidenhain electronic microcator with a digital readout for measurements in the z-direction (with a precision of 0.5 µm), and an X–Y
motorized stage (M2000, Prior). Live images from a high-resolution
color camera (JAI CV-3200, Japan) mounted on a ×2.5 photo eyepiece
(Olympus, DK) were forwarded to a computer running the CAST
Stereology software package (v. 2.1.5.8, Visiopharm, Hørsholm,
Denmark). Sampling in the z-axis was performed with a disector
height of 20 µm and upper and lower guard zones of at least 5 µm.
Area frame was 360 µm2 for oligodendrocytes and 3250 µm2 for the
rest of the cells. The cells were counted using a ×60 oil immersion objective (Olympus, PlanApo N, NA 1.42), giving a final onscreen magnification of ×2700. Neurons and glial cells (subdivided into astrocytes,
oligodendrocytes, and microglia) were counted only if they came into
Stereological Analysis
The precision of the estimates is expressed as the coefficient of error
(CE) and was calculated as reported previously (Gundersen et al.
1999). As a measure of the variability of the estimates within a group,
the observed interindividual coefficient of variation (CV) (SD/mean) is
reported in parentheses after group means in the Results section. In
this study, a mean of 231 points (range 121−458) was counted for each
brain, corresponding to total white matter volumes, with an average
CE(P) of <4%. For the density estimations, a mean of 170 (range 110
−345) neurons was counted in 397 disectors, and a mean of 588 (range
376−918) glial cells was counted in 181 disectors per infant brain. The
glial cells were distributed by type as follows: mean counts of 223
(range 115−331) oligodendrocytes, 343 (range 224−562) astrocytes,
and 24 (range 10−45) microglia. This resulted in CE(Q−) estimates of
8.4% for neurons, 7.1% for oligodendrocytes, 5.9% for astrocytes, and
22.8% for microglia. A mean of 8.8 cells per brain could not be identified, which represented <1.2% of the total cell number. The sum of
counted cells is acceptable (CE(Q−) <10%), with the exception of the
microglia, which was estimated with less precision due to their rarity.
Statistical Analysis
The total cell numbers for oligodendrocytes and astrocytes appeared to
increase linearly with age, so we applied a linear regression analysis to
describe the total number of cells, using age in months as the independent regression variable.
The coefficient of determination, R 2, is the proportion of the variation explained by the regression model, which is an index of how
well the model fits the dependent variable.
Results
Number of Cells in the White Matter
The mean number of white matter cells was 23.6 × 109, ranging
from 9.6 to 35.9 × 109.
Neuron number: the 9 infants were estimated to have a
mean of 0.68 × 109 (CV = SD/mean = 0.28) white matter
neurons (range 0.49–0.94 × 109) (Fig. 2a).
Glial cell number: the total number of glia cells was
22.8 × 109 (range 8.71–35.6 × 109). The glial cells were subdivided into oligodendrocytes, astrocytes, and microglia (Fig. 1).
There was a mean of 19.2 × 109 oligodendrocytes (range 7.06–
28.9 × 109) (Fig. 2c), 3.4 × 109 astrocytes (range 1.46–6.7 × 109)
(Fig. 2d), and 0.20 × 109 (0.32) (range 0.14–0.33 × 109) microglia (Fig. 2b).
Linear Increase in Oligodendrocytes and Astrocytes
During Childhood
We observed a linear increase in oligodendrocyte and astrocyte
counts during the first 3 years of life. For oligodendrocytes, the
regression gave y = 0.57 × 109x + 12.1 × 109, where y is the total
number of oligodendrocytes, and x is the number of months
after birth. The goodness of the fit was R 2 = 0.84, and the slope
significantly different from zero (P = 0.0005), with 95% confidence intervals (95% CIs) of 0.35–0.79 × 109 for the slope,
Cerebral Cortex January 2016, V 26 N 1 91
Figure 2. Total bilateral number of cells in the subcortical white matter by age (n = 9). (a) Neurons, (b) microglia, (c) oligodendrocytes, and (d) astrocytes. The gray symbol in b
indicates the male subject who died from meningitis. Open symbols: female and solid symbols: males.
and 8.52–15.7 × 109 for the ordinate intercept (Fig. 2c). The
number of astrocytes increased with age with linear regression
as y = 0.17 × 109x + 1.39 × 109. The goodness of the fit was
R 2 = 0.89, and the slope is significantly different from zero
(P = 0.0001), with 95% CIs of 0.11–0.22 × 109 for the slope, and
0.55–2.22 × 109 for the ordinate intercept (Fig. 2d).
We applied linear regression analysis to describe the total
number of neurons and microglia as well, but the slopes of the
linear regression analyses were not significantly different from
zero, indicating an absence of proliferation during the 3 year
postnatal period.
White Matter Cell Distribution
Neurons accounted for a mean of 3.4% (range 1.4−8.0%),
whereas oligodendrocytes constituted 81.3% (range 74.0
−87.7%), astrocytes 13.9% cells (range 8.8−18.8%), and microglia 1.1% (range 0.6−1.9%) of all cells counted. Figure 3 shows
an example of the cell distribution in the white matter of brain
hemispheres from 4 cases: newborn, 8 months, 19 months,
and 33 months of age.
Discussion
The major finding of this study is that the total number of oligodendrocytes and astrocytes in the subcortical white matter
of human infants increases as a linear function of age during
the first 3 years of life. The numerical increase in oligodendrocyte numbers was from approximately 7 billion to 28 billion,
indicating a mean increase of 600 million oligodendrocytes per
92 Development of the Cell Population in the Brain White Matter
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Sigaard et al.
month during the first 3 years of life. Considering the large
degree of variance in the total number of brain cells between
individuals, it is quite extraordinary that the postnatal increase
in oligodendrocyte numbers can be expressed so well by a
linear model. In our material, the proliferation of subcortical
white matter astrocytes is also directly related to age, increasing
from 1.5 to 6.7 billion during the first 3 years of life. The linear
regression slope indicated a mean birth rate of 170 million astrocytes per month. In contrast to the linear proliferation of oligodendrocytes and astrocytes, we found a constant total number
of neurons and microglia in the white matter during the first
3 years of postnatal life. In total, approximately 750 million surviving new cells are added to the white matter each month,
during the first 3 years of life, corresponding to a birth rate of
17 000 new cells per minute or nearly 300 per second.
There is as yet no quantitative data on the total number of
cells in the white matter of adult humans; for the purpose of
comparison, we have estimates of the total number of neurons,
oligodendroglia, astroglia, and microglia in the entire brain
white matter from 3 normal adults in their 70s (unpublished
data). For this group, the total number of oligodendroglia was
37 billion, suggesting an increase of at least 10 billion after
3 years of age. The astroglia count was 9 billion in the adult
white matter, compared with the approximately 6 billion at 3
years of age. It seems likely that the proliferation of oligodendrocytes and astroglia is 65–75% complete at 3 years of age, and
apt to continue in the following years, although the linear
growth phase must be approaching completion. The distribution of the different cell types in the infants was approximately
constant with age (Fig. 3).
Figure 3. Cell distribution in 4 infants: newborn, and aged 8, 19, and 33 months. Oligo, oligodendrocytes; astro, astrocytes; micro, microglia; UnID, unidentified cells.
The mean total neuron number in white matter was the same
in the infants (0.68 × 109) as in adult brains (0.69 × 109) (unpublished data). In general, neurons resident in the white matter are
considered remnants from the fetal subplate, and are comprised
of a heterogeneous mixture of excitatory and inhibitory neurons
(Judas et al. 2010; Connor et al. 2011). These neurons are believed to influence cortical and thalamic circuitry by local
effects, and to exhert a regulation of microvasculature blood
flow in the brain. The sparse population of microglia in the subcortical white matter (0.20 × 109) did not increase with age and
was not different in the adult brain (0.28 × 109) (unpublished
data).
Distinguishing between the largest glia cells and the smaller
neurons in Giemsa stained tissue can be a problem. The use of
strict morphological criteria, in the absence of staining with
immunohistochemistry, may not be sufficient for correct assignment of cell type in all cases. A more reliable separation of
neurons and glia might have been obtained through the use of
sensitive and robust antibodies for a specific glial marker such
as glial fibrillary acidic protein. This was not possible in the
present study due to the long-term, formalin fixation of the
brain tissue. However, our morphological criteria for cell differentiation have proved to be consistent in a number of stereological studies (Pelvig et al. 2003, 2008; Fabricius et al. 2013),
including immunohistochemistry (Hou et al. 2012).
Another limitation of this study is the low sample size,
which was necessary due to our strict inclusion criteria. Some
of the infants had died from a congenital heart condition, and
it cannot be excluded that heart disease, with impaired cerebral perfusion, might have influenced the total number of
brain cells. However, except for one infant, the brain weights
were within normal limits, and the total number of cells
showed no correlation to the pathological diagnoses. Since the
statistical power of the study is low due to inclusion of only
one brain per time point, these data must be considered as preliminary; more studies with a larger number of brains per time
point would be necessary to substantiate our findings. Finally,
the results for microglia are less precise than for other cell
types, due to the naturally low abundance of these cells in
human white matter under normal conditions. However, it is
in line with our expectations that the number of microglia cells
did not correlated to age.
Improved knowledge of the development of white matter in
the human brain may have important implications for neuropsychiatric disease. Indeed, increased densities and altered distributions of white matter neurons in the frontal, temporal, and
parietal lobe white matter have been implicated as a causative
factor in complex central nervous system disorders, such as
schizophrenia (Eastwood and Harrison 2003; Connor et al.
2011). Because of methodological differences in previous
studies, which place main focus on different white matter
zones (i.e., “superficial” and “deep” white matter), there is
little consensus regarding which regions are affected in schizophrenia (Connor et al. 2011). However, there is some link
between the disorder and changes in white matter composition
during neurodevelopment, which is further implied by the
occurrence of abnormalities in oligodendrocyte number and
morphology, as reported in postmortem studies (Roy et al.
2007). Diffusion tensor imaging studies have demonstrated
altered white matter microstructure in autism and bipolar disorder, which may have arisen from alterations in axonal organization and white matter tracts during development (Adler
et al. 2006; Travers et al. 2012).
This study provides data on the cell populations in subcortical white matter of infants aged 0−33 months, being the first
study to quantify proliferation of oligodendrocytes and
Cerebral Cortex January 2016, V 26 N 1 93
astrocytes in the white matter during early childhood in a
unique collection of brains from young children. This knowledge provides valuable information about the maturation of
the brain white matter in the early phase of childhood, and is
intended to serve as a reference for future attempts to understand the natural history of diseases that are associated with
changes in the white matter, such as, for example, multiple
sclerosis and neuropsychiatric disorders (Roy et al. 2007;
Fields 2008; Nakahara et al. 2012).
Author’s Contribution
B.P. conceived and supervised the project and assisted in
writing the manuscript. R.K.S. performed the experiments, collected, and analyzed the data, and wrote the manuscript. M.K.
assisted in data collection.
Funding
This work was supported by the Danish Council for Independent Research, Medical Sciences (FSS: 12-124750).
Notes
Dr Bjarne Beck is acknowledged for collecting some of the brain specimens. The authors thank Ms Susanne Sørensen for her skillful technical assistance. The authors acknowledge professional editing of the
manuscript by Inglewood Biomedical Editing. Conflict of Interest: The
authors declare no competing financial interests.
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