Abstract
Human fetal brain development is a complex process which is vulnerable to disruption at many stages. Although histogenesis is well-documented, only a few studies have quantified cell numbers across normal human fetal brain growth. Due to the present lack of normative data it is difficult to gauge abnormal development. Furthermore, many studies of brain cell numbers have employed biased counting methods, whereas innovations in stereology during the past 20–30 years enable reliable and efficient estimates of cell numbers. However, estimates of cell volumes and densities in fetal brain samples are unreliable due to unpredictable shrinking artifacts, and the fragility of the fetal brain requires particular care in handling and processing. The optical fractionator design offers a direct and robust estimate of total cell numbers in the fetal brain with a minimum of handling of the tissue. Bearing this in mind, we have used the optical fractionator to quantify the growth of total cell numbers as a function of fetal age. We discovered a two-phased development in total cell numbers in the human fetal forebrain consisting of an initial steep rise in total cell numbers between 13 and 20 weeks of gestation, followed by a slower linear phase extending from mid-gestation to 40 weeks of gestation. Furthermore, we have demonstrated a reduced total cell number in the forebrain in fetuses with Down syndome at midgestation and in intrauterine growth-restricted fetuses during the third trimester.
Highlights
The neocortex is the main locus of cognition in the human brain and its expansion relative to that in non-human primates is a main anatomic distinction
We have focused our investigations on the total cell numbers in the maturing neocortex or in transient fetal zones destined to develop into neocortex (Kostovic and Judas, 1995)
Since our histological methods do not distinguish between neurons and glial cells, we report total cell numbers, i.e. the sum of future neurons and glial cells
Summary
The neocortex is the main locus of cognition in the human brain and its expansion relative to that in non-human primates is a main anatomic distinction. There have been few developmental studies of cell numbers in the human fetal and neonate forebrain (Winick, 1968; Dobbing and Sands, 1973; Rabinowicz et al, 1996), none of which employed stereological methods. The Optical Fractionator and the Developing Human Forebrain assumptions that all cells (counting objects) are of uniform shape and size or are isotropically orientated in the specimen (Weibel and Gomez, 1962; Rose and Rohrlich, 1987) Violation of these assumptions give rise to significant bias in the estimation of cell numbers, but stereological methods accommodate these factors. A series of stereological studies has contributed invaluable knowledge of the proliferation of total neocortical cell numbers in human fetal brain by use of the optical fractionator (Samuelsen et al, 2003, 2007; Larsen et al, 2006, 2008, 2010). The SP undergoes intensive reorganization and reaches its maximum thickness at 22 fetal weeks, begins to regress after fetal week 35, and disappears by the second postnatal year (Kostovicet al., 2014)
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