The weight gain of a given organ with time is a measure of growth of that organ. Weight gain is indeed the simplest and the easiest criterion of growth, provided that the presence of an unusual amount of water in edematous condition does not affect the actual situation. However, the weight curve of tissues including the brain, like that of the body, is not linear with time but follows a sigmoidal pattern (Fig. 2), meaning that there is a period of more rapid growth compared with that occurring before or after that period. This period of rapid growth is known as the growth spurt and is a determinant for the so-called "critical" or "vulnerable'' period because at this time even a slight disturbance in the growth-supporting environment may have a profound effect on the overall growth and development of the tissue.
The anatomical heterogeneity of the brain makes the developmental study of the tissue particularly difficult because it is almost impossible to dissect its hundreds of tiny functioning parts and study them. However, valuable information has been obtained from the study of the major regions of the brain—the forebrain, cerebellum, and brain stem (Fig. 2)—although such studies are of limited value with regard to the growth spurts of the composite structures in each of these regions.
Generally, the growth process of the brain, like that of any other organ, encompasses two major processes—growth and development. The growth process consists of an increase in the number of cells until the
adult cellular population is achieved in the tissue. This process of growth by cell multiplication is known as hyperplasia and is determined by the genetic makeup of the individual organs. The process of development, on the other hand, is one in which the cells obtained through hyperplasia are developed into mature functioning units as a result of deposition of different cellular constituents (e.g., protein and lipid). This process is termed hypertrophy. Therefore, mature cells differ from immature ones in both size and chemical composition. For the brain, the major events in hypertrophy are myelination and synaptogenesis.
Brain cells are mostly diploid, and the amount of DNA in all diploid cells of a given species is constant, with the value being slightly different in different species. For example, the value is 6.2 pg for the rat diploid cells and 6.0 pg in humans. Therefore, the total number of cells in a brain can be determined by dividing its total content of DNA by the value per cell.
Once the number of cells of an organ is known, the weight per cell and the protein content, RNA content, or lipid content per cell can be determined from the total weight of the tissue and the total content of protein, RNA, and so on. These values are used as an approximate measure of the size of the cells of that tissue. An increase in these values indicates an increase in cell size (i.e., hypertrophy). However, the general problem associated with this assumption for the brain tissue lies in the different cell types: One cell type is likely to have an amount of protein or lipid very different from that of another cell type.
Within these limitations, the neurochemical approach has made an important contribution toward our understanding of the general pattern of growth and development of tissues including the brain. Based on these principles, Myron Winick proposed that organs grow and develop in three consecutive phases (Fig. 3). During the first phase, growth proceeds entirely by cell multiplication (hyperplasia alone), with a proportional increase in weight and in protein, RNA, or lipid content, so that the cell size, as measured by weight/DNA or protein/DNA, remains constant. At the end of this phase, the rate of DNA accretion gradually slows, but the accumulation of other constituents continues. This constitutes the second phase of mixed hyperplasia and hypertrophy, in which there is an increase in cell size and a smaller increase in cell number. In the third phase, DNA growth stops altogether and the cells develop by increasing in size by continued synthesis and accumulation of proteins and lipids. This is the phase of hypertrophy. Finally, when net protein or lipid synthesis, and therefore the weight of the cells, is established, the tissue attains the state of maturity.
The scheme proposed for the brain by Davison and Dobbing in terms of growth and development of
Protein/DNA ratio (cell size)
Hyperplasia Hyperplasia Hypertrophy Maturity alone and hypertrophy alone
Figure 3 Relationship between DNA, protein, and protein/DNA ratio during the three phases of tissue growth (reproduced with permission of Oxford University Press).
different types of cells and their associated structures fits well with the general scheme of Winick:
Stage I: Organogenesis and neuronal multiplication (hyperplasia alone?)
Stage II: The brain growth spurt, including
II(a). A maturation period of axonal and dendritic growth, glial multiplication, and myelination (hyperplasia plus hypertrophy)
II(b). a later period of growth in size (hypertrophy alone)
Stage III: The mature, adult state (maturity)
According to this scheme, organogenesis, followed by neuronal multiplication, takes place in the first stage. The brain growth spurt occurs in the second stage. It includes maturation of the axons and dendrites, multiplication of cells, and myelination. The third stage consists almost entirely of continued myelination and increase in tissue size, at the end of which the brain is thought to attain structural maturity.
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