Book - Brain and behavioural development 2
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Dickerson JWT. and McGurk H. Brain And Behavioural Development. (1982) Blackie & Son Ltd., Glasgow.
Brain and Behavioural Development - 1982: 1 Neural Development | 2 Comparative Neural | 3 Malnutrition | 4 Hormones and Growth Factors | 5 Cortical Activity | 6 Functional Asymmetry | 7 Plasticity | 8 Sex Differences
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Chapter Two - Comparative Aspects of Brain Growth and Development
Brian L. G. Morgan and John W. T. Dickerson
Growth is traditionally measured as the change in weight of the body and its organs with time. Expressed in this way, the growth curve of the brain in all mammalian species is not linear but follows a sigmoidal pattern (Davison and Dobbing, 1968). The transient period of rapid development represented by such curves is known as the brain growth spurt, and this becomes more apparent when the changes with time are expressed in terms of a velocity, or rate, curve. When expressed in this way, species differences become apparent in the timing of the growth spurt of the brain with respect to a physiological milestone such as birth. Davison and Dobbing suggested that the growth spurt of the brain constituted a ‘vulnerable’ or ‘critical’ period when adverse influences would have their greatest effect on brain growth. It is clear, however, that anatomical, physiological, biochemical and psychological functions of the brain all have a critical period of development when they are maturing at their most rapid rate.
There is no single critical period. The critical period of anatomical development is not the same as the critical period of psychological development. Within each aspect of growth, we also have different critical periods; for instance, the period of most rapid cellular division is not the same as that for the most rapid period of myelination or that when dendritic arborization is maximal. Different regions of the brain may be characterized by a different critical period for a similar function. For example, the maturation of a particular enzyme may occur earlier in the cerebrum than in the cerebellum. All critical periods of growth of the brain occur during intra-uterine life or in the early postnatal period. Further, we find that the order of maturational processes is much the same in all mammalian brains. However, the critical periods of growth in each process may occur at different times in relation to birth, which makes interspecies comparisons difficult. A comparison between brain growth in the rhesus monkey and in the human illustrates this point, as the rhesus monkey’s brain is more mature at birth (Cheek, 1975) than the human brain (Dobbing and Sands, 1973). Hence in order to compare the effects of malnutrition just after birth in the human with the situation in the monkey, we would need to study the effects of malnutrition prenatally in the monkey.
Growth of the brain can occur either by an increase in cell number (hyperplasia), by an increase in cell size (hypertrophy), or by an increase in the amount of extracellular material in the organ. The diploid nuclei of any one species contain a constant amount of DNA which is different from that for any other species (Boivin et al ., 1961; Enesco and Leblond, 1962). In the rat, this is 6.2 picograms and in the human 6.0 picograms. With the exception of a few tetraploid Purkinje cells in the cortices of the cerebrum and cerebellum, all cells in the human brain are diploid (Lapham, 1968). Thus by dividing total brain DNA content by the amount per cell, we can calculate the number of cells. Similarly by estimating total DNA in different anatomical parts of the brain, it is possible to calculate the cell number in each of the different regions. It may be assumed that the proportion of tetraploid cells, particularly in the human brain, is unlikely to be sufficiently large to affect the basic principle.
Neurochemical analyses can provide figures for protein per cell (protein/DNA) and lipid content per cell (lipid/DNA) which with the weight/ DNA ratio give an estimate of cell size. An increase in any of these ratios represents an increase in cell size, whereas an increase in the total amount of DNA in the brain is indicative of an increase in cell numbers.
Thus, whilst total DNA content gives an accurate assessment of cell numbers, it does not differentiate between different cell types in the brain. By using the ratios delineated above, we can also obtain an average figure for cell size. Brain RNA content increases in proportion to the increase in DNA, which maintains an RNA/DNA ratio at a constant level throughout the growing period (Winick and Noble, 1965). The nervous system has many different cell types which can be broadly categorized into glial cells and neurones. The mature rat brain has twice as many glial cells as neurones (Cragg, 1968). Large cerebral neurones differ from small cerebellar neurones. Astrocytes differ from oligodendroglia in size and shape. Those cells associated with the vasculature have yet different dimensions. Furthermore, all of these individual cell types probably have different protein and RNA contents (Winick, 1976).
During gestation in the rat, there is a slow increase in brain weight which at birth is approximately 0.2 g. After birth, the rate of brain growth increases dramatically such that the weight increases several fold during the next 21 days to reach 1.4 g at weaning. We then see a gradual rise in weight to reach a near plateau of 1.8 g at 10 weeks of age. After this time, there is only a small increment in brain growth throughout the life of the animal (Chevallier et al, 1975; Dobbing and Sands, 1971). Brain DNA levels similarly increase rapidly during the first two weeks of life, the rate of accretion reaching its maximum at seven days. Protein accretion mimics brain weight throughout development (Fish and Winick, 1969; Dobbing and Sands, 1971).
Different regions of the brain show different patterns of growth (Fig. 2.1). In the cerebrum of the rat brain, DNA synthesis continues until 21 days postnatally (Fish and Winick, 1969). By this time, the brain has attained about 75 % of its mature weight (Dobbing and Sands, 1971), and the cerebrum accounts for 50% of the total weight (Winick, 1970). After 21 days of life, the cells continue to increase in size by pushing out neuronal processes and so increasing their protein and lipid contents. Total cerebral protein content is achieved at around 65 days of life and brain content at 99 days of age (Fish and Winick, 1969).
Figure 2.1 The total DNA content of the different regions of the brain in rats of different ages (from Winick, 1976, with permission).
The hippocampus has rather unique growth characteristics: on days 14-17 we see an increase in brain cell numbers due to the migration of neurones from under the lateral ventricle into the hippocampus. The hippocampus is also characterized by a postnatal division of its neurones (Altman, 1966; Altman and Das, 1966).
In the cerebellum, DNA synthesis proceeds rapidly for the first 17 days postnatally and then declines rapidly. By 21 days, adult cell numbers are present. At this stage, the cerebellum weighs approximately 15 % of the total brain weight and contains 50 % of the DNA in the whole brain. Thus, the brain’s cellularity is heavily weighted to the cerebellum (Fish and Winick, 1969). A further increase in the DNA content of the cerebellum has been found to occur between 52 and 140 days of age (Dickerson et al , 1972). After day 17, the net protein synthesis also declines for a transient period and the individual cerebellar cell size decreases. This reduction in cell size possibly is an indication of the maturation of larger, more primitive cells into smaller, more mature cells (Winick, 1976).
In the brain stem, cell numbers increase until about 14 days of age (Winick, 1976). After this, there is a great increase in DNA: protein ratios due to the extension of neuronal processes from other brain regions into the brain stem. By day 21, the brain stem accounts for 30% of brain weight (Fish and Winick, 1969).
Neuronal cell division in rat cerebrum ceases before birth (Winick, 1970) whereas in the cerebellum there is a large increase in the microneurone population during the phase of rapid DNA synthesis postnatally. Increases in numbers of granule, basket, stellate and glial cells (Altman, 1966; Altman and Das, 1966) are common to many areas of the brain postnatally.
Less is known of the brain development of other species. In the pig, the most rapid rate of cell division is around birth (Dickerson and Dobbing, 1967). In the miniature swine DNA accumulation is complete by 56 days of age in the cerebrum, 21 days in the cerebellum and 35 days in the brain stem (Badger and Tumbleson, 1975). In the rabbit, the cerebrum and brain stem reach maximum levels by 120 days, and the cerebellum by 75 days (Ftarel et al , 1972). In the guinea pig (Dobbing and Sands, 1970) and monkey (Cheek, 1975), the most rapid rates of division are before birth. Thus both of these animals are more mature at birth than either the rat or man.
In man, brain wet weight increases until about six years of age (Dobbing and Sands, 1973). Patterns of cellular growth have not been delineated as well in the human brain as in the rat brain. Before birth, DNA synthesis is fairly linear. Soon after birth, we see a decline in this rate of accretion but synthesis continues until at least six years of age, and possibly longer. Two peaks of DNA synthesis can be distinguished during the development of the human brain (Fig. 2.2). The first is reached at about 18 weeks of gestation, which corresponds to the maximal rate of neuronal synthesis, and the second peak occurs around birth, which represents the time of most rapid glial cell division (Dobbing and Sands, 1973).
Figure 2.2 (a) Total DNA phosphate, equivalent to total cell number, in the forebrain of human foetuses and infants; (b) A semi-logarithmic plot of the same data as shown in (a). In (b) regression lines with 95% confidence limits are added (redrawn from Dobbing and Sands, 1973, with permission).
Figure 2.3 Total DNA content in the different regions of the human brain during development (from Winick, 1976, with permission).
In man (Fig. 2.3), the forebrain and brain stem DNA levels reach 70% of mature values by two years of life and gradually increase from that point to reach a maximum at six years of life. In the cerebellum, DNA content proceeds more rapidly and achieves adult levels by two years of age. Cellularity in man is also heavily weighted in favour of cerebellum which weighs only 10% of total brain weight but contains 30 % of total brain DNA. Extensive microneurone proliferation occurs postnatally in the cerebellum (Raaf and Kernohan, 1944) and possibly in other areas too until about 20 months of age, in comparison to 2-3 months of life in the rhesus monkey (Rakic, 1971).
Winick (1976) has proposed a theory (Fig. 2.4) to account for growth in the body. He maintains that for any organ of any species, growth can be divided into three phases. In the first, we see a rapid division of cells with cell size remaining constant. In the second, DNA synthesis continues to increase, albeit at a lower rate than before, and protein synthesis maintains its momentum. Hence, there is an increase in cell size and a smaller increase in cell numbers. In the third, there is an increase in cell size as DNA synthesis stops and protein continues to be produced. Growth finally stops when protein synthesis is equal to protein degradation, which is at maturity. Winick emphasizes that there is gradual change from one phase to another in this scheme and a good deal of overlap exists.
Figure 2.4 Changes in brain DNA, protein, and protein/DNA ratios during the periods of cellular growth (from Winick, 1976, with permission).
Dobbing et al. have criticized this theory in a recent publication (Sands et al , 1979). They show that mean cell size increases at an earlier stage than proposed by Winick and quickly reaches a constant level. Furthermore, their results indicate that cell multiplication continues unabated throughout tissue growth until growth comes to an end. These studies were carried out using kidney, liver and heart and results have not as yet been reported for the brain.
The control of both the rate of DNA synthesis and its period of synthesis are largely unknown. Winick and colleagues (Brasel et al , 1970) have demonstrated a correlation between the activity of the enzyme DNA polymerase and the rate of cell division in the whole rat brain and its regions. Thus, the period of hyperplastic growth is accompanied by high activity of enzymes associated with cellular proliferation. There have also been suggestions that the rate of RNA turnover increases in the growing brain. This is accompanied by an increase in the activity per cell of alkaline RNase, an enzyme involved in RNA degradation (Rosso and Winick, 1975). An interesting finding was the presence of two species of cytoplasmic RNA in developing rat brain which disappear at about the time of the cessation of cell division (Lewis and Winick, 1977). Winick and Lewis (1977) have, in fact, implicated a 40 and 34S rRNA in the control of the timing of active cellular proliferation in the rat. These considerations may have important consequences for catch-up growth following a period of nutritional deprivation, a matter which is discussed in Chapter 3.
The polyamines spermidine and spermine, and their precursor, putrescine, participate in many of the processes necessary for nucleic acid and protein synthesis, acting as organic cations by stabilizing the macromolecules and cell organelles involved. In the human brain, the rise in the concentration of spermidine which occurs prior to birth in the cerebellum and brain stem, and perinatally in the forebrain (McAnulty et al ., 1977) corresponds to a period of rapid DNA replication and increase in cell number (Dobbing and Sands, 1973). The concentration of putrescine was also found to reach its peak perinatally. It is of interest that the first phase of the rapid increase in the DNA content of the human brain, corresponding with the period of neuroblast replication, occurred at about the same time as the rapid increase in putrescine concentration. It is postulated that the increase in the concentration of putrescine at the time of extensive neuronal multiplication was due to a rise in the activity of the enzyme ornithine decarboxylase (ODC) which accompanies rapid cell proliferation (Russell, 1970). It is perhaps significant that the concentrations of the ganglioside, G Dla , associated with synaptic growth also increase in the forebrain at this time (Yusuf et al ., 1977).
The brain contains a large amount of lipid in the form of simple lipids such as cholesterol and complex lipids such as phospholipids, glycolipids and other esters which contain various fatty acids. Cholesterol itself is not esterified in the mature brain. The proportion of the total cholesterol that is esterified in the human brain falls from about 5 % in early foetal life in the forebrain and cerebellum to about 1 % at about 200 days gestation with a small rise and subsequent fall during early postnatal life (Yusuf, 1976; see p. 84). The changes in the proportion of cholesterol esters in the brain stem are rather smaller.
The brain lipid content increases gradually during development. As most of the lipid is contained in myelin it is not surprising that the major increase in lipid concentration occurs in white matter during myelination (Davison and Dobbing, 1968). The rate of myelin synthesis in the postnatal period is greater than DNA synthesis which accounts for increased cholesterol/DNA and phospholipid/DNA ratios (Rosso et al ., 1970).
In the human brain, the lipid content is fairly constant until after seven months of gestation when lipid deposition increases in grey matter to reach adult levels by three months of age. Fat deposition continues at a more gradual rate in white matter. By two years of age, 90 % of adult levels have been accumulated and by 10 years, adult levels are achieved. Lipid per cell rises from shortly after birth until at least two years of age (Brante, 1949; Tingey, 1956; Cummings et al , 1958).
In the CNS, myelin is formed from the membranes of oligodendroglial cells and myelination begins after these cells have ceased dividing (Altman, 1969). These glial cells then surround the nerve axons in a spiral fashion and a progressive deposition of lipids occurs within the developing myelin sheath (Bunge, 1968) which results in the transformation of oligodendroglial cell membranes into the specialized adult myelin with its lamellated structure. Pure myelin can be separated from homogenates of nervous tissue by differential centrifugation through sucrose gradients. The adult structure contains 80 % of its dry weight as lipid and myelin does, in fact, account for approximately 50 % of the total lipid of the adult brain. The process of myelination can be studied histologically making use of stains which are specific for the membrane. At present this is the only technique available for the investigation of microscopic areas of the brain. Using this method it has been shown that the myelination of the human brain occurs in cycles with the process starting and proceeding to completion in different areas at different ages from late in gestation through to about 30 years of age (Yakovlev and Lecours, 1967).
Quantitation of the amount of myelin in the brain and descriptions of the process of myelination have been attempted in terms of those lipids that are relatively highly concentrated in the membrane, so-called ‘marker substances’. Cerebroside and cerebroside sulphate are characteristic myelin lipids. Cholesterol is also found in high concentrations in myelin, but it is also present in other cell membranes and whereas cerebroside is not found in the brain before the commencement of myelination, cholesterol is found in the human brain before there is any histological evidence of myelin (Kritchevsky and Holmes, 1962). As already pointed out, the cholesterol found in the mature nervous system, in contrast to that in the plasma, is practically all present in the free state.
It has been estimated that myelin accounts for over 25 % of the weight of the mature brain (Chase, 1976) and evidence from the rate of accumulation of cerebroside sulphatide shows that it accumulates over a relatively short period. Between 34 weeks gestation and term the amount of this lipid in the human brain increases by some 300 to 400 %. The amount rises more rapidly between 12 and 24 weeks of age by which time 50 % of the adult amount is accumulated and the adult amount is probably formed before 4 years of age. Evidence from animal experiments using cholesterol (Dobbing, 1964) or sulphatide (Chase et al , 1967; Ghittoni and Raveglia, 1973) suggests that the early period of myelination may be critical in determining whether the adult amount of myelin is going to be formed. The replication of the oligodendroglial cells whose membranes form myelin is a key factor in the formation of new myelin.
Phospholipids are important constituents of all cell membranes, including myelin. Before birth, the phospholipid pattern of the human forebrain, cerebellum and brainstem is similar with choline phosphoglycerides as the major phospholipids (Yusuf and Dickerson, 1977). After birth the brainstem showed the greatest change in pattern with ethanolamine phosphoglyceride (EPG) becoming dominant. This latter change is probably due to the preponderance of white matter in the brainstem, for EPG accounts for the major proportion of the total phospholipids in white matter (Svennerholm and Vanier, 1972). In myelin isolated from human brain, the ratio of the plasmalogen form of EPG to the diacyl form increases with age (Fishman et al , 1975) with most of the increase occurring in the first year after birth. It could therefore be that the increase in the relative proportion of EPG in the brainstem largely reflects the increase of plasmalogen in myelin.
The lipids of myelin are oriented with respect to the myelin proteins, some of which can be isolated as a complex proteolipid. Proteolipid deposition would appear to follow the same course as cholesterol in rat whole brain (Agrawal et al, 1976). In view of what has been said about the way in which myelin is formed, it is of interest that the amino acid composition of proteolipid protein prepared from the white matter of human foetal or young infant brains contained significantly more aspartic acid, proline, and leucine and significantly less phenylalanine and tyrosine, than that prepared from the brains of patients 18 months of age or older (Prensky and Moser, 1967). The amino acid composition of the younger white matter proteolipid protein was, in fact, similar in composition to that prepared from grey matter at any age. Rat and mouse myelin contain two specific basic proteins which increase during the development of the sheath. The synthesis of these proteins in the mouse appears to reach a peak at about 18 days after birth (Campagnoni et al , 1978).
The principal glycolipids in the brain are cerebrosides and gangliosides. Gangliosides consist of iV-acetylneuraminic acid (NeuNAC), sphingosine and three molecules of either glucose or galactose. A number of different species of gangliosides have been isolated from brain and four of these species constitute the major gangliosides of normal human and rat brain and account together for about 95% of the total ganglioside content (Table 2.1). In the mammalian central nervous system, gangliosides contain 65 % and glycoproteins 32 % of the total NeuNAC, and the rest is free (Brunngraber et al, 1972). The brain has the highest concentration of gangliosides of any tissue in the body with that of grey matter being 15 times as high as that of the liver (Svennerholm, 1970). This represents 5-10% of the total lipid content of some nerve tissue cell membranes (Ledeen, 1978).
Small quantities of glycolipids are found in all cellular and subcellular brain fractions, but the majority are found in the neurones (Suzuki, 1967; Ledeen, 1978). Similarly, while sialoglycoproteins are present in small amounts in glial cells, the bulk once again is bound to neurones (Dekirmenjian et al , 1969).
Table 2.1 Major gangliosides of normal human brain (Svennerholm’s nomenclature). From Dickerson (1981).
4)Glu(l 1 )Cer
Gal(l -► 3)GalNAc(l
4)Glu(l -» l)Cer
Gal(l -> 3)GalNAc(l
-> 4)Gal(l -> 3
4)Glu(l -> l)Cer
G T i
-* 4)Gal(l ->
4)Glu(l -♦ l)Cer
4 - 2)NeuNAC
Gal = galactose
GalNAc = N-acetylgalactosamine Glu = glucose Cer — ceramide
NeuNAC = iV-acetylneuraminic acid
The adult human brain is thought to contain 10 11 neurones. Early studies suggested that neuronal cell bodies accounted for only a small fraction of total grey matter gangliosides (Hamberger and Svennerholm, 1971; Norton and Poduslo, 1971). Later studies showed that by far the largest proportion of the gangliosides is located in the dendritic and axonal plexuses (Hess et al ., 1976). On the basis of the results of studies involving the measurement of ganglioside levels in isolated synaptosomes it has been widely postulated that the synaptic plasma membranes are the major loci of gangliosides (Lapetina et a/., 1968; Dekirmenjian et al ., 1969; Morgan and Winick, 1980a). Recent electron microscopy work by Svennerholm and collaborators has demonstrated without doubt that this view is correct (Svennerholm, 1980). However, we have noted (Table 2.1) that there are several different species of gangliosides in the brain, and it has been suggested that in the rat cerebrum, the microsomal disialo- ganglioside, G Dla , may serve as a marker for dendritic arborization.
Several investigators have studied the ganglioside content of the developing rat brain. Pritchard and Cantin (1962) found a linear increase in the concentration of gangliosides in the grey matter up to 25 days of age. James and Fotherby (1963) observed a similar linear increase in ganglioside NeuNAC in the whole brain between three and 16 days of age. Suzuki (1965) found a rapid increase in the amount of gangliosides at about 10 days of age with no increase after approximately 22 days. Merat and Dickerson (1973) found that the concentration of ganglioside NeuNAC in the forebrain rose rapidly during the interval of 1-21 days after birth, was reduced at three months and subsequently rose to mature values by six months. In the cerebellum, the peak concentration was reached by two months of age and the lowest at nine months (the adult value), while in the brain stem, the concentration rose more slowly and had a broad peak from 15 days to two months. Comparison of the pattern of change in these three parts of the rat brain with the changes in the same three parts of the pig brain (Fig. 2.5; Merat and Dickerson, 1973) shows that the major difference is in the timing of the changes and clearly shows that the brain of the pig develops earlier in relation to birth than that of the rat. This is in agreement with what is known about the timing of the growth spurt, cell replication and myelination of the brain in these two species (Davison and Dobbing, 1966,1968; Dickerson and Dobbing, 1967).
There are also definite changes in the patterns of the different gangliosides (G Mi , G Dla , G Dlb and G Tlb being the main types present in mammalian brain) from one area of the brain to another and from one developmental period to another. In the rat brain, it has been shown that some monosialogangliosides (G M1 ) are converted to disialogangliosides (G Dla and G Dlb ) and trisialoganglio- sides (G xlb ) during development, and that the turnover of gangliosides in the immature animal is more than in the adult (Holm and Svennerholm, 1972).
The timing of the developmental pattern of brain gangliosides established by chemical analysis is similar to that found by histological techniques for the development of neuronal processes. The density of axons increases at a maximal rate between the ages of six and 18 days in the rat, while dendritic density increases maximally between 18 and 24 days (Eayrs and Goodhead, 1959).
It has been suggested that gangliosides play an important role in behaviour (Irwin and Samson, 1971; Dunn and Hogen, 1975; Morgan and Winick, 19806,c). Theoretical models have been proposed in which sialo-compounds are viewed as important constituents in the functional units of neuronal membranes in that they exert an ion binding and releasing function. They may also play a role in the storage and release of neurotransmitters.
Synaptogenesis includes the growth of the presynaptic axon, contact with and ‘recognition’ of the appropriate postsynaptic neurone, replacement of growth cone organelles and assembly at the active zone of pre- and postsynaptic dense material, complete with ion channels and transmitter receptor molecules. There is some evidence to implicate surface glycoproteins incorporated into the synaptic membrane in the recognition process (Rees, 1978). NeuNAC has been shown to be required for the synaptosomal uptake of 5-hydroxytryptamine (serotonin) (Dette and Weseman, 1978). Gangliosides have also been shown to be a key factor in the maintenance of excitability of isolated cerebral tissue (Mcllwain, 1961).
Figure 2.5 The concentration of ganglioside NeuNAc in the forebrain (FB), cerebellum (CB), and brain stem (BS) of the growing rat (a) and pig (b). Values in the forebrain shown A, in the cerebellum shown #, and in the brain stem shown O (from Merat and Dickerson, 1973).
Energy metabolism of the brain varies considerably from birth to old age, as does the blood flow. Data from in vitro brain preparations (Himwich and Fazekas, 1941) and blood-flow measurements from intact animals (Kennedy et al, 1972) give substance to the view that cerebral oxygen consumption is low at birth, rises rapidly with cerebral growth and reaches its maximum level when maturation is completed. A number of enzymes of oxidative metabolism in the brain show a similar rise in level of activity (Sokoloff, 1974).
Blood flow reaches peak values at different times in the different regions of the brain according to the speed of maturation of each region (Sokoloff, 1974). Those regions characterized by high levels of white matter show their highest blood flow when myelination is at its peak. From these high values, we see a gradual decline to mature values with increasing age. The changes in blood flow possibly reflect changes in metabolic rate in the brain.
At six years of age, a child has its maximum cerebral blood flow and oxygen consumption. At this time, the brain tissue is consuming 5.2 ml O 2 /100 g per minute, which means that total brain consumption amounts to 60 ml/min or over half the total body basal oxygen consumption. This is much higher than in the adult and possibly accounts for the extra energy needed to sustain the biosynthetic functions of growth and development of the brain (Kennedy and Sokoloff, 1957; Sokoloff, 1966).
As well as cerebral energy metabolism changing with age and brain development, the nutrients used to sustain oxidative metabolism also change. Just after birth, the rat and human are hypoglycaemic and their blood ketone levels low (Krebs et al , 1971). Milk is high in fat (rat milk is 50% fat on a dry weight basis—Dymsza et al , 1964) and therefore ketogenic, and so as the rat pup begins to suckle, its blood ketone levels rise perhaps 10-fold or more (Krebs et al , 1971). Although human milk is not as high in fat content in comparison to the rat a similar ketogenic state exists in the suckling period.
Ketosis in the young rat pup lasts until it is weaned at 21 days on to a rat chow which is high in carbohydrate and fairly low in fat (Krebs et al, 1971). During the first 21 days of life, the ketones form an important cerebral fuel for energy metabolism (Cremer and Heath, 1974). Similar evidence in the dog (Spitzer and Weng, 1972) and human infant (Persson et al , 1972) has substantiated the importance of ketones.. The enzymes involved in ketone utilization are most active during the early postnatal period and least active in adult life and hence the developing brain has a much greater ability to extract and utilize ketones from the blood. After weaning when ketosis subsides, these enzymes become less active and glucose becomes the major substrate for cerebral energy metabolism (Klee and Sokoloff, 1967; Krebs et al, 1971; Middleton, 1973; Carney et al , 1980).
More recent studies in adult rat brain (Hawkins and Biebuyck, 1979) have suggested that 3-hydroxybutyrate metabolism in the brain is limited by permeability. Furthermore, the permeability characteristics vary from region to region throughout the brain depending on the nature of the blood-brain barrier. These workers suggested that ketone bodies should be considered fuel supplements, rather than substitutes, which partially supply specific areas. If utilization is dependent on the blood-brain barrier, it might be expected that utilization would be more even throughout the brain of the neonate because of its higher metabolic requirements associated with an under-developed barrier.
During the first 30 days of life, more than 50 % of the glucose metabolized by the brain is passed through the hexose monophosphate shunt (Winick, 1970). The hexose monophosphate shunt has two advantages for the developing brain —it supplies firstly ribose molecules for nucleic acid synthesis and secondly TPNH, which is used in lipid synthesis.
The newborn mammalian brain, including the human brain, will withstand hypoxia for a longer period of time than the adult brain (Winick, 1976). This possibly reflects the predominance of glycolysis during the early stages of brain development. After birth, respiration becomes more and more important until it assumes the dominant role in glucose metabolism. This change is gradual and proceeds in a caudocephalic direction from spinal cord to cerebral cortex (Porcellati, 1972).
The rate of glucose utilization in the adult brain of most mammalian species is 0.3-1.0 mmol/kg/min and more than 90% of this glucose is metabolized via glycolysis. Some of the pyruvate formed in this way is converted to lactate, but the majority is further metabolized in the mitochondria by the citric acid cycle to give carbon dioxide and water (Winick, 1976).
The brain utilizes carbon skeletons which arise from glucose metabolism to make glutamate and aspartate by metabolic pathways associated with the citric acid cycle as shown in Fig. 2.6. Alanine is synthesized from pyruvate by transamination, glutamine from glutamate by amidation and aminobutyrate from glutamate by decarboxylation. Without exception these amino acids are in dynamic equilibrium with intermediates of carbohydrate metabolism and hence are able to re-enter the carbohydrate pools and can be oxidized to carbon dioxide and water.
Figure 2.6 Some important pathways of glucose metabolism in the mammalian brain.
Other pathways are present in the brain which bypass certain steps in the Krebs cycle. One such pathway is the y-amino butyrate (GABA) shunt. In this, as shown in the diagram, the succinyl-COA step in the Krebs cycle is bypassed (Lajtha et a/., 1959; McKhann et al , 1960). This pathway may carry a significant share of the flux between a-ketoglutarate and succinate in the citric acid cycle in all species. In the adult guinea pig brain it accounts for 10% of the cortical turnover of glucose (Machiyama et al, 1965). We have no idea at what stage of development this first appears.
Glycogen has a fairly high rate of turnover and is an important part of both neurones and glial cells (Porcellati, 1972), but exactly what role it fulfils in development has yet to be defined.
The unique position of glucose in brain metabolism in the adult brain is partly due to the blood-brain barrier, which impedes entry into the brain of most substrates. Little is known of the development of the blood-brain barrier—we do not know if the barrier develops at the same time for all substrates or whether it develops permeability at different times for different substrates.
There is a high rate of influx of amino acids into the neonatal brain (Seta et al, 1972) which is believed to be due to the absence of a blood-brain barrier (Sessa and Perez, 1975). We also find that extracellular markers such as sucrose and insulin are not impeded in their entry into the neonatal brain in the same way as they are in the adult brain until 16-20 days of age (Bradbury, 1975), which is coincident with the development of intracellular levels of amino acids typical of the mature animal. By three weeks after birth, the brain levels of glutamine and the acidic amino acids increase and the basic and neutral amino acids decrease (Machiyama et al , 1965; Agrawal et al, 1966). This differential effect on transportation of amino acids with maturation is probably due to the development of amino acid transport systems within the blood brain barrier, each of which transports a specific group of amino acids to cater for the brain’s needs for that group independent of the other systems.
Three separate, saturable, stereospecific carrier mediated transport systems exist in the adult brain for neutral, basic and acidic amino acids respectively (Oldendorf and Szabo, 1976). Within each group of amino acids, there is competition so that the transport of one member of a specific group is competitively inhibited by the other members of that group. It has been shown that the adult brain can use these transport systems to concentrate amino acids against a tissue gradient. These processes are very susceptible to oxygen and metabolic inhibitors which restrict the flow of amino acids (Guroff et al, 1961; Tsukada et al, 1963; Neame, 1964).
The amino acids essential to the brain, namely L-phenylalanine, L-tyrosine, L- leucine, L-valine, L-methionine and L-threonine, are transported more efficiently than the non-essential amino acids mentioned previously such as L-aspartate and L-glutamate (Oldendorf, 1971; Banos et al, 1973). The brain seemingly takes up all amino acids except taurine; the branched chain amino acids are transported more rapidly than the others (Felig et al, 1973). However, the transport systems have a limited capacity to transport significant quantities of amino acids into the brain. They have low maximal transport capacities and are saturated at quite low concentrations. Arterial blood concentrations of amino acids are also low. In combination these phenomena limit the availability of amino acids for brain metabolic processes (Sokoloff et al, 1977).
Amino acids reaching the brain are utilized for amine neurotransmitter synthesis (the development of the enzymes involved having been well defined— Winick, 1976), protein synthesis and to a limited extent for energy production. Amino acids of the same species as those endogenously synthesized as a byproduct of glucose metabolism may be taken up from the blood and similarly oxidized (Sokoloff et al, 1977). The essential amino acids can also be oxidized by brain tissue.
In vitro brain slices oxidize branched chain amino acids, such as leucine, valine and isoleucine, to carbon dioxide at a similar rate to the kidney, liver and diaphragm (Swaiman and Milstein, 1965; Odessey and Goldberg, 1972). In fact, more than 90 % of the leucine taken up by tissue slices is oxidized and less than 10% goes to protein synthesis (Odessey and Goldberg, 1972; Chaplin et al,. 1976).
The change in amino acid transport capacity demonstrated by the developing brain is one mechanism by which amino acid supply of the maturing brain may be lowered. The similarity in the decrease in protein synthesis and this reduced transport suggests an important role of amino acid supply in controlling protein synthesis in neonatal brain (Winick, 1976).
Proteins are important constituents of all tissues, and are closely involved in metabolism as enzymes, in transport and as structural components. In association with lipids, proteins regulate the properties of membranes and the interchange of ions and molecules both within cells and between cellular and extracellular fluid. Many proteins are being formed continually throughout life and rapid alterations occur even within the diurnal variation of a single day- one theory of memory involves changes in ribonucleic acid (RNA) bases and consequently in protein synthesis (Hyden and Egyhazi, 1964). The complexity of the proteins of the brain therefore makes it impossible to consider a ‘critical’, or ‘vulnerable’ period in brain protein development.
The amount of total protein in the brain continues to increase after the number of cells has reached its mature value. The consequent increase in the protein : DNA ratio is therefore a reflection of the increase in the average size of the cells. The accumulation of protein in the human brain is probably linear from the sixth month of gestation until the second postnatal year and subsequently decreases.
In experimental animals it is possible to study protein synthesis by measuring the rates of incorporation of radioactively labelled amino acids into brain proteins. Studies of this sort have shown that protein synthesis is more active in the immature than in the mature brain (Winick, 1976). Moreover the average half-life of proteins in rat brain increases with age due to the synthesis of more protein with a longer turnover time. Thus, if individual proteins are considered, it has been estimated that some have a half-life of only 3 or 4 days compared with a mean of 17 days. The half-life of in vivo protein synthesis in the human brain is not known but Winick has estimated that if this is assumed to be 14 days there is an overall synthesis of four grams of protein per day.
The decline with age in the in vivo incorporation of amino acids occurs at the same time as a reduction in the in vitro capacity of brain ribosomes to synthesize peptide chains in cell free systems (Yamagami and Mori, 1970; Andrews and Tafa, 1971). Recently it has been shown that polyribosomes prepared from rat brains of different ages have similar activities in w7ro-(Fellous et al , 1974). This suggests that the reduced potential for protein synthesis in adult rat brains may be due to a loss of polyribosome aggregates and an increased inactive monosome population. As yet, the reasons for this are not clearly defined. It could be due to a reduced activity of tRNA, tRNA amino acid synthesis and other elongation factors (the pH 5 fraction of enzymes) in the older brain (Fellous et al , 1974). On the other hand, there may be a reduced quantity of these soluble factors which would lead to a reduced incorporation of the supernatant postmitochondrial fraction obtained from neonatal as opposed to foetal rat brains (Gilbert and Johnson, 1974). Brain tRNA and amino acyl-t- RNA synthetase activity do not seem to change with brain development (Johnson, 1969) but EF1 is rate limiting in brain cell free systems (Girgis and Nicholls, 1972).
Animal models and human brain development
Because of the difficulty in obtaining human tissue, most information relating to human brain development must be extrapolated from studies on other mammals. Different species have different life spans, and we have no way of telling whether a day in the life of a rat is really equivalent to a month in the life of a human (Donaldson, 1908). Furthermore, this may be true at one period of life but not at another. Thus, using time as a gauge of developmental age of the brain is of little value.
Figure 2.7 The rate of increase in weight with age as a percentage of adult weight for various mammalian species. The units of age for the different species are as follows: guinea pig (days); sheep (5 days); rhesus monkey (4 days); man (months); rat (days); rabbit (2 days); pig (weeks) (from Dobbing and Sands, 1979, with permission).
Dobbing and colleagues (Dobbing and Sands, 1979) have drawn up growth velocity curves for the brain in a number of species (Fig. 2.7). These curves enable us to divide different mammals into prenatal, perinatal and postnatal brain developers from the positions of their peak velocities or growth spurts relative to the time of birth: birth itself has little or no effect on the developmental processes. The relative size of the area beneath the curve on either side of birth enables one to compare the fraction of the growth spurt that occurred before birth with that occurring postnatally. As stated earlier, this growth spurt constitutes a period when the brain is particularly vulnerable to adverse stimuli (Dobbing, 1974).
When comparing the effects of an adverse stimulus on the brain growth of an animal with that expected in a human, we can apply an equivalent degree of stimulus on the animal for an equivalent portion of the vulnerable period, to that experienced in the human, and in this way we should get an indication of the effect on overall brain growth in the human. Using this approach all animal models are of equal value in elucidating any effect on human brain growth (Dobbing and Sands, 1979). However, as we have stated before, the brain growth spurt is not a homogeneous event. Every region and every developmental process going on in that particular region has a different growth spurt. Hence, to compare the effects of a stimulus on a particular developmental process in a particular anatomical area of the brain and make cross-species extrapolations necessitates knowing the exact timing of the rate of maximal development of the particular process being examined. Winick and co-workers have been responsible for gathering a good deal of basic data on hyperplasia and hypertrophy in different brain regions. But we still lack sufficient knowledge of the development of a large number of such processes and so, although the concept of critical periods of brain growth is a good one, it is not always possible to use it to gain insight to all phases of human brain growth.
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Brain and Behavioural Development - 1982: 1 Neural Development | 2 Comparative Neural | 3 Malnutrition | 4 Hormones and Growth Factors | 5 Cortical Activity | 6 Functional Asymmetry | 7 Plasticity | 8 Sex Differences
Cite this page: Hill, M.A. (2019, October 16) Embryology Book - Brain and behavioural development 2. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Book_-_Brain_and_behavioural_development_2
- © Dr Mark Hill 2019, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G