Different groups of neurons are incorporated into different networks of functional activities in the brain known as neuronal systems. If parts of these systems or their connections are lost (as in the case of degeneration or trauma) or are not properly working (as the result of toxins or the transient overexposure to neuro-active compounds), the functional capacity of the system is affected. The neuronal cell acquisition of the human nervous system takes place both before and after birth, and continues in young children up to approximately three years of age. Neuronal networks are formed throughout this period too but continue to be formed up to approximately 18 years of age, i.e. until after puberty, when the nervous system is said to be fully matured. Brain development is an orchestrated process whereby the "birth" of neurons during fetal life is genetically defined, but the differentiation, maturation and organisation of neurons depends on the appearance of other groups of neurons and on molecular signals from non-neuronal cells. Thus, the connectivity of neurons depends on the temporal profile of particular signals. During development, neurons are often born in excess and compete for survival by establishing connections with their targets (see figure 2.1).
64 2 Neurotransplantation and Gene Transfer 105,-
64 2 Neurotransplantation and Gene Transfer 105,-
post-conceptional age (y) Figure 2.1: Prenatal and Life-time Changes of Neuronal Cell Number in the Sexual
Dimorphic Nucleus of the Preoptic Area in Male and Female Humans The curves show the fast acquisition of cells in the perinatal period reaching maximal levels only at the age of three to four years for both sexes, and a maturational period with (normal) cell loss until puberty significantly higher in girls than in boys, leading to an average 5-fold difference (note the logarithmic scale). It is just a single example of the long lasting brain developmental period in humans and the influence - in this case sexual hormones - of factors outside of the CNS. Adapted from Swaab et al. (1992)
The early period of development of the brain is very sensitive to the external factors that may interfere with brain cell activity. It is claimed that any circumstance known to interfere with the functioning of the adult nervous system, when imposed on the developing brain, will (or at least could) alter the functional capacities of the brain permanently (Swaab and Boer 2001). In other words, the regulatory systems of neuronal circuits in the mature brain, the blueprint of which is determined by the genotype, are "set" differently by external factors and experiences during the maturing period. The lasting effects that occur following exposure to neuro-active chemicals present in food, the environment or in medicines and drugs, as well as to external factors like stress, which act on the developing nervous system via endogenous hormonal and neurotransmitter responses, are the result of changes in the cellular make-up, organisation and the synaptic strength of neuronal systems. Pre- and postnatal estrogen exposure modifies later psy-chosexual capacities and gender identity, corticosteroids affect psychomotor behaviour, maternal smoking enhances the incidence of homosexuality amongst female offspring and could be correlated with aggressive behaviour in children of both sexes, neuroleptics impair later learning ability, cocaine impairs later vigilance (detection of actions), and there are more examples to illustrate this interaction (Swaab and Boer 2001). In humans it is difficult to isolate the precise cause of certain characteristics amongst the myriad of stimuli to which a child is exposed. However, as shown above, individual experiences organise the functional capacity of the brain. The knowledge that small changes in the nervous system induced during the perinatal period of brain developmental result in lasting changes to physiology and behaviour, was previously described as behavioural teratology or functional neuroteratology6. Nowadays, this topic also attracts attention in studies on gene-environment interactions as the role of external influences on brain development may be identifiable in the gene expression profiles of nervous structures and may underlie the occurrence or onset of neurological and psychiatric disorders in later life. Above myriad of influences stresses the fact that each brain develops uniquely in its own particular environment, i.e. to its own phenotype. Therefore, the moulding of the nervous system during the development of the brain strongly contributes to the identity and personality of the individual including their capacity to adapt to, or cope with, external challenges.
The influence of external factors on the organisation of the nervous system continues throughout life through self-reorganisation and changes in number and strength of synaptic connections. This process is called brain plasticity. The window of opportunities for these self-adaptive changes of the nervous system is also set during the period of brain development. For instance, the cognitive abilities of humans depend on the level of plasticity in the nervous systems. A professional activity, for example playing music or learning a second language, will modify the organisation of the brain for the performance of these tasks in everyday life. However, not every nervous system has the same capabilities in this respect.
The lesson to learn from all this is that intervention in the brain by cell implantation or the genetic modification of cells will modify the organisation of the brain. Therefore, besides the intended therapeutic effects of an intervention on the neural disorder, lasting collateral functional effects cannot be excluded, and must, perhaps, even be expected. This, however, does not mean that restorative neurosurgery should be ruled out completely, although we must consider these factors when assessing the risks and benefits of a particular treatment. Ideally, any side effects occurring in patients will be very subtle and will not be obvious in normal daily life.
6 This has to be distinguished from classical teratology, i.e., when gross malformations are visible.
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