Neural grafting
One way is to transplant into the damaged brain a new supply of neurons of the missing kind. If the transplanted neurons are themselves taken from a brain at the right stage of development, they will grow in an adult host brain and form new connections, leading at least to a partial restoration of normal function. This has been most convincingly demonstrated in the dopamine system running from the substantia nigra to the caudate-putamen at the base of the forebrain. Destruction of this dopaminergic pathway leads to movement disorders in rats, and to Parkinson’s disease in humans (Hornykiewicz, 1973; Ungerstedt, 1971). Transplants of dopamine cell bodies lead to a clear restoration of some motor functions in the rat (Dunnett et al., 1981), and alleviate some of the symptoms of Parkinson’s disease in human patients (Hagell et al., 1999). If the transplant is made into the site in the substantia nigra where the original dopamine cell bodies would have been located, it will not grow its axons to the original target for the dopamine pathway. So the transplant has to be made into the caudateputamen. This means that the incoming connections to the original dopamine cell bodies will not be made to the transplanted dopamine cell bodies, as these are not where the original cells were located. How do we explain the success of this transplanting procedure? The most plausible explanation is that the implanted dopamine cells make synaptic connections where they can release dopamine in appropriate amounts, although this dopamine release will not be controlled normally by the activities of the remainder of the brain. The success of this procedure also illustrates the key role of dopamine – to enable other neurons in the motor system to operate normally, rather than carrying some specific signals of its own. The dopamine system itself does not seem to give instructions about which muscle to move next.
The capture and transmission of more specific information by transplanted neural tissue has been demonstrated in retina transplant experiments. A retina is transplanted so as to make connections with the brain of a developing rat. In adulthood, the rat can learn to respond to illumination of the transplanted retina as readily as it responds to illumination of its own natural retina (Coffey, Lund & Rawlins, 1989). While these kinds of transplant procedures in no way reconstruct the original circuitry in its entirety, more recent developments offer some hope of coming much closer to this ideal. In these procedures, instead of neurons that have already differentiated into a particular neuronal variety, neuronal stem cells are transplanted. These neuronal precursors have the potential to develop into any kind of neuron. So when they are transplanted into a damaged brain, they migrate to the areas in which cells are missing and form new structures that become integrated into the host brain (Lundberg et al., 1997). It is possible that this kind of technique will result in a far more complete recreation of the missing circuitry (Svendsen & Smith, 1999).
In some birds, the brain region related to memory (the hippocampus) varies in size according to demand. In the Americas, cowbirds parasitize other birds’ nests in the same way that the European cuckoo does, by laying eggs in them to be brought up by foster parents. Successful brood parasites need to know where the hosts’ nests are, and how the egg laying is going in each nest. It is not much use laying your egg after the host’s eggs have been incubated, giving them a head start in the race to hatching, nor is it a good idea to lay your egg before the host has laid any eggs at all. Cowbirds therefore need to keep careful track of what is going on during the breeding season. It is now clear that at this time the cowbird hippocampus increases in size relative to other structures in the brain. In one species of cowbird, only the female keeps track of nest development. In this species, the female’s hippocampus increases in relative size during the breeding season and decreases again afterwards, but the male’s does not. In another species, both male and female keep track of nests, and the hippocampus in both sexes increases for the breeding system. A third species of cowbird is not a brood parasite at all, and in this species the hippocampus shows no sign of growing or shrinking (Reboreda, Clayton & Kacelnik, 1996). In humans, hippocampal damage leads to such a profound amnesia that the patient is more or less incapable of living an independent life. Yet birds appear to need a hippocampus only some of the time. At other times they get rid of it, even though they will have to regrow it next year. Why? It has been suggested to me (by my colleague Professor Sir John Krebs) that the answer lies in energy saving, since the brain uses a great deal of energy, and a reduction in energy load may be vitally important. Small birds in cold climates can lose a significant proportion of their body weight overnight, so even a marginal saving could make a vital difference. Whatever the reason, the bird’s ability provides a striking example of the potential for reforming circuitry in adult brains.
Neurogenesis in adult mammals The potential for neural replacement (neurogenesis) is almost completely absent in the adult mammalian brain – but not entirely absent (Gage, Ray & Fisher, 1995). Intriguingly, one of the two areas of the adult mouse brain that how neurogenesis lies in the dentate gyrus (part of the hippocampus). Elderly mice living in enriched environments show an increase in the numbers of new neurons formed, as well as increased numbers of surviving dentate granule cell neurons (Kemperman, Kuhn & Gage, 1997). Perhaps the mammalian brain more closely parallels the avian brain in its potential for reconstructing central nervous circuitry than we have tended to assume. Recent work shows evidence of neurogenesis in the adult hippocampus of primates, including humans (Eriksson et al., 1998; Kornack & Rakic, 1999). A structural imaging experiment has shown that London taxi drivers – whose job demands an extraordinary knowledge of London streets – have a relatively larger posterior hippocampus compared to age-matched controls (Maguire et al., 2000). The extent of the increase in size correlated with the length of time spent as a taxi driver. It is thus conceivable that constant use of a spatial navigation system has led to growth of the adult human hippocampus, or at least to selective protection from age-related hippocampal shrinkage. One day we may be able to take advantage of this potential, and use it for clinical therapy.
One way is to transplant into the damaged brain a new supply of neurons of the missing kind. If the transplanted neurons are themselves taken from a brain at the right stage of development, they will grow in an adult host brain and form new connections, leading at least to a partial restoration of normal function. This has been most convincingly demonstrated in the dopamine system running from the substantia nigra to the caudate-putamen at the base of the forebrain. Destruction of this dopaminergic pathway leads to movement disorders in rats, and to Parkinson’s disease in humans (Hornykiewicz, 1973; Ungerstedt, 1971). Transplants of dopamine cell bodies lead to a clear restoration of some motor functions in the rat (Dunnett et al., 1981), and alleviate some of the symptoms of Parkinson’s disease in human patients (Hagell et al., 1999). If the transplant is made into the site in the substantia nigra where the original dopamine cell bodies would have been located, it will not grow its axons to the original target for the dopamine pathway. So the transplant has to be made into the caudateputamen. This means that the incoming connections to the original dopamine cell bodies will not be made to the transplanted dopamine cell bodies, as these are not where the original cells were located. How do we explain the success of this transplanting procedure? The most plausible explanation is that the implanted dopamine cells make synaptic connections where they can release dopamine in appropriate amounts, although this dopamine release will not be controlled normally by the activities of the remainder of the brain. The success of this procedure also illustrates the key role of dopamine – to enable other neurons in the motor system to operate normally, rather than carrying some specific signals of its own. The dopamine system itself does not seem to give instructions about which muscle to move next.
The capture and transmission of more specific information by transplanted neural tissue has been demonstrated in retina transplant experiments. A retina is transplanted so as to make connections with the brain of a developing rat. In adulthood, the rat can learn to respond to illumination of the transplanted retina as readily as it responds to illumination of its own natural retina (Coffey, Lund & Rawlins, 1989). While these kinds of transplant procedures in no way reconstruct the original circuitry in its entirety, more recent developments offer some hope of coming much closer to this ideal. In these procedures, instead of neurons that have already differentiated into a particular neuronal variety, neuronal stem cells are transplanted. These neuronal precursors have the potential to develop into any kind of neuron. So when they are transplanted into a damaged brain, they migrate to the areas in which cells are missing and form new structures that become integrated into the host brain (Lundberg et al., 1997). It is possible that this kind of technique will result in a far more complete recreation of the missing circuitry (Svendsen & Smith, 1999).
In some birds, the brain region related to memory (the hippocampus) varies in size according to demand. In the Americas, cowbirds parasitize other birds’ nests in the same way that the European cuckoo does, by laying eggs in them to be brought up by foster parents. Successful brood parasites need to know where the hosts’ nests are, and how the egg laying is going in each nest. It is not much use laying your egg after the host’s eggs have been incubated, giving them a head start in the race to hatching, nor is it a good idea to lay your egg before the host has laid any eggs at all. Cowbirds therefore need to keep careful track of what is going on during the breeding season. It is now clear that at this time the cowbird hippocampus increases in size relative to other structures in the brain. In one species of cowbird, only the female keeps track of nest development. In this species, the female’s hippocampus increases in relative size during the breeding season and decreases again afterwards, but the male’s does not. In another species, both male and female keep track of nests, and the hippocampus in both sexes increases for the breeding system. A third species of cowbird is not a brood parasite at all, and in this species the hippocampus shows no sign of growing or shrinking (Reboreda, Clayton & Kacelnik, 1996). In humans, hippocampal damage leads to such a profound amnesia that the patient is more or less incapable of living an independent life. Yet birds appear to need a hippocampus only some of the time. At other times they get rid of it, even though they will have to regrow it next year. Why? It has been suggested to me (by my colleague Professor Sir John Krebs) that the answer lies in energy saving, since the brain uses a great deal of energy, and a reduction in energy load may be vitally important. Small birds in cold climates can lose a significant proportion of their body weight overnight, so even a marginal saving could make a vital difference. Whatever the reason, the bird’s ability provides a striking example of the potential for reforming circuitry in adult brains.
Neurogenesis in adult mammals The potential for neural replacement (neurogenesis) is almost completely absent in the adult mammalian brain – but not entirely absent (Gage, Ray & Fisher, 1995). Intriguingly, one of the two areas of the adult mouse brain that how neurogenesis lies in the dentate gyrus (part of the hippocampus). Elderly mice living in enriched environments show an increase in the numbers of new neurons formed, as well as increased numbers of surviving dentate granule cell neurons (Kemperman, Kuhn & Gage, 1997). Perhaps the mammalian brain more closely parallels the avian brain in its potential for reconstructing central nervous circuitry than we have tended to assume. Recent work shows evidence of neurogenesis in the adult hippocampus of primates, including humans (Eriksson et al., 1998; Kornack & Rakic, 1999). A structural imaging experiment has shown that London taxi drivers – whose job demands an extraordinary knowledge of London streets – have a relatively larger posterior hippocampus compared to age-matched controls (Maguire et al., 2000). The extent of the increase in size correlated with the length of time spent as a taxi driver. It is thus conceivable that constant use of a spatial navigation system has led to growth of the adult human hippocampus, or at least to selective protection from age-related hippocampal shrinkage. One day we may be able to take advantage of this potential, and use it for clinical therapy.
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