LONDON - Transplants of cells into the brain, a strategy already tried with some success to treat the neurodegenerative disorder Parkinson's disease, may not be enough on its own to restore function. A recent study in rats suggests retraining may be necessary so that, in effect, the animal has to "learn to use the transplant."
Apart from Parkinson's disease, cell transplant strategies are being considered for a range of conditions, including Huntington's disease, Alzheimer's disease and spinal cord injury. The latest results suggest that transplanting cells and getting them to grow and perhaps secrete neurotransmitters or other substances will not alone be sufficient to rectify the deficiencies created by these diseases.
Researchers in the UK have been studying this problem by observing rats that have received experimental damage to the striatum of the brain, but on one side only. One of the main functions of the striatum is learning new stimuli and how to respond to them. Rats that have received a lesion in the striatum on the right side of the brain fail to respond to a stimulus presented on their left side, and vice versa.
Stephen Dunnett, at the Department of Experimental Biology at the University of Cambridge in the UK, and his colleagues used this phenomenon to help them study the effects of cell grafts transplanted into the lesion sites. Their results are reported in the Aug. 31, 1999, Proceedings of the National Academy of Sciences in a paper titled, "Associative plasticity in striatal transplants."
They worked with rats trained to carry out a task in order to receive a food reward. The rats were presented with an array of nine holes into which they could poke their noses. Each animal had to poke its nose into the center hole, and wait. After a variable time delay, a brief light flash occurs in one of the two holes to the side of the rat. Once the rat has poked its nose into this hole, it receives a food reward at the back of the cage.
Rats that had the striatum destroyed on one side of the brain can perform this task only if the response is on the same side of the body. This is because the descending nerve pathways passing through the striatum cross over at the level of the brain stem to control movement on the other side of the body.
Before surgery, the animals were trained to obtain the food rewards by responding to flashes on both their right and their left. They were then divided into three groups: those that had lesions damaging the striatum of the brain on one side (the lesion group); those that had such lesions but which had also been given grafts of embryonic striatal cells (the graft group); and those that had been given sham lesions and sham grafts (the control group).
After surgery, the rats were given free access to food and water for four months. They were then put on a diet in which they were given only 90 percent of the food normally required (to make them hungrier than usual), and given further training. Half of each group was given 30 daily sessions where the light flashed only on the opposite side to the surgery (the impaired contralateral side), and then 30 daily sessions where the light flashed only on the same side as the surgery (the unimpaired ipsilateral side). The remaining animals had 30 daily sessions in which the light flashed only on the same side to the surgery, followed by 30 daily sessions where the light flashed only on the opposite side.
The aim was to find out whether giving the animals prior training on the (unimpaired) ipsilateral side subsequently improved their performance when the light flashed on the (impaired) contralateral side.
The results showed that rats receiving transplants were unable to perform the task on the contralateral side when first retested, but that if they were trained with a flash on the contralateral side each day for 30 days, they showed a "marked recovery."
Dunnett told BioWorld International, "Animals which have a lesion on one side have a massive deficit on the opposite side of their bodies, and that deficit is permanent. When we put the grafted animals back in to this test situation, they were as deficient as the lesioned animals, but as we trained them, they quickly recovered."
Summarizing their results in PNAS, Dunnett and his co-authors wrote, "Only specific training on the impaired contralateral side conferred functional benefit. These results suggest that graft maturation and integration is insufficient by itself to mediate recovery on this task unless specific, extensive training subsequently is undertaken." The results are consistent, they added, with the hypothesis that the restoration of appropriate anatomical connections is necessary but not sufficient for the restoration of normal striatal function.
The area of the brain involved here, Dunnett explained, is concerned with the motor control of skills, such as riding a bicycle, that require whole sets of motor procedures that must be learned and remembered, even if they subsequently become automatic. He told BioWorld International, "Having a lesion in this part of the brain means that you not only abolish the ability to do the task but everything the animal had learned before. When a viable graft becomes established, it is not simply sufficient for the graft to connect up, the whole system has to be retrained in the basic habits and skills that the lesion caused to be lost."
The implications for clinical trials of therapies involving such grafts, he added, are that "we need not only to get the surgery right, we also need to get the training and rehabilitation right."