Mapping movements within a moving motor map

news he topographic arrangement of T cortical neurons controlling Mappingmovementswithina moving body movements might have the capacity to rearrange itself in motormap adults. By systematically mapping the sites across the rat motor cortex that elicit movement of various body parts both before and after imposing small perturbations, two groups have recently found that the movement map of the primary motor cortex can change 1,2. During the past decade, the long-held belief that the cortical representation of the sensory periphery is hard wired in adults has become less and less tenable. When considering the cortical representation of a given peripheral focus, we must now take into account the reorganizing capacity within the primary sensory areas of adult animals. The pliability in cortical sensory maps was first identified within the primary somatosensory cortex but since then comparable reorganizations have also been demonstrated within the primary visual and auditory cortex 3-6. Common to each of these is a change in the responsiveness of cortical neurons to incoming signals. The two recent findings in the rat motor cortex 1,2 not only identify the potential for cortical plasticity within yet another cortical field but, more importantly, show that a change can be induced in cortical output as well as in cortical receptive areas. Instead of relying upon multi-unit recordings, these new observations are based upon one of the oldest, though perhaps the most relevant 7, indicator of motor cortex output: stimulation-elicited movements. Nudo, Jenkins and Merzenich 1 focus on the forelimb and vibrissal representations within the rat motor cortex by mapping the movements elicited by brief trains of intracortical microstimulation (ICMS) pulses applied in a series of microelectrode penetrations that span these regions. After the initial mapping procedure, repetitive ICMS is applied for an extended interval (1-3 hours) near the center of one of the representations, and then the cortex is carefully re-mapped. The repetiTINS, VoL 14, No. 6, 1991

tive ICMS application causes a dent on long feedback loops, either C. Asanuma change in the movement map with through the spinal cord or the Laboratoryof an enlargement in the represen- periphery 1. Second, it is likely that Neurophysiology, tation of the movement elicited at the changes do not reflect a 're- NIMH,NIHAnimal the stimulated site (Fig. 1). In the wiring' of the cortical circuitry. In Center,Poolesville, stimulated cortex, the border be- both studies, the changes occur MD 20837, USA. tween the forelimb and vibrissal within hours and decay fairly representations shifts by as much rapidly. Decades ago, surface recording as 670 pm (a distance considerably smaller than the head of a pin, and/or stimulation methods estabbut nevertheless substantial when lished functional localization within the overall size of these motor the cortex and provided toporepresentations in the rat is con- graphic maps of these functions. Not only have these established sidered). A comparable shift follows ionto- maps proliferated recently, with phoretic applications of the GABA their images (often mirror images) antagonist bicuculline into the reflected in additional cortical same zone of rat motor cortex 2. In regions, but some, which seemed the latest of a series of studies well entrenched, have repeatedly examining motor cortex changes undergone partition 1°-12. Now, following various perturbations in more and more, these maps seem both developing and adult rats 8, to be becoming elusive, turning, as Jacobs and Donoghue find that it were, into moving targets under when bicuculline is infused into the onslaught of repeated microan identified movement represen- electrode penetrations. What are tation such as the forelimb zone we to conclude from these most (Fig. 1), subsequent ICMS map- recent revelations concerning the ping reveals that stimulation in pliability of cortical motor maps? nearby sites that originally elicited At the very least these studies vibrissa movements now gives rise point to a capacity of considerable to forelimb movements z. Thus, clinical significance towards effecalthough the perturbation is quite tively rehabilitating localized different from that used in the trauma victims (indeed, significant study by Nudo et al., the con- post-traumatic alterations in the sequences are strikingly similar. cortical influence over spinal motoIn addition to identifying the phenomenon, these studies provide some clues concerning the A B neural substrates underlying these changes. First, it seems likely that the changes are due to an intrai.: !.:. .... cortical mechanism. Of course, one would expect the bicuculline infusions e to have principally local effects on the intrinsic GABA circuits that are known to be present / ICMS \ / in the cortex 9, but this seems to be bicuculline also true of the changes following repetitive intracortical stimulation. Current levels below the threshold Fig. 1. Transient map changes in the rat motor cortex needed to elicit movements are resulting from repetitive ICMS or bicuculline application. apparently sufficient to effect the (A) Control (B) Repetitive ICMS or bicuculline application changes in the repetitive ICMS in the forefimb representation results in an enlargement of the forelimb representation, with forelimb movements experiments. This implies that the elicited from sites previously representing the vibrissa or observed changes are occurring the neck. The changes can be identified within hours, and locally within the cortex rather are transient. Shaded zones represent dual representation than at a distance, and are depen- sites. 217

neurons have recently begun to be detected in amputeesX3). However, beyond this, they remind us that a view of the cortex as a static array of hard-wired, parallel circuits is blatantly in error. The mobility now demonstrated in the motor cortex map not only proves that the potential for change is not unique to the primary sensory cortical areas, but suggests that this dynamic capacity is a ubiquitous property of the adult neocortex.

Selected references 1 Nudo, R. J., Jenkins, W. M. and Merzenich, M. M. (1990)Somatosens. Motor Res. 7, 463-483 2 Jacobs, K. M. and Donoghue, J. P. (1991) Science 251,944-947 3 Merzenich, M. M. and Kaas, J. H. (1982) Trends Neurosci. 5, 434-436 4 Kaas, J. H. et al. (1990) Science 248, 229-231 5 King, A. J. and Moore, D. R. (1991) Trends Neurosci. 14, 31-37 6 Kaas, J. H. (1991) Annu. Rev. Neurosci. 14, 137-167 7 Lemon, R. (1988) Trends Neurosci. 11,501-506

8 Sanes, J. N. and Donoghue, J. P. Exp. Brain Res. (in press) 9 Naegele, J. R. and Barnstable, C. J. (1989) Trends Neurosci. 12, 28-34 10 Woolsey, C. N., ed. (1981) Cortical

Sensory Organization, Vol. 1: Multiple Somatic Areas, Humana Press 11 Woolsey, C. N., ed. (1981) Cortical Sensory Organization, VoL 2: Multiple Visual Areas, Humana Press 12 Woolsey, C. N., ed. (1982) Cortical Sensory Organization, VoL 3: Multiple Auditory Areas, Humana Press 13 Hall, E. J., Flament, D., Fraser, C. and Lemon, R. N. (1990) Neurosci. Lett. 116, 379-386

into a category of fairly common human mutations in which there is deamination of a methylated cytoa genetic mutation resurfaced when sine 5' to a guanine. Based upon a Bias Frangione and his collabor- polymorphism that differs between ators in the Netherlands found the families and is located less than a point mutation that changed a 20 kilobases away, it is very unguanine to a cytosine; this mu- likely that the two families are tation caused a glutamic acid to related. glutamine substitution at position Given the conservative nature of 22 of the ]3-amyloid protein in the mutation, demonstrating that Dutch patients with hereditary cer- the valine to isoleucine transition is ebral hemorrhage and amyloidosis sufficient to cause the disease will (see Ref. 8, and also the article by require the preparation of transJ. Haan, J. A. Hardy and R. A. C. genic animals; this is probably the Roos in this issue, p. 231). While highest priority of most laboramost cases of this disease show tories researching Alzheimer's neither the entire spectrum of disease around the world at presAlzheimer changes nor display ent. Given the linkage data, it is dementia, these patients do pre- also possible that another mutation cipitate ]3-amyloid protein in the in the ]3-amyloid precursor in these walls of their cerebral vessels - a families is causative. Since the defect which predisposes them to disease is heterogeneous and the cerebral hemorrhage. anonymous probe site on chromoThese findings, as well as the some 21 does not appear to be suggestion of non-allelic hetero- linked to the disease in some geneity among cases of familial families, there will also be an Alzheimer's disease 9, led the intensive search for additional group at St Mary's Hospital Medi- mutations, such as those found for cal School in London to examine prion diseases 1°. It is clear from additional families and discover a the cases of Down syndrome that cytosine to thymine transition at [3-amyloid deposition can occur base pair 2149 in one of these without a mutation. In these cases families1. This transition results in over expression is likely to be a valine to isoleucine substitution sufficient for the deposition; this within the predicted intra-mem- idea reinforces the current embranous portion of the /3-amyloid phasis on processing of the preprecursor near (but not within) the cursor. carboxy-terminus of the 13-amyloid With the discovery of a mutation peptide. The mutation creates a in the ]3-amyloid precursor locus in BcII restriction site; this allowed two families, it seems increasingly its rapid detection in family mem- likely that the neuritic lesions of bers and the demonstration of its Alzheimer's disease, including the co-segregation with Alzheimer's neurofibrillary tangles, result from disease by linkage analysis. Among injury induced by [3-amyloid dean additional 18 families screened, position. However, the brain can one other family with the same withstand a large amyloid burden defect was detected. Both the without any apparent clinical imindex family and the second family pairment. Once dystrophic neurshow early onset of Alzheimer's ites form around senile plaques disease. The mutation might fall and elsewhere in the neuropil,

Alzhdmerplaquesand tangles:advanceson both fronts Kenneth $. Kosik Deptof Neurology, HarvardMedical Schooland Centerfor NeurologicDiseases, Deptof Medicine (Divisionof Neurology), Brigham and Women'5 Hospital Boston, MA02115, USA,

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he classical pathology of Alzheimer's disease continues to T provide a fertile basis for a modern molecular understanding of the disease process. Important recent discoveries concerning a mutation of the amyloid precursor protein that may cause the disease in two families 1, and the unraveling of the paired helical filament (PHF) 2 underscore the value of investigations based upon the known hallmarks of the disease - the senile plaques and neurofibrillary tangles. The pace of Alzheimer research quickened when George Glenner provided the first sequence of the [3-amyloid protein, the material deposited in the core of the senile plaque 3. The amino acid sequence was sufficient to prepare oligonucleotide probes and clone the cDNA encoding the precursor of the 13-amyloidprotein 4-6. When the site of the gene for this precursor was located on chromosome 21, there was great excitement in the field. It seemed that a genetic basis for the disease had been identified, since patients with Down syndrome or trisomy 21 have long been known to develop invariably the neuropathological features of Alzheimer's disease. The discovery of linkage between this gene on chromosome 21 and the occurrence of Alzheimer's disease in several large kindreds further heightened the excitement 7. However, it was soon shown that the anonymous probes used to link Alzheimer's disease to a site on chromosome 21 were millions of bases away from the [3-amyloid precursor gene locus. Interest in the 13-amyloid precursor protein as a primary site of

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TINS, VOI. 14, No. 6, 1991