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Acetylcholine Revisited Were Effective Does Suggest That the Observed Effect Was Due to Ach Release Anders Bjorklund and Stephen B

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Acetylcholine Revisited Were Effective Does Suggest That the Observed Effect Was Due to Ach Release Anders Bjorklund and Stephen B NEWS AND VIEWS COGNITIVE FUNCTION------------------------------ bearing the choline acetyltransferase gene Acetylcholine revisited were effective does suggest that the observed effect was due to ACh release Anders Bjorklund and Stephen B. Dunnett and activation of cholinergic receptors in the area surrounding the transplants. This IF impaired cortical cholinergic function afferent neuronal connections. is compatible with studies in which deficits associated with damage to the basal fore­ This brings us to what the new studl associated with forebrain cholinergic brain cholinergic neuron system is in­ can tell us about the normal role of the damage are alleviated by cholinomimetic strumental in dementia-related cognitive forebrain cholinergic system in cognitive drugs such as physostigmine or tacrine. declinel,2, then restoration of forebrain function. Interpretation of the data of Moreover, non-cholinergic drugs that act cholinergic neurotransmission might be Winkler et al. is by no means straightfor­ to enhance cortical function in a more enough to improve at least some aspects of ward in this respect. There is the question general way can provide a similar recovery impaired learning and memory, particu­ of specificity at three levels- whether the of the behavioural deficits associated with larly in conditions such as Alzheimer's functional deficit induced by excitotoxic NBM lesions and other types of cho­ 11 12 disease. The neurotransmitter acetylcho­ NBM lesions (and, by inference, in linergic blockade • . This suggests that a line (ACh) is suspected to be an important Alzheimer's dementia) is indeed cho­ pharmacological reversal of deficits acting participant in the maintenance of normal linergic, cortical and cognitive in nature, at the neocortical level can be mediated cognitive function, but it is not clear to which may not be the case. In fact, neither by as-yet rather ill-defined processes of what extent deficits seen after basal fore­ the lesion nor the behavioural task used in 'cognitive enhancement', and does not brain lesions can be attributed to loss of this study indicates a degree of specificity necessarily indicate that the underlying cortical cholinergic neurotransmission. that would allow any firm conclusions. deficit is itself cholinergic. An alternative Detailed analysis of the damage in­ explanation for the present results could Recovery duced by injections of excitotoxic amino be that, rather than acting as a replace­ Now, on page 484 of this issue, Winkler acids into the NBM has shown that both ment for the lost cholinergic innervation, et al. 3 show that, in rats, supplying ACh to cholinergic and non-cholinergic neurons ACh secreted by the engineered cell grafts the fronto-parietal cortex, achieved by are affected and that ibotenic acid, the acts in the host neocortex to promote the transplantation of fibroblasts engineered toxin used here, damages pallidal neurons animal's ability to compensate for the 7 to release ACh in a constitutive manner, as much as cholinergic neurons . Indeed, lesion-induced injury. can alleviate behavioural deficits induced more selective injury to NBM cholinergic by excitotoxic lesions of the forebrain neurons by quisqualic acid, AMP A or the Message cholinergic neurons located in the nucleus saporin-192-IgG immunotoxin is associ­ Although the mechanisms underlying basalis magnocellularis (NBM). On the ated with minimal deficits in the water­ behavioural recovery after brain damage basis of their results, the authors propose maze task, even though cholinergic de­ are complex, this should not distract from that the presence of ACh in the neocortex nervation of the neocortex is more exten­ the central message of Winkler et al., 8 9 could be essential for the recovery of sive than that caused by ibotenic acid · . namely that genetically engineered cells spatial memory. The available evidence thus favours the can be used to provide a local supply of This study is of particular interest in that view that the deficits in water-maze learn­ biologically active molecules to an it is the first to use cells engineered by ex ing seen after NBM lesions in the rat are as affected brain region in order to promote vivo gene transfer techniques to explore likely to be attributable to damage in functional recovery and repair. This the role of cholinergic mechanisms in efferent pathways of the neostriatum as of approach should provide new ex­ functional recovery after damage to the cholinergic projections to the neocortex, perimental tools for cell transplantation in central nervous system. The results are and are as likely to involve some form of animal disease models and offers promise important for two reasons. First, func­ sensorimotor dysfunction or attentional for the development of prospective res­ tional recovery was obtained by implants disturbance as any impairment in cogni­ torative therapies of brain damage and 10 of cells that secrete ACh locally in a tive function . This issue needs a wider neurodegenerative disease. D non-regulated, constitutive manner, repertoire of behavioural tasks, as well as whereas the NBM lesions are known to more specific cholinergic lesions, before it Anders Bjorklund is in the Department of disrupt long-distance connections from can be resolved. Medical Cell Research, University of Lund, subcortical areas and remove synaptic We can conclude, therefore, that the S-223 62 Lund, Sweden. Stephen B. regulation of intrinsic cortical circuits. behavioural deficits in NBM-lesioned rats Dunnett is in the MRC Cambridge Centre Second, recovery was seen after focal may not be purely cholinergic, nor entire­ for Brain Repair, and the Department of placements of the ACh cell transplants ly cortical, nor cognitive in nature. But the Experimental Psychology, University of into the fronto-parietal cortex (six on each available data indicate that local supply of Cambridge, Cambridge CB2 2PY, UK. side), whereas the non-ACh-producing ACh to the denervated cortex is sufficient control cells had no effect. This observa­ to promote significant functional recovery 1. Drachman, D. A. & Sahakian, B. J. in The Psychobiology tion, which is consistent with results from in this model. Previous studies using trans­ ofAging: Problems and Perspectives (ed. Stein, D.) 34 7-368 (Elsevier, Amsterdam, 1980). intracortical transplants of cholinergic plants of developing forebrain cholinergic 2. Coyle,J. T., Price, D. L. &Delong, M. R. Science219, neuroblasts from the fetal basal neurons from rat embryos were based on 1184-1190 (1983). 6 forebrain4- , suggests that local ACh the idea that fetal cholinergic neurons may 3. Winkler, J., Suhr, S. T., Gage, F. H., Thai, L. J. & Fisher, L. J. Nature375, 484--487 (1995). delivery to restricted areas of the neo­ be able to substitute both structurally and 4. Fine, A., Dunnett, S. B., Bjorklund, A. & Iversen, S.D. cortex may be sufficient to induce signifi­ functionally for the lost cholinergic affe­ Proc. natn. Acad. Sci. U.S.A. 82,5227-5230 (1985). 5. Dunnett, S. B. eta/. Neuroscience16, 787-797 cant functional recovery in this model. rents in NBM-lesioned animals. The new (1985). These findings are pertinent to our un­ results suggest that impulse-dependent, 6. Hodges, H. eta/. Neuroscience45, 587-607 (1991). 7. Page, K. J. eta/. Neuroscience43, 457-472 (1991). derstanding of the mechanisms of sub­ regulated synaptic release may not be 8. Dunnett, S. B., Everitt, B. J. &Robbins, T. W. Trends cortical cholinergic regulation of cortical necessary for ACh to induce functional Neurosci.14, 494-501 (1991). function: in particular, they suggest that recovery. 9. Gallagher, M. &Colombo, P. J. Curr. Opin. Neurobiol. 5, 161-168 (1995). cortical circuits may depend upon diffuse In fact, Winkler et al. 's genetically en­ 10. Whishaw, I. Q., Mittleman, G., Bunch, S. T. &Dunnett, cholinergic activation to sustain their basic gineered fibroblasts release ACh (and S. B. Behav. Brain Res. 24,125-138 (1987). 11. Sarter, M., Bruno, J.P. & Dudchenko, P. function, rather than upon temporally or choline) in a non-regulated, constitutive Psychopharmacology101, 1-17 (1990). spatially patterned inputs relayed via manner. The fact that only the fibroblasts 12. Mondadon, C. Behav. Brain Res. 59,1-9 (1993). 446 NATURE · VOL 375 · 8 JUNE 1995 .
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