Abstract
THE cholinergic system plays a crucial role in learning and memory. Lesions of cholinergic nuclei1-4, pharmacological manipulations of cholinergic systems5-8, intracerebral transplantation of fetal tissue9-11 and anatomical changes in cholinergic pathways during ageing 12-14 have all been correlated with altered cognitive behaviour. However, it has not been proved that regional acetylcholine is causally required for learning and memory. Here we describe how we achieved a permanent and selective impairment of learning and memory by damaging the nucleus basalis magno-cellularis, a nucleus that provides the major cholinergic innervation of the neocortex15,16, in adult rats. To test the hypothesis that acetylcholine is essential for restoration of cognitive function, we implanted genetically modified cells that produce acetylcholine17 into denervated neocortical target regions. After grafting, rats with increased neocortical acetylcholine levels showed a significant improvement in a spatial navigation task. Acetylcholine is thus not only necessary for learning and memory, as previously argued, but its presence within the neocortex is also sufficient to ameliorate learning deficits and restore memory following damage to the nucleus basalis.
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References
Alkon, D. L. et al. Brain Res. Rev. 16, 193–220 (1991).
Dekker, A. J., Connor, D. J. & Thal, L. J. Neurosci. Biobehav. Rev. 15, 299–317 (1991).
Page, K. J., Everitt, B. J., Robbins, T. W., Marston, H. M. & Wilkinson, L. W. Neuroscience 43, 457–472 (1991).
Berger-Sweeney, J. et al. J. Neurosci. 14, 4507–4519 (1994).
Decker, M. W. & McGaugh, J. L. Synapse 7, 151–168 (1991).
Murray, C. L. & Fibiger, H. C. Neuroscience 14, 1025–1032 (1985).
Mandel, R. J. & Thal, L. J. Psychopharmacologica 96, 421–425 (1988).
Mandel, R. J., Gage, F. H. & Thal, L. J. Behav. Brain Res. 31, 221–229 (1989).
Dunnett, S. B. et al. Neuroscience 16, 787–797 (1985).
Gage, F. H. & Björklund, A. J. Neurosci. 6, 2837–2847 (1986).
Nilsson, O. G., Shapiro, M. L., Gage, F. H., Olton, D. S. & Björklund, A. Expl Brain Res. 67, 195–215 (1987).
Perry, E. K. et al. Br. med. J. 2, 1457–1459 (1978).
Whitehouse, P. J. et al. Science 215, 1237–1239 (1982).
Bartus, R. T., Dean, R. L., Beer, B. & Lippa, A. S. Science 217, 408–416 (1982).
Fibiger, H. C. Brain Res. Rev. 4, 327–388 (1982).
Mesulam, M. M., Mufson, E. J., Wainer, B. H. & Levey, A. I. Neuroscience 10, 1185–1201 (1983).
Fisher, L. J. et al. J. Neumchem. 61, 1323–1332 (1993).
Connor, D. J., Langlais, P. J. & Thal, L. J. Brain Res. 555, 84–90 (1991).
Arendt, T. et al. Neuroscience 33, 435–462 (1989).
Boegman, R. J., Cockhill, J., Jhamandas, K. & Beninger, R. J. Neuroscience 51, 129–135 (1992).
Dunnett, S. B., Everitt, B. J. & Robbins, T. W. Trends Neurosci. 14, 494–501 (1991).
Girod, R. et al. J. Neurosci. (in the press).
Freed, W. J., Poltorak, M. & Becker, J. B. Expl. Neurol. 110, 139–166 (1990).
Gage, F. H. & Fisher, L. J. Neuron 6, 1–12 (1991).
Muir, J. L., Page, K. J., Sirinathsinghji, D. J. S., Robbins, T. W. & Everitt, B. J. Behav. Brain Res. 57, 123–131 (1993).
Grant, S. G. N. & Silva, A. J. Trends Neurosci. 17, 71–75 (1994).
Takahashi, J. S., Pinto, L. H. & Viaterna, M. H. Science 264, 1724–1733 (1994).
Bliss, T. V. P. & Collingridge, G. L. Nature 361, 31–39 (1993).
Paxinos, G. & Watson, C. The Rat Brain in Stereotaxic Coordinates (Academic, New York, 1986).
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Winkler, J., Suhr, S., Gage, F. et al. Essential role of neocortical acetylcholine in spatial memory. Nature 375, 484–487 (1995). https://doi.org/10.1038/375484a0
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DOI: https://doi.org/10.1038/375484a0
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