Changes in Basal Forebrain Cholinergic Systems Following Excitotoxic Cell Death in the Hippocampus and Cerebral Neocortex

  • M. V. Sofroniew
  • C. N. Svendsen
  • O. Isacson
Part of the Advances in Behavioral Biology book series (ABBI, volume 38A)


Many areas of the brain that exhibit neurodegenerative changes in Alzheimer-type dementias (DAT) appear to be interconnected via neuronal projections. The severity of pathology in the neocortex correlates statistically with known patterns of intracortical connections (Pearson et al., 1985), and the major affected subcortical regions, such as the nucleus basalis, locus coeruleus and dorsal raphe project prominently to the allo- or neocortex (Saper et al., 1987). Observations such as these have led to suggestions that the degeneration in some regions of the brain might be secondary to loss of neurons in other areas, resulting from a loss of target-derived trophic support (Appel, 1981; Hefti, 1983). The evidence that this might be the case is particularly suggestive for cholinergic neurons of the basal forebrain.


Nerve Growth Factor Cholinergic Neuron Basal Forebrain Medial Septum Nerve Growth Factor Receptor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Appel, S. H., 1981, A unifying hypothesis for the cause of amyotrophic lateral sclerosis, Parkinsonism, and Alzheimer disease, Ann. Neurol., 10, 499.PubMedCrossRefGoogle Scholar
  2. Arendt, T., Bigl, V., Tennstadt, A., and Arendt, A., 1985, Neuroscience, 14, 1.PubMedCrossRefGoogle Scholar
  3. Ayer-LeLievre, C., Olson, L., Ebendahl, T., Seiger, A., and Person, H., 1988, Expression of the beta-nerve growth factor gene in hippocampal neurons, Science, 240, 1339.PubMedCrossRefGoogle Scholar
  4. Cuello, A. C. and Sofroniew, M. V., 1984, The anatomy of the CNS cholinergic neurons, Trends in Neurosciences 7, 74.CrossRefGoogle Scholar
  5. Dawbarn, D., Allen, S. J., and Semenenko, F. M., 1988, Coexistence of choline acetyltransferase and nerve growth factor receptors in the rat basal forebrain, Neurosci. Lett., 94, 138.PubMedCrossRefGoogle Scholar
  6. Etienne, P., Robitaille, Y., Wood, P., Gauthier, S., Nair, N. P. V., and Quirion, R., 1986, Nucleus basalis neuronal loss, neuritic plaques and choline acetyltransferase activity in advanced Alzheimer’s disease Neuroscience,. 19, 1279.PubMedCrossRefGoogle Scholar
  7. Fischer, W., Wictorin, K., Bjorklund, A., Williams, L. R., Varon, S., Gage, F. H., 1987, Amelioration of cholinergic neurons atrophy and spatial memory impairment in aged rats by nerve growth factor, Nature. 329, 65.PubMedCrossRefGoogle Scholar
  8. Gage, F. H., Chen, K. S., Buzsaki, G., Armstrong, D., 1988, Experimental approaches to age related cognitive impairments, Neurobiol. Aging 9 645.PubMedCrossRefGoogle Scholar
  9. Gage, F. H., Wictorin, K., Fischer, W., Williams, L. R., Varon, S., and Bjorklund, A., 1986, Retrograde cell changes in medial septum and diagonal band following fimbria-fornix transection: quantitative temporal analysis, Neuroscience, 19, 241PubMedCrossRefGoogle Scholar
  10. Gähwiler, B. H., Enz, A. and Hefti, F., 1987, Nervre growth factor is involved in the establishment of septo-hippocampal cholinergic projection, Neurosci. Lett., 75, 6.PubMedCrossRefGoogle Scholar
  11. Goedert, M., Fine, A., Hunt, S. P., and Ullrich, A., 1986, Nerve growth factor mRNA in peripheral and central rat tissues and in the human central nervous system: Lesion effects in the rat brain and levels in Alzheimer’s disease, Mol. Brain Res., 1 85.CrossRefGoogle Scholar
  12. Hefti, F., 1983, Is Alzheimer’s disease caused by lack of nerve growth factor? Ann. Neurol.. 13, 109.PubMedCrossRefGoogle Scholar
  13. Hefti, F., 1986, Nerve growth factor promotes survival of septal cholinergic neurons after fimbrial transections, J. Neurosci., 6, 2155.PubMedGoogle Scholar
  14. Hefti, H., Hartikka, J., Eckenstein, F., Gnahn, H., Heumann, R., Schwab, M., 1985, Nerve growth factor (NGF) increases choline acetyltransferase but not survival or fiber outgrowth of cultured fetal septal cholinergic neurons, Neuroscience 14, 55.PubMedCrossRefGoogle Scholar
  15. Hefti, F., Hartikka, J., and Knusel, B., 1989, Function of neurotrophic factors in the adult and aging brain and their possible use in the treatment of neurodegenerative diseases, Neurobiol. Aging 10, 1.CrossRefGoogle Scholar
  16. lsacson, O. and Sofroniew, M. V., 1990, Neurochemical and morphological evidence for remodelling of intrinsic and afferent systems following loss and replacement of cortical neurons, in preparation.Google Scholar
  17. lsacson, O., Wictorin, K., Fischer, W., Sofroniew, M. V., and Bjorklund, A., 1988, Fetal cortical cell suspension grafts to the excitotoxically lesioned neocortex: anatomical and neurochemical studies of trophic interactions, in: Progress in Brain Research, Vol. 78, D. M. Gash and J. R. Sladek, eds, Elsevier, Amsterdam.Google Scholar
  18. Korsching, S., 1986, The role of nerve growth factor in the CNS, Trends Neurosci. 9 570.CrossRefGoogle Scholar
  19. Kromer, L. F., 1987, Nerve growth factor treatment after brain injury prevents neuronal death, Science, 235, 214.PubMedCrossRefGoogle Scholar
  20. O’Brien, T. S., Svendsen, C. N., Isacson, O., and Sofroniew, M. V., 1990, Loss of True blue labelling from the medial septum following transection of the fimbria-fornix: evidence for the death of cholinergic and noncholinergic neurons, Brain Res. in press.Google Scholar
  21. Pearson, R. C. A., Esiri, M. M., Hiorns, R. W., Wilcock, G. K., and Powell, T. P. S., 1985, Anatomical correlates of the distribution of the pathological changes in the neocortex in Alzheimer’s disease, Proc. Nat. Acad. Sci. U.S.A. 82, 4531.CrossRefGoogle Scholar
  22. Pearson, R. C. A., Gatter, K. C., and Powell, T. P. S., 1983a, Retrograde cell degeneration in the basal nucleus in monkey and man, Brain Res., 261, 321.PubMedCrossRefGoogle Scholar
  23. Pearson, R. C. A., Sofroniew, M. V., Cuello, A. C., Powell, T. P. S., Eckenstein, F., Esiri, M. M., and Wilcock, G. K., 1983b, Persistance of cholinergic neurons in the basal nucleus in a brain with senile dementia of the Alzheimer’s type demonstrated by immunohistochemical staining for choline acetyltransferase, Brain Res. 289, 375.PubMedCrossRefGoogle Scholar
  24. Perry, R. H., Candy, J. M., Perry, E. K., Irving, D., Blessed, G., Fairbairn, A. F., and Tomlinson, B. E., 1982, Extensive loss of choline acetyltransferase activity is not reflected by neuronal loss in the nucleus of Meynert in Alzheimer’s disease, Neurosci. Lett. 33, 311.PubMedCrossRefGoogle Scholar
  25. Saper, C. B., Wainer, B. H., and German, D. C., 1987, Axonal and transneuronal transport in the transmission of neurological disease: potential role in system degenerations, including Alzheimer’s disease, Neuroscience. 23, 389.PubMedCrossRefGoogle Scholar
  26. Seiler, M. and Schwab, M., 1984, Specific retrograde transport of nerve growth factor (NGF) from neocortex to nucleus basalis in the rat, Brain Res., 300, 33.PubMedCrossRefGoogle Scholar
  27. Sofroniew, M. V. and Pearson, R. C. A., 1985, Degeneration of cholinergic neurons in the basal nucleus following kainic or n-methyl-D-aspartic acid application to the cerebral cortex in the rat, Brain Res., 339, 186.PubMedCrossRefGoogle Scholar
  28. Sofroniew, M. V., Dunnett, S. B. and lsacson, O., 1990, Remodelling of intrinsic and afferent systems in neocortex with cortical transplants, in: Progress in Brain Research, in press.Google Scholar
  29. Sofroniew, M. V., lsacson, O., and Bjorklund, A., 1986, Cortical grafts prevent atrophy of cholinergic basal nucleus neurons induced by excitotoxic cortical damage, Brain Res., 378, 409.PubMedCrossRefGoogle Scholar
  30. Sofroniew, M. V., Pearson, R. C. A., and Powell, T. P. S., 1987, The cholinergic nuclei of the basal forebrain of the rat: normal structure, development and experimentally induced degeneration, Brain Res., 411, 310.PubMedCrossRefGoogle Scholar
  31. Sofroniew, M. V., Galletly, N. P., Isacson, O., and Svendsen, C. N., 1989, Survival of adult basal forebrain cholinergic neurons after loss of target neurons, Science, in press.Google Scholar
  32. Sofroniew, M. V., Pearson, R. C. A., Eckenstein, F., Cuello, A. C., and Powell, T. P. S., 1983, Retrograde changes in cholinergic neurons in the basal forebrain of the rat following cortical damage, Brain Res., 289, 370.PubMedCrossRefGoogle Scholar
  33. Stephens, P. H., Cuello, A. C., Sofroniew, M. V., Pearson, R. C. A., and Tagari, P., 1985, Effects of unilateral decortication on choline acetyltransferase activity in the nucleus basalis and other areas of the rat brain, J. Neurochem., 45, 1021.PubMedCrossRefGoogle Scholar
  34. Talamo, B. R., 1989, Pathological changes in olfactory neurons in patients with Alzheimer’s disease, Nature, 337, 736.PubMedCrossRefGoogle Scholar
  35. Tuszynski, M. H., Armstrong, D. M., and Gage, 1990, F. H., Basal forebrain cell loss following fimbria/fornix transection Brain Res., in press.Google Scholar
  36. Uchida, Y., Ihara, Y., and Tomonaga, M., 1988, Alzheimer’s disease brain extract stimulates the survival of cerebral cortical neurons from neonatal rats, Biochem. Biophys. Res. Comm., 150, 1263.PubMedCrossRefGoogle Scholar
  37. Whitehouse, P. J., Price, D. L., Struble, R. G., Clark, A. W., Coyle, J. T., and Delong, M. R., 1982, Alzheimer’s disease and senile dementia: loss of neurons in the basal forebrain, Science 215, 1237.PubMedCrossRefGoogle Scholar
  38. Whittemore, S. R., Friedman, P. L., Larhammer, D., Persson, H., Gonzalez-Carvajari, M., and Holets, V. R., 1988, Rat beta-nerve growth factor sequence and site of synthesis in the adult hippocampus, J. Neurosci. Res., 20, 403.PubMedCrossRefGoogle Scholar
  39. Williams, L. R., Varon, S., Peterson, G. M., Wictorin, K., Fischer, W., Bjorklund, A., and Gage, F. H., 1986, Continuous infusion of nerve growth factor prevents basal forebrain neuronal death after fimbria fornix transection, Proc. Nat. Acad. Sci. U.S.A., 83, 9231.CrossRefGoogle Scholar
  40. Zweig, R. M., Schegg, K. M., Peacock, J. H., and Melarkey, D., 1989, A case of Alzheimer’s disease and hippocampal sclerosis with normal cholinergic activity in basal forebrain, neocortex and hippocampus, Neurology, 39, 288.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1990

Authors and Affiliations

  • M. V. Sofroniew
    • 1
    • 2
  • C. N. Svendsen
    • 1
    • 2
  • O. Isacson
    • 1
    • 2
  1. 1.Department of AnatomyUniversity of CambridgeEngland
  2. 2.McLean HosptialHarvard Medical SchoolBostonUSA

Personalised recommendations