Choline-Induced Spatial Memory Facilitation Correlates with Altered Distribution and Morphology of Septal Neurons

  • Rebekah Loy
  • D. Heyer
  • C. L. Williams
  • W. H. Meck
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 295)


Within the basal forebrain is a population of magnocellular neurons that provides cholinergic innervation to the hippocampus, olfactory bulb, amygdala and cortex. Extensive lesion and pharmacological studies in animals and humans support the hypothesis that these basal forebrain cholinergic neurons, in particular the medial septal nucleus (MSN) and the vertical nucleus of the diagonal band of Broca (DBv), and the nucleus basalis (NB), which project to the hippocampus and neocortex, respectively, have an important role in memory function. Memory loss associated with Alzheimer’s disease correlates highly with degeneration of NB neurons and with reduction of cortical acetylcholinesterase and choline acetyltransferase (ChAT) activities (Whitehouse et al., 1982; Bartus et al., 1985). In addition, lesions of MSN/DBv and/or NB in rodents, or selective blockade of cholinergic activity by muscarinic receptor antagonists in either animal or human subjects, elicit learning and memory deficits (Davies, 1985; Meck et al., 1987).


Nerve Growth Factor Basal Forebrain Nucleus Basalis Nerve Growth Factor Receptor ChAT Activity 
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  1. Arimatsu, Y., and Miyamoto, M., 1989, Colocalization of NGF receptor immunoreactivity and [3h]GABA uptake activity in developing rat septum/diagonal band neurons in vitro, Neyrosci Lett., 99:39.CrossRefGoogle Scholar
  2. Ashkenazi, A., Ramachandran, J., and Capon, D.J., 1989, Acetylcholine analog stimulates DNA synthesis in brain- derived cells by a specific muscarinic receptor subtype. Nature, 340:146.PubMedCrossRefGoogle Scholar
  3. Auburger, G., Heumann, R., Heilweg, R., Korsching, S., and Thoenen, H., 1987, Developmental changes of nerve growth factor and its mRNA in the rat hippocampus: comparison with choline acetyltransferase, Dev. Biol., 120:322.PubMedCrossRefGoogle Scholar
  4. Bartus, R.T., Dean, R.L. III., Goas, J.A., and Lippa, A.S., 1980, Age-related changes in passive avoidance retention: Modulation with dietary choline, Science, 209:301.PubMedCrossRefGoogle Scholar
  5. Bartus, R.T., Dean, R.L., Pontecorvo, M.J. and Flicker, C., 1985, The cholinergic hypothesis: A historical overview, current perspective, and future directions, Ann. N.Y. Acad. Sci., 444:332.PubMedCrossRefGoogle Scholar
  6. Ben-Barak, J. and Dudai, Y., 1979, Cholinergic binding sites in rat hippocampal formation: properties and ontogenesis. Brain Res, 166:245.PubMedCrossRefGoogle Scholar
  7. Chandler, C.E., Parsons, L.M., Hosang, M., and Shooter, E.M., 1984, A monoclonal antibody modulates the interaction of nerve growth factor with PC 12 cells, J. Biol. Chem. 259:6882.PubMedGoogle Scholar
  8. Daitz, H.M., and Powell, T.P.S., 1954, Studies of the connexions of the fornix system, J. Neuro. Neurosurg. Psychiat., 17:75.CrossRefGoogle Scholar
  9. Davies, P., 1985, A critical review of the role of the cholinergic system in human memory and cognition. Ann. N.Y. Acad. Sci., 444:212.PubMedCrossRefGoogle Scholar
  10. Dreyfus, C.F., Bernd, P., Martinez, J.H., Rubin, S.J., and Black, I.B., 1989, GABAergic and cholinergic neurons exhibit high-affinity nerve growth factor binding in rat basal forebrain, Exper. Neurol., 104:181.CrossRefGoogle Scholar
  11. Fischer, W., Wictorin, K., Bjorklund, A., Williams, L.R., Varon, S., and Gage, F.H., 1987, Amelioration of cholinergic neuron atrophy and spatial memory impairment in aged rats by nerve growth factor, Nature, 329:65.PubMedCrossRefGoogle Scholar
  12. Goldschmidt, R.B., and Steward, 0., 1980, Time course of increases in retrograde labeling and increases in cell size of entorhinal cortex neurons sprouting in response to unilateral entorhinal lesions, J. Comp. Neurol., 189:359.PubMedCrossRefGoogle Scholar
  13. Gould, E., Farris, T.W., and Butcher, L.L, 1989, Basal forebrain neurons undergo somatal and dendritic remodeling during postnatal development: a single-section Golgi and choline acetyltransferase analysis, Devel. Brain Res., 46:297.CrossRefGoogle Scholar
  14. Hefti, F., 1986, Nerve growth factor promotes survival of septal cholinergic neurons after fimbrial transections, J. Neurosci., 6:2155.PubMedGoogle Scholar
  15. Hefti, F., and Werner, W.J., 1986, Nerve growth factor and Alzheimer’s disease, Ann. Neurol., 20:275.PubMedCrossRefGoogle Scholar
  16. Hendrickson, A., and Dineen, J.T., 1982, Hypertrophy of neurons in dorsal lateral geniculate nucleus following striate cortex lesions in infant monkeys, Neurosci. Lett., 30:217.PubMedCrossRefGoogle Scholar
  17. Higgins, G.A., Koh, S., Chen, K.S., and Gage, F.H., 1989, NGF induction of NGF receptor gene expression and cholinergic neuronal hypertrophy within the basal forebrain of the adult rat. Neuron, 3:247.PubMedCrossRefGoogle Scholar
  18. Hunt, S., and Schmidt, J., 1978, Some observations on the binding patterns of a-bungarotoxin in the central nervous system of the rat. Brain Res., 157:213.PubMedCrossRefGoogle Scholar
  19. Hunt, S., and Schmidt, J., 1979, The relationship of a-bungarotoxin binding activity and cholinergic termination within the rat hippocampus. Neurosci, 4:585.CrossRefGoogle Scholar
  20. Johnson, E.M.Jr., Taniuchi, M., Clark, H.B., Springer, J.E., Koh, S., Tayrien, M.W., and Loy, R., 1987, Demonstration of the retrograde transport of nerve growth factor receptor in the peripheral and central nervous system, J. Neurosci., 7:923.PubMedGoogle Scholar
  21. Koh, S., Chang, P., Collier, J.T., and Loy, R., 1989, Loss of NGF receptor immunoreactivity in basal forebrain neurons of aged rats: correlation with spatial memory impairment. Brain Res.. 498:397.PubMedCrossRefGoogle Scholar
  22. Koh, S., and Loy, R., 1988, Age-related loss of nerve growth factor sensitivity in rat basal forebrain neurons. Brain Res.. 440:396.PubMedCrossRefGoogle Scholar
  23. Koh, S., and Loy, R., 1989, Development of NGF-sensitive rat basal forebrain neurons and their afferent projections to hippocampus and cortex, J. Neurosci., 9:2999.PubMedGoogle Scholar
  24. Kornack, D.R., Lu, B., and Black, I.B., 1989, Sexually dimorphic expression of the NGF receptor gene in rat brain. Soc. Neurosci, Abs., 15:954.Google Scholar
  25. Kordower, J.H., Gash, D.M., Bothwell, M., Hersh, L., and Mufson, E.F., 1989, Nerve growth factor receptor and choline acetyltransferase remain colocalized in the nucleus basalis (Ch4) of Alzheimer’s patients, Neurobiol. Aging, 10:67.PubMedCrossRefGoogle Scholar
  26. Large, T.H., Bodary, S.C., Clegg, D.O., Weskamp, G., Otten, U., and Reichardt, L.F., 1986, Nerve growth factor gene expression in the developing rat brain. Sciencer 234:352.CrossRefGoogle Scholar
  27. Levi-Montalcini, R., and Booker, R., 1960, Excessive growth of the sympathetic ganglia evoked by a protein isolated from mouse salivary glands, Proc. Natl. Acad. Sci., 46:373.PubMedCrossRefGoogle Scholar
  28. Lipton, S.A., Frosch, M.P., Phillips, M.D., Tauck, D.L., and Aizenman, E., 1988, Nicotinic antagonists enhance process outgrowth by rat retinal ganglion cells in cultures. Science, 239:1293.PubMedCrossRefGoogle Scholar
  29. Lipton, S.A., and Kater, S.B., 1988, Neurotransmitter regulation of neuronal outgrowth, plasticity and survival. Trends in Neurosci.A 12:265.CrossRefGoogle Scholar
  30. Loy, R., Heyer, D., Clagett-Dame, M., and DiStefano, P.S., 1989, Localization of NGF receptor in human basal forebrain using two new monoclonal antibodies: comparison of normal and Alzheimer brains, Soc. Neurosci. Abs. 15:1364.Google Scholar
  31. Loy, R., and Sheldon, R.A., 1987, Sexually dimorphic development of cholinergic enzymes in the rat septohippocampal system. Dev, Brain Res./ 34:156.CrossRefGoogle Scholar
  32. Loy, R., Tayrien, M.W., and Springer, J., 1985, Sexual dimorphism in regional muscarinic receptor binding in rat hippocampus, Anat. Ree., 211:100A.Google Scholar
  33. Mandel, R.J., Gage, F.H., and Thai, L.J., 1989, Spatial learning in rats: correlation with cortical choline acetyltransferase and improvement with NGF following NBM damage, Exp. Neurol., 104:208.PubMedCrossRefGoogle Scholar
  34. Meek, W.H., and Church, R.M., 1987, Nutrients that modify the speed of internal clock and memory storage processes, Behav. Neurosci., 101:465.CrossRefGoogle Scholar
  35. Meek, W.H., Church, R.M., Wenk, G.L., and Olton, D.S., 1987, Nucleus basalis magnocellularis and medial septal area lesions differentially impair temporal memory, J. Neurosci., 7:3505.Google Scholar
  36. Meek, W.H., Smith, R.A., and Williams, C.L., 1988, Pre- and postnatal choline supplementation produces long-term facilitation of spatial memory, Devel. Psychobiol., 21:339.CrossRefGoogle Scholar
  37. Meek, W.H., Smith, R.A., and Williams, C.L., 1989, Organizational changes in cholinergic activity and enhanced spatial memory as a function of pre- and/or postnatal choline supplementation, Behav. Neurosci 103:1234.Google Scholar
  38. Meek, W.H., and Williams, C.L., 1990, Choline supplementation during pre- and postnatal development eliminates proactive interference in spatial memory, Devel. Brain Res. in press.Google Scholar
  39. Milner, T.A., Loy, R., and Amaral, D.G., 1983, An anatomical study of the development of the septo-hippocampal projection in the rat. Dev. Brain Res., 8:343.CrossRefGoogle Scholar
  40. Mizumori, S.J., Patterson, T.A., Sternberg, H., Rosenzweig, M.R., Bennett, E.L., and Timiras, P.S., 1985, Effects of dietary choline on memory and brain chemistry in aged mice. Ngyroliql, Aging, 6:51.CrossRefGoogle Scholar
  41. Morris, R.G.M., 1984, Development of a water-maze procedure for studying spatial learning in the rat, J. Neurosci. Meth., 11:47.CrossRefGoogle Scholar
  42. Mufson, E.J., Bothwell, M.A., and Kordower, J.H., 1989, Loss of nerve growth factor receptor-containing neurons in Alzheimer’s disease: a quantitative analysis across subregions of the basal forebrain, Exper. Neurol., 105:221.CrossRefGoogle Scholar
  43. Nadler, J.V., Matthews, D.A., Cotman, C.W., and Lynch, G.S., 1974, Development of cholinergic innervation in the hippocampal formation of the rat. II. Quantitative changes in choline acetyltransferase and acetylcholinesterase activities. Develop. Biol., 36:142.PubMedCrossRefGoogle Scholar
  44. Paxinos, G., and Watson, C., 1986, The Rat Brain in Stereotaxic Coordinates, Second Edition. Academic Press, Orlando, FL.Google Scholar
  45. Pearson, R.C.A., Sofroniew, M.V., and Powell, T.P.S., 1984, Hypertrophy of immunohistochemically identified cholinergic neurons of the basal nucleus of Meynert following ablation of the contralateral cortex in the rat. Brain Res, 311:194.PubMedCrossRefGoogle Scholar
  46. Pearson, P.C.A., Sofroniew, M.V., and Powell, T.P.S., 1985, Hypertrophy of cholinergic neurones of the rat basal nucleus following section of the corpus callosum. Brain 338:337.CrossRefGoogle Scholar
  47. Rinne, J.O., Paljarvi, L., and Rinne, U.K., 1987, Neuronal size and density in the nucleus basalis of Meynert in Alzheimer’s disease, J. Neurol. Sci, 79:67.PubMedCrossRefGoogle Scholar
  48. Rotter, A., Field, P.M., and Raisman, G., 1979, Muscarinic receptors in the central nervous system of the rat. III. Postnatal development of binding of [3H]propylbenzilylcholine mustard. Brain Res., Rev., 1:185.CrossRefGoogle Scholar
  49. Shelton, D.L., Nadler, J. V., and Cotman, C.W., 1979, Development of high affinity choline uptake and associated acetylcholine synthesis in the rat fascia dentata. Brain Res, 163:263.PubMedCrossRefGoogle Scholar
  50. 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
  51. Springer, J.E., Koh, S., Tayrien, M.W., and Loy, R., 1987, Basal forebrain magnocellular neurons stain for nerve growth factor receptors: correlation with cholinergic cell bodies and effects of axotomy, J. Neurosci. Res, 17:111.PubMedCrossRefGoogle Scholar
  52. Taniuchi, M., and Johnson, E.M. Jr., 1985, Characterization of the binding properties and retrograde axonal transport of a monoclonal antibody directed against the rat nerve growth factor receptor, J. Cell Biol, 101:1100.PubMedCrossRefGoogle Scholar
  53. Toran-Allerand, D., and MacLusky, N.J., 1989, Co-localization of NGF and estrogen receptors: implications for the basal forebrain, Soc. Neurosci. Abs. 15:954.Google Scholar
  54. Tucker, R.W., Meade-Cobun, K., and Ferris, D., 1990, Cell shape and increased free cytosolic calcium [Ca2+]i induced by growth factors. Cell Calcium. 11:201.PubMedCrossRefGoogle Scholar
  55. Vogels, O.J.M., Broere, C.A.J., Ter Laak, H.J., Ten Donkelaar, H.J., Nieuwenhuys, R., and Schulte, B.P.M., 1990, Cell loss and shrinkage in the nucleus basalis of Meynert complex in Alzheimer’s disease, Neurobiol. Aging, 11:3.PubMedCrossRefGoogle Scholar
  56. 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
  57. Whittemore, S.R., Ebendal, T., Larkfors, L., Olson, L., Sciger, A., Stromberg, I., and Persson, H., 1986, Developmental and regional expression of ß-nerve growth factor messenger RNA and protein in the rat central nervous system, Proc. Natl. Aqad. Sci.. 83:817.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Rebekah Loy
    • 1
  • D. Heyer
    • 1
  • C. L. Williams
    • 2
  • W. H. Meck
    • 2
  1. 1.Department of NeurologyUniversity of RochesterRochesterUSA
  2. 2.Departments of PsychologyBarnard College and Columbia UniversityNew YorkUSA

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