Evolution of Cholinergic Cortical Innervation after nbM-Lesioning (An Experimental Alzheimer Model)

  • Adolfo Toledano


The social and economic transcendence of Alzheimer’s disease (AD) leads to an increasing interest in basic and clinical research on this neurodegenerative disorder. Scientific research programs on AD are continuously expanding and the number of AD-related publications and scientific meetings are multiplying year by year.


Cholinergic Neuron Basal Forebrain Nucleus Basalis Alzheimer Model Neurobiol Aging 
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. Alheid GF, Heimer L (1988): New perspectives in basal forebrain organization of special relevance for neuropsichiatric disorders: the striatopallidal, amygdaloid and corticopetal components of substantia innominata. Neuroscience 27:1–39CrossRefGoogle Scholar
  2. Armstrong DM, Benzing WC, Evans J, Terry RD, Shields D, Hansen LA (1989): Substance P and somatostatin coexists within neuritic plaques. Implications for the pathogenesis of Alzheimer’s disease. Neuroscience 31:663–671CrossRefGoogle Scholar
  3. Balazs R, Jorgensen OS, Hack N (1988) N-methyl-D-aspartate promotes the survival of cerebellar granule cells in culture. Neuroscience 27:437–451CrossRefGoogle Scholar
  4. Bartus RT (1988): The need for common perspectives in the development and use of animal models for age-related cognitive and neurodegenerative disorders Neurobiol Aging 9:445–451CrossRefGoogle Scholar
  5. Bartus RT, Dean RL, Beer B, Lippa AS (1982): The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408–417CrossRefGoogle Scholar
  6. Bartus RT, Dean RL, Pontecorvo MJ, Flicker C (1985) a: The cholinergic hypothesis: a historical overview, current perspective, and future directions. In: Memory Dysfunctions: An Integration of Animal and Human Research from Preclinical and Clinical Perspective Olton DS, Gamzu E, Corkin S, eds. (Ann NY Acad Sci Vol. 444) New York: The New York Academy of Sciences Press, pp. 332–358Google Scholar
  7. Bartus RT, Dean RL, Flicker C (1987): Cholinergic Psychopharmacology: an integration of human and animal research on memory. In: Psychopharmacology: The Third Generation of Progress, Metzler HY, ed. New York: Raven Press, pp. 219–232Google Scholar
  8. Bartus RT, Flicker C, Dean RL, Pontecorvo M, Figueiredo JC, Fisher Sk (1985)b: Selective memory loss following nucleus basalis lesions: long term behavioral recovery despite persistent cholinergic deficiencies. Pharmacol Biochem Behav 23:125–135CrossRefGoogle Scholar
  9. Bartus RT, Pontecorco MJ, Flicker C, Dean RL, Figueiredo JC (1986): Behavioral recovery following bilateral lesions of the nucleus basalis does not occur spontaneously. Pharmacol Biochem Behav 24:1287–1292CrossRefGoogle Scholar
  10. Bear MF, Carnes KM, Ebner FF (1985): Investigation of cholinergic circuitry in cat striate cortex using acetylcholinesterase histochemistry. J Comp Neurol 234:411–430CrossRefGoogle Scholar
  11. Bennett-Clarke CA (1988): Cortical projections from somatostatin neurons of the basal forebrain in the rat. Soc Neurosci Abst 81:8–8Google Scholar
  12. Bertoni-Freddari C, Guiuli C, Pieri C, Paci D (1986): Quantitative investigation of the morphological plasticity of synaptic function in rat dentate gyrus during aging. Brain Res 366:187–192CrossRefGoogle Scholar
  13. Bigil V, Woolf NJ (1982): Cholinergic projections from the basal forebrain to frontal, parietal, temporal, occipital and cingulate cortices: a combined fluorescent tracer and acetylcholinesterase analysis. Brain Res Bull 8:727–749CrossRefGoogle Scholar
  14. Briegon A, Greenberger V, Segal M (1984): Quantitative histochemistry of brain acetylcholinesterase and learning rate in the aged rat. Neurobiol Aging 7:215–217CrossRefGoogle Scholar
  15. Buell SJ, Coleman PD (1979): Dendritic growth in the aged human brain and failure of growth in senile dementia. Science 206:854–856CrossRefGoogle Scholar
  16. Butcher LL, Woolf NJ (1986): Central cholinergic systems: synopsis of anatomy and overview of physiology and pathology. In: The Biological Substrates of Alzheimer’s Disease, Scheibel AB, Weschler AF, Brazier MAB, eds. Orlando, San Diego: Academic Press, pp. 73–86Google Scholar
  17. Casamenti F, Di Patre PL, Bartolini L, Pepeu B (1988): Unilateral and bilateral nucleus basalis lesions: differences in Neurochemical and behavioural recovery. Neuroscience 24:209–215CrossRefGoogle Scholar
  18. Chrobak JJ, Hanin I, Schmechel DE, Walsh THJ (1988): AFG4A-induced working memory impairment: behavioral, neurochemical and histological correlates Brain Res 463:107–117CrossRefGoogle Scholar
  19. Chui HCW, Bondareff CZ, Slager U (1984): Stability of neuronal number in the human nucleus basalis of Meynert with age. Neurobiol Aging 5:83–88CrossRefGoogle Scholar
  20. Collertpn D (1986): Cholinergic function and intellectual decline in Alzheimer’s disease. Neuroscience 19:1–28CrossRefGoogle Scholar
  21. Coyle JT, Price DL, Delong MR (1983): Alzheimer’s disease: A disorder of cortical cholinergic innervation. Science 219:1184–1190CrossRefGoogle Scholar
  22. Crawley JN, Wenk GL (1989): Co-existence of galanin involved in memory processes and dementia? Trends Neurosci 12:278–281CrossRefGoogle Scholar
  23. Davies P (1979): Neurotransmitter-related enzymes in senile dementia of the Alzheimer type. Brain Res 171:319–327CrossRefGoogle Scholar
  24. De Belleroche J, Gardiner IM, Hamilton MH, Birdsall JM (1985): Analysis of muscarinic receptor concentration and subtypes following lesion of rat substantia innominata. Brain Res 340:201–209CrossRefGoogle Scholar
  25. Deutsch JA (1971): The cholinergic synapse and the site of memory. Science 174:788–794CrossRefGoogle Scholar
  26. Dohanich GP, McEven BS (1986): Cholinergic limbic projections and behavioral role of basal forebrain nuclei in the rat. Brain Res Bull 26:477–482CrossRefGoogle Scholar
  27. Drachman DA, Leavitt J (1974): Human memory and the cholinergic system. Arch Neurol 30:113–121CrossRefGoogle Scholar
  28. Dreyfus CF, Bernd P, Martinez HJ, Rubin SJ, Black IB (1989): GABergic and cholinergic neurons exhibit high-affinity nerve growth factor binding in rat basal forebrain. Exp Neurol 104:181–185CrossRefGoogle Scholar
  29. Dunnett SB, Whisham IO, Jones GH, Bunch SF (1987): Behavioral, biochemical and histochemical effects of different neurotoxic amino acids injected into nucleus basalis magnocellularis of rats. Neuroscience 20:653–669CrossRefGoogle Scholar
  30. El-Defrawy SR, Coloma F, Jhamandas K, Boegman RJ, Beninger RJ, Wirxhing BA (1985): Functional and neurochemical cortical cholinergic impairment following neurotoxic lesions of the nucleus basalis magnocellularis in the rat. Neurobiol Aging 6:325–330CrossRefGoogle Scholar
  31. El-Defrawy SR, Coloma F, Jhamandas K, Boegman RJ, Shipton L (1986): Lack of recovery of cortical cholinergic function following quinolic or ibotenic acid injections into the nucleus basalis magnocellularis in rats. Exp Neurol 91:628–633CrossRefGoogle Scholar
  32. Ellmans GL, Courtney KD, Andres V, Featherstone RM (1961): A new and rapid colerimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95CrossRefGoogle Scholar
  33. Fisher RS, Buchwald NA, Hull CD, Levine MS (1988): GABAergic basal fore-brain neurons project to the neocortex: The localization of glutamic acid decarboxylase and choline acetyltransferase in feline corticopetal neurons. J Com Neurol 272:489–502CrossRefGoogle Scholar
  34. Fonnum F (1975): A rapid radiochemical method for the determination of choline acetyltransferase. J Neurochem 24:407–409CrossRefGoogle Scholar
  35. Freund TF, Antal M (1988): GABA-containing neurons in the septum control inhibitory interneurons in the hippocampus. Nature 36:170–173CrossRefGoogle Scholar
  36. Gage FH, Batchelor P, Chen KS, Chin D, Higgins GA, Koh S, Deputy S, Rosenberg MB, Fisher W, Bojörklund A (1989): NGF receptor reexpresion and NGF-mediated cholinergic neuronal hypertrophy in the damaged adult neostriatum. Neuron 2:1177–1184CrossRefGoogle Scholar
  37. Gage FH, Bojörklund A, Stenevi U (1983): Reinnervation of the partially deaffer-ented hippocampus by compensatory collateral sprouting from aparent cholinergic and adrenergic afférents. Brain Res 268:27–37CrossRefGoogle Scholar
  38. Gajdusek DC (1987): A new recognized mechanism of pathogenesis in Alzheimer’s disease, Amyotrophic Lateral Sclerosis, and other degnerative neurological diseases: the beta-fibriloses of brain. In: Nutrition, Health and Peace, Jarillawa RJ, Schowoebel SL, eds. Palo Alto: Linus Pauling Institute, pp. 21–55Google Scholar
  39. Gardiner IM, De Belleroche J, Prom BK, Hamilton MH (1987): Effect of lesion of the nucleus basalis of rat on acetylcholine release in cerebral cortex. Time course of compensatory events. Brain Res 407:263–271CrossRefGoogle Scholar
  40. Gower AJ (1986): Lesioning of the nucleus basalis in the rat as a model of Alzheimer’s disease. Trends Pharmacol Sci 12:432–434CrossRefGoogle Scholar
  41. Goyal RK (1989): Muscarinic receptor subtypes: physiology and clinical implications. New Engl J Med 321:1022–1029CrossRefGoogle Scholar
  42. Greiner HE, Haase AF, Seyfried CA (1988): Neurochemical studies on the mechanism of action of pyritinol. Pharmacopsychiat 21:26–32CrossRefGoogle Scholar
  43. Haroutunian V, Davis KL, Davis Bm, Horvath PP, Johns CA, Morhs RC (1985): The study of cholinomimetics in Alzheimer’s disease and animal models. In: Psychopharmacology: Recent Advances and Future Prospects; Iversen SD, ed. Oxford, New York: Oxford University Press, pp. 218–259Google Scholar
  44. Haroutunian V, Kanof PD, Davis KL (1986a): Partial reversal of lesion induced deficits in cortical cholinergic markers by nerve growth factor. Brain Res 386:397–399CrossRefGoogle Scholar
  45. Haroutunian V, Kanof PD, Tsuboyama GK, Campbell GA, Davis KL (1986b): Animal models of Alzheimer’s disease: behavior, pharmacology, transplants. Can J Neurol Soc 13:385–393Google Scholar
  46. Hefti F (1986): Nerve growth factor promotes survival of septal cholinergic neurons after fimbrial transections. J Neurosci 6:2155–2162Google Scholar
  47. Hefti F, Dravid A, Hartikka J (1984): Chronic intraventricular injections of nerve growth factor elevate hippocampal choline acetyltransferase in adult rats with partial septo-hippocampal lesions. Brain Res 293:305–311CrossRefGoogle Scholar
  48. Hefti F, Hartikka J, Krusel B (1989): Function of neurotrophic factors in the adult and aging brain and their possible use in the treatment of neurodegenerative diseases. Neurobiol Aging 10:515–533CrossRefGoogle Scholar
  49. Hepler DJ, Olton DS, Wenk GL, Coyle JT (1985): Lesions in nucleus basalis magnocellularis and medial septal area of rats produce qualitatively similar memory impairment. J Neurosci 5:866–873Google Scholar
  50. Herrmann WM, Kubicki SK, Rohmel J (1988): Vigilance classification system: Development, sample values, and applications in nootropic drug research. Z Gerontopychol Psychiat l(s):l-33.Google Scholar
  51. Johnston MV, McKinney M, Coyle JT (1981): Neocortical cholinergic innervation: a description of extrinsic and intrinsic components in the rat. Exp Brain Res 43:159–172CrossRefGoogle Scholar
  52. Karnovsky MJ, Roots LA (1964): Direct-coloring thiocholine method for Cholinesterase. J Histochem Cytochem 12:219–221CrossRefGoogle Scholar
  53. Kiss J, McGovern J, Patel AJ (1988): Immunohistochemical localizaton of cells containing nerve growth factor receptors in the different regions of the adult rat forebrain. Neuroscience 27:731–748CrossRefGoogle Scholar
  54. Knezevic, S, Mubrin Z, Risberg J, Vucinic G, Spilich G, Gubarev N, and Wannen-Macher W (1989). Pyritinol treatment of SDAT patients: Evaluation of psychiatric and neurological examination, psychometric testing, and rCBF measurements. International Journal of Clinical Psychopharmacology 4(1):25–28CrossRefGoogle Scholar
  55. Koelle GB, Friedenwald JS (1949): A histochemical method for localizing Cholinesterase activity. Proc Soc Exp Biol Med 70:617–622Google Scholar
  56. Krnjevic K, Silver A (1965): A histochemical study of cholinergic fibers in the cerebral cortex. J Anat 99:711–759Google Scholar
  57. Lamour Y, Dutar P, Jobert A (1982): Topographic organization of basal forebrain neurons projecting to the rat cerebral cortex. Neurosci Lett 34:117–122CrossRefGoogle Scholar
  58. Mann DMA, Yates PO, Marcyniuk B (1984a): Monoaminergic neurotransmitter systems in presenile Alzheimer’s disease and in senile dementia of Alzheimer type. Clin Neurophatol 3:199–205Google Scholar
  59. Mann DM A, Yates PO, Marcyniuk B (1984b): Changes in nerve cells of the nucleus basalis of Meynert in Alzheimer’s disease and their relationship to aging and the the accumulation of lipofuscin pigment. Mech Aging Dev 25:189–204CrossRefGoogle Scholar
  60. Marston HM, Martin KJ, Robbins TW (1987): Effect of the cholinergic administration of pyrithioxin on behavior and cholinergic function in young and aged rats. J Psycho Pharmacol l(4):237–243Google Scholar
  61. Martin KJ, Widdowson L (1989): The role of membrane phospholipids in acetylcholine synthesis: Observations with pyritinol. In: Pharmacological Interventions on Central Cholinergic Mechanism in Senile Dementia (Alzheimer’s Disease), Kewitz, Thompson, Bickel, eds. München: Zuchschwerlt, Vorlag, pp. 129–132Google Scholar
  62. Mash DC, Flynn DD, Potter LT (1985): Loss of M2 muscarinic receptors in the cerebral cortex in Alzheimer’s disease and experimental cholinergic denervation. Science 228:1115–1117CrossRefGoogle Scholar
  63. Maysinger D, Garofolo L, Jalsenjak I, Cuello AC (1989): Effects of microencapsulated monosialoganglioside GM1 on cholinergic neurons. Brain Res 496:165–172CrossRefGoogle Scholar
  64. McKinney M, Coyle JT (1982): Regulation of neocortical muscarinic receptors effects of drug treatment and lesions. J Neurosci 2:97–105Google Scholar
  65. Mesulam MM, Mufson EJ, Levey AI, Weiner EJ (1983a): Cholinergic innervation of cortex by the basal forebrain: Cytochemistry and cortical connections of the septal area, diagonal band nuclei, nucleus basalis (substantia innnominata) and hypothalamus in the rhesus monkey. J Comp Neurol 214:170–197CrossRefGoogle Scholar
  66. Mesulam MM, Mufson Ej, Wainer BH, Levey AI (1983b): Central cholinergic pathways in the rat: an overview based on an alternative nomenclature (Ch1-Ch6). Neuroscience 10:1185–1201CrossRefGoogle Scholar
  67. Miquel J, Johnson JE, Cervos-Navarro J (1983): Comparison of CNS aging in human and experimental animals In: Brain Aging: Neuropsychology and Neuropharmacology (Aging, Vol 21) Cervos-Navarro J, Sarcander HI, eds. New York: Raven Press, pp. 231–258Google Scholar
  68. Morgan DG (1989): Considerations in the treatment of neurological disorders with trophic factors. Neurobio Aging, 10:547–549CrossRefGoogle Scholar
  69. Norman AB, Blaker SN, Thal L, Creese J (1986): Effects of aging and cholinergic deafferentation on putative muscarinic cholinergic receptor subtypes in rat cerebral cortex. Neurosci Lett 70:289–294CrossRefGoogle Scholar
  70. Noronha-Blob L, Lowe VC, Hanson RC (1987): Heterogeneity of muscarinic receptors coupled to phosphoiinositide breakdown in guinea pig brain and peripheral tissues. Life Sci 41:967–975CrossRefGoogle Scholar
  71. Ordy JM, Thomas GJ, Volpe BT, Dunlop WP, Colombo PM (1988): An animal model of human-type memory loss based on aging, lesion, forebrain ischemia, and drug studies with the rat. Neurobiol Aging 9:667–683CrossRefGoogle Scholar
  72. Orzi F, Diana G, Casamenti F, Palombo E, Fieschi C (1988): Local cerebral glucose utilization following unilateral and bilateral lesions of the nucleus basalis magnocellularis in the rat. Brain Res 462:99–103CrossRefGoogle Scholar
  73. Palacios JM (1982): Autoradiografic localization of muscarinic cholinergic receptors in the hippocampus of patients with senile dementia. Brain Res 243:173–175CrossRefGoogle Scholar
  74. Palacios JM, Cortes R, Probst A (1987): Receptor plasticity in the human brain: some autoradiographic studies. J Recep Res 7:581–597Google Scholar
  75. Palacios JM, Spiegel R (1986): Muscarinic cholinergic agonist: pharmacological and clinical perspectives. Prog Brain Res 70:485–497CrossRefGoogle Scholar
  76. Pearson RC A, Weal JW, Powell TPS (1986): Hypertrophy of cholinergic neurones of the basal nucleus in the rat following damage of the contralateral nucleus. Brain Res 382:149–152CrossRefGoogle Scholar
  77. Pedata F, Lo Conte G, Sorbi S, Marconcini-Pepeu I, Pepeu G (1982): Changes in high affinity choline uptake in rat cortex following lesions of the magno-cellular forebrain nuclei. Brain Res 233:359–367CrossRefGoogle Scholar
  78. Pintor A, Fortuna S, Volpe MT, Michalek H (1988): Muscarinic plasticity in the brain of senescent rats: down-regulation after repeated administration of diisopropyl fluorophosphate. Life Sci 42:2113–2121CrossRefGoogle Scholar
  79. Robbins TW, Everitt BJ, Marston HM, Wilkinson J, Jones GH, Page KJ (1989): Comparative effects of ibotenic acid-and quisqualic acid-induced lesions of the substantia innominata on attentional function in the rat: further implications for the role of the cholinergic neurons of the nucleus basalis in cognitive processes. Behav Brain Res 35:221–240CrossRefGoogle Scholar
  80. Rye DB, Wainer BH, Mesulam MM, Mufson EJ, Saper CB (1984): Cortical projections arising from the basal forebrain: a study of cholinergic components employing combined retrograde tracing and immunohistochemical localizations of choline acetyltransferase. Neuroscience 13:627–643CrossRefGoogle Scholar
  81. Santos-Benito FF, Gonzalez JL, de la Torre F (1988): Choline acetyltransferase activity in the rat brain cortex, homogenate, synaptosomes, and capillaries after lesioning the nucleus basalis magnocellularis. J Neurochem 50:395–399CrossRefGoogle Scholar
  82. Schwaber JS, Rogers WT, Satoh K, Fibiger HC (1987): Distribution and organization of cholinergic neurons of the rat forebrain demonstrated by computer-aided data acquisition and three dimensional reconstruction. J Comp Neurol 263:309–325CrossRefGoogle Scholar
  83. Senut MC, Menetrey D, Lamour Y (1989): Cholinergic and peptidergic projections from the medial septum and the nucleus of the diagonal band of Broca to dorsal hippocampus, angulate cortex and olfactory bulb: a combined wheat-germ agglutinin-apohorseradish peroxidase-gold immunohistochemical study. Neuroscience 30:385–403CrossRefGoogle Scholar
  84. Shute CD, Lewis PR (1963): Cholinergic neurons pathways in the brain. Nature 199:1160–1164CrossRefGoogle Scholar
  85. Shute CD, Lewis PR (1967): The ascending cholinergic reticular system: neocor-tical, olfactory and subcortical projections. Brain 90:497–520CrossRefGoogle Scholar
  86. Smith G (1988): Animal models of Alzheimer’s disease: experimental cholinergic denervation. Brain Res Rev 13:103–118CrossRefGoogle Scholar
  87. Snider WD, Johnson EM (1989): Neurotrophic molecules. Ann Neurol 26:489–506CrossRefGoogle Scholar
  88. Sofroniew MV, Pearson RCA, Powell TPS (1987): The cholinergic nuclei of the basal forebrain of the rat: normal structure, development and experimentally induced degeneration. Brain Res 411:310–331CrossRefGoogle Scholar
  89. Springer JE, Tayrien MW, Loy R (1987): Regional analysis of age-related changes in the cholinergic system of the hippocampal formation and basal forebrain of the rat. Brain Res 407:180–184CrossRefGoogle Scholar
  90. Stichel CC, Dolabela de Lima A, Singer W (1987): A search for choline ace-tyltransferase-like immunoreactivity in neurons of cat striate cortex. J Comp Neurol 258:99–111CrossRefGoogle Scholar
  91. Toledano A (1988): Hypotheses concerning the aetiology of Alzheimer’s disease. Pharmacopsychiat 21:17–25CrossRefGoogle Scholar
  92. Toledano A (1989): Alzheimer experimental. Modelos biologicos y su utilidad en la caracterizacion de medicamentos encefalotropicos. In: Trastornos cerebrales organicos. Toledano A, Maurer K and Wurtman RJ, eds. Braunschweig: Vieweg, pp. 15–43Google Scholar
  93. Toledano A, Barca MA, Moradillo I (1988): Mitochondrial dehydrogenases during sensescence of the cerebellar cortex. A comparative electron microscope study. Cell Molec Biol 34:175–189Google Scholar
  94. Vige X, Briley M (1989): Muscarinic receptor plasticity in rats lesioned in the nucleus basalis of Meynert Neuropharmacol 28:727–732CrossRefGoogle Scholar
  95. Walker LC, Koliatsos VE, Kitt CA, Richardson RT, Rokaeus A Price DL (1989): Peptidergic neurons in the basal forebrain magnocellular complex of the rhesus monkey. J Comp Neurol 280:272–282CrossRefGoogle Scholar
  96. Watson M, Vickroy TW, Fibiger HC, Roeske WR, Yamamura HI (1985): Effects of bilateral iobotenate induced lesions of the nucleus basalis magnocellularis upon selective cholinergic biochemical markers in the rat anterior cerebral cortex. Brain Res 346:387–391CrossRefGoogle Scholar
  97. Wenk GL, Markowska AL, Olton DS (1989): Basal forebrain lesions and memory: alterations in neurotensin not acetylcholine, may cause amnesia. Behav Neurosci 103:765–769CrossRefGoogle Scholar
  98. Wenk H, Bigl V, Meyer U (1980): Cholinergic projections from magnolcellular nuclei of the basal forebrain to cortical areas in rats. Brain Res Rev 2:295–361CrossRefGoogle Scholar
  99. Wenk GL, Olton DS (1984): Recovery of neocortical choline acetyltransferase activity following iobotenic acid injection into the nucleus basalis of Meynert in rats. Brain Res 293:184–186CrossRefGoogle Scholar
  100. Wisniewsky HM, Sinatra RS, Iqbal K, Grundke-Iqbal I (1981): Neurofibrillary and synaptic pathology in the aged brain. In: Aging and Cell Structures Vol. 1, Johnson JE, ed. New York: Plenum Press, pp. 105–142Google Scholar
  101. Zaczek R, Coyle JT (1982): Excitatory amino acids analogues: neurotoxicity and seizures. Neurophannacol 21:15–26CrossRefGoogle Scholar

Copyright information

© Birkhäuser Boston 1992

Authors and Affiliations

  • Adolfo Toledano

There are no affiliations available

Personalised recommendations