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Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 1997 Nov 29;352(1362):1711–1717. doi: 10.1098/rstb.1997.0153

Animal models of memory impairment.

M Gallagher 1
PMCID: PMC1692094  PMID: 9415923

Abstract

Memory impairment in the elderly resembles a mild temporal lobe dysfunction. Alterations in the hippocampal formation are also a probable basis for cognitive deficits in some animal models of ageing. For example, aged rats are impaired in hippocampal-dependent tests of spatial memory. Recent studies have revealed considerable structural integrity in the aged hippocampus, even in aged rats with the most impaired spatial memory. In contrast, atrophy/loss of cholinergic neurons in the basal forebrain and deficiency in cholinergic transduction in hippocampus correlate with the severity of spatial memory impairment in aged rats. This evidence supports the longstanding view that age-related loss of memory has a cholinergic basis. In this context, it is somewhat surprising that the use of a selective cholinergic immunotoxin in young rats to further test this hypothesis has revealed normal spatial memory after removing septo-hippocampal cholinergic neurons. Young rats with immunotoxic lesions, however, have other behavioural impairments in tests of attentional processing. These lines of research have implications for understanding the neurobiological basis of memory deficits in ageing and for selecting an optimal behavioural setting in which to examine therapies aimed at restoring neurobiological function.

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Selected References

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  1. Barnes C. A. Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat. J Comp Physiol Psychol. 1979 Feb;93(1):74–104. doi: 10.1037/h0077579. [DOI] [PubMed] [Google Scholar]
  2. Bartus R. T., Dean R. L., Pontecorvo M. J., Flicker C. The cholinergic hypothesis: a historical overview, current perspective, and future directions. Ann N Y Acad Sci. 1985;444:332–358. doi: 10.1111/j.1749-6632.1985.tb37600.x. [DOI] [PubMed] [Google Scholar]
  3. Baxter M. G., Bucci D. J., Gorman L. K., Wiley R. G., Gallagher M. Selective immunotoxic lesions of basal forebrain cholinergic cells: effects on learning and memory in rats. Behav Neurosci. 1995 Aug;109(4):714–722. doi: 10.1037//0735-7044.109.4.714. [DOI] [PubMed] [Google Scholar]
  4. Baxter M. G., Bucci D. J., Sobel T. J., Williams M. J., Gorman L. K., Gallagher M. Intact spatial learning following lesions of basal forebrain cholinergic neurons. Neuroreport. 1996 May 31;7(8):1417–1420. doi: 10.1097/00001756-199605310-00019. [DOI] [PubMed] [Google Scholar]
  5. Baxter M. G., Gallagher M. Intact spatial learning in both young and aged rats following selective removal of hippocampal cholinergic input. Behav Neurosci. 1996 Jun;110(3):460–467. doi: 10.1037//0735-7044.110.3.460. [DOI] [PubMed] [Google Scholar]
  6. Baxter M. G., Holland P. C., Gallagher M. Disruption of decrements in conditioned stimulus processing by selective removal of hippocampal cholinergic input. J Neurosci. 1997 Jul 1;17(13):5230–5236. doi: 10.1523/JNEUROSCI.17-13-05230.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Berger-Sweeney J., Heckers S., Mesulam M. M., Wiley R. G., Lappi D. A., Sharma M. Differential effects on spatial navigation of immunotoxin-induced cholinergic lesions of the medial septal area and nucleus basalis magnocellularis. J Neurosci. 1994 Jul;14(7):4507–4519. doi: 10.1523/JNEUROSCI.14-07-04507.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chiba A. A., Bucci D. J., Holland P. C., Gallagher M. Basal forebrain cholinergic lesions disrupt increments but not decrements in conditioned stimulus processing. J Neurosci. 1995 Nov;15(11):7315–7322. doi: 10.1523/JNEUROSCI.15-11-07315.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chouinard M. L., Gallagher M., Yasuda R. P., Wolfe B. B., McKinney M. Hippocampal muscarinic receptor function in spatial learning-impaired aged rats. Neurobiol Aging. 1995 Nov-Dec;16(6):955–963. doi: 10.1016/0197-4580(95)02015-2. [DOI] [PubMed] [Google Scholar]
  10. Coyle J. T., Price D. L., DeLong M. R. Alzheimer's disease: a disorder of cortical cholinergic innervation. Science. 1983 Mar 11;219(4589):1184–1190. doi: 10.1126/science.6338589. [DOI] [PubMed] [Google Scholar]
  11. Davies P., Maloney A. J. Selective loss of central cholinergic neurons in Alzheimer's disease. Lancet. 1976 Dec 25;2(8000):1403–1403. doi: 10.1016/s0140-6736(76)91936-x. [DOI] [PubMed] [Google Scholar]
  12. Fischer W., Chen K. S., Gage F. H., Björklund A. Progressive decline in spatial learning and integrity of forebrain cholinergic neurons in rats during aging. Neurobiol Aging. 1992 Jan-Feb;13(1):9–23. doi: 10.1016/0197-4580(92)90003-g. [DOI] [PubMed] [Google Scholar]
  13. Gage F. H., Dunnett S. B., Björklund A. Spatial learning and motor deficits in aged rats. Neurobiol Aging. 1984 Spring;5(1):43–48. doi: 10.1016/0197-4580(84)90084-8. [DOI] [PubMed] [Google Scholar]
  14. Gallagher M., Burwell R., Burchinal M. Severity of spatial learning impairment in aging: development of a learning index for performance in the Morris water maze. Behav Neurosci. 1993 Aug;107(4):618–626. doi: 10.1037//0735-7044.107.4.618. [DOI] [PubMed] [Google Scholar]
  15. Gallagher M., Holland P. C. Preserved configural learning and spatial learning impairment in rats with hippocampal damage. Hippocampus. 1992 Jan;2(1):81–88. doi: 10.1002/hipo.450020111. [DOI] [PubMed] [Google Scholar]
  16. Gallagher M., Rapp P. R. The use of animal models to study the effects of aging on cognition. Annu Rev Psychol. 1997;48:339–370. doi: 10.1146/annurev.psych.48.1.339. [DOI] [PubMed] [Google Scholar]
  17. Hyman B. T., Van Hoesen G. W., Damasio A. R. Alzheimer's disease: glutamate depletion in the hippocampal perforant pathway zone. Ann Neurol. 1987 Jul;22(1):37–40. doi: 10.1002/ana.410220110. [DOI] [PubMed] [Google Scholar]
  18. Hyman B. T., Van Hoesen G. W., Damasio A. R., Barnes C. L. Alzheimer's disease: cell-specific pathology isolates the hippocampal formation. Science. 1984 Sep 14;225(4667):1168–1170. doi: 10.1126/science.6474172. [DOI] [PubMed] [Google Scholar]
  19. Issa A. M., Rowe W., Gauthier S., Meaney M. J. Hypothalamic-pituitary-adrenal activity in aged, cognitively impaired and cognitively unimpaired rats. J Neurosci. 1990 Oct;10(10):3247–3254. doi: 10.1523/JNEUROSCI.10-10-03247.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Jones D. N., Barnes J. C., Kirkby D. L., Higgins G. A. Age-associated impairments in a test of attention: evidence for involvement of cholinergic systems. J Neurosci. 1995 Nov;15(11):7282–7292. doi: 10.1523/JNEUROSCI.15-11-07282.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Landfield P. W., Baskin R. K., Pitler T. A. Brain aging correlates: retardation by hormonal-pharmacological treatments. Science. 1981 Oct 30;214(4520):581–584. doi: 10.1126/science.6270791. [DOI] [PubMed] [Google Scholar]
  22. Meaney M. J., Aitken D. H., van Berkel C., Bhatnagar S., Sapolsky R. M. Effect of neonatal handling on age-related impairments associated with the hippocampus. Science. 1988 Feb 12;239(4841 Pt 1):766–768. doi: 10.1126/science.3340858. [DOI] [PubMed] [Google Scholar]
  23. Moore H., Dudchenko P., Bruno J. P., Sarter M. Toward modeling age-related changes of attentional abilities in rats: simple and choice reaction time tasks and vigilance. Neurobiol Aging. 1992 Nov-Dec;13(6):759–772. doi: 10.1016/0197-4580(92)90100-c. [DOI] [PubMed] [Google Scholar]
  24. Morris R. G., Garrud P., Rawlins J. N., O'Keefe J. Place navigation impaired in rats with hippocampal lesions. Nature. 1982 Jun 24;297(5868):681–683. doi: 10.1038/297681a0. [DOI] [PubMed] [Google Scholar]
  25. Mouloua M., Parasuraman R. Aging and cognitive vigilance: effects of spatial uncertainty and event rate. Exp Aging Res. 1995 Jan-Mar;21(1):17–32. doi: 10.1080/03610739508254265. [DOI] [PubMed] [Google Scholar]
  26. Parasuraman R., Greenwood P. M., Haxby J. V., Grady C. L. Visuospatial attention in dementia of the Alzheimer type. Brain. 1992 Jun;115(Pt 3):711–733. doi: 10.1093/brain/115.3.711. [DOI] [PubMed] [Google Scholar]
  27. Rapp P. R., Amaral D. G. Individual differences in the cognitive and neurobiological consequences of normal aging. Trends Neurosci. 1992 Sep;15(9):340–345. doi: 10.1016/0166-2236(92)90051-9. [DOI] [PubMed] [Google Scholar]
  28. Rapp P. R., Gallagher M. Preserved neuron number in the hippocampus of aged rats with spatial learning deficits. Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9926–9930. doi: 10.1073/pnas.93.18.9926. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Rasmussen T., Schliemann T., Sørensen J. C., Zimmer J., West M. J. Memory impaired aged rats: no loss of principal hippocampal and subicular neurons. Neurobiol Aging. 1996 Jan-Feb;17(1):143–147. doi: 10.1016/0197-4580(95)02032-2. [DOI] [PubMed] [Google Scholar]
  30. Sahakian B. J., Owen A. M., Morant N. J., Eagger S. A., Boddington S., Crayton L., Crockford H. A., Crooks M., Hill K., Levy R. Further analysis of the cognitive effects of tetrahydroaminoacridine (THA) in Alzheimer's disease: assessment of attentional and mnemonic function using CANTAB. Psychopharmacology (Berl) 1993;110(4):395–401. doi: 10.1007/BF02244644. [DOI] [PubMed] [Google Scholar]
  31. Torres E. M., Perry T. A., Blockland A., Wilkinson L. S., Wiley R. G., Lappi D. A., Dunnet S. B. Behavioural, histochemical and biochemical consequences of selective immunolesions in discrete regions of the basal forebrain cholinergic system. Neuroscience. 1994 Nov;63(1):95–122. doi: 10.1016/0306-4522(94)90010-8. [DOI] [PubMed] [Google Scholar]
  32. West M. J., Coleman P. D., Flood D. G., Troncoso J. C. Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease. Lancet. 1994 Sep 17;344(8925):769–772. doi: 10.1016/s0140-6736(94)92338-8. [DOI] [PubMed] [Google Scholar]
  33. West M. J. Regionally specific loss of neurons in the aging human hippocampus. Neurobiol Aging. 1993 Jul-Aug;14(4):287–293. doi: 10.1016/0197-4580(93)90113-p. [DOI] [PubMed] [Google Scholar]
  34. Wiley R. G., Oeltmann T. N., Lappi D. A. Immunolesioning: selective destruction of neurons using immunotoxin to rat NGF receptor. Brain Res. 1991 Oct 18;562(1):149–153. doi: 10.1016/0006-8993(91)91199-b. [DOI] [PubMed] [Google Scholar]

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