The effects of intrahippocampal BDNF and NGF on spatial learning in aged long evans rats

Abstract

Spatial learning rate was compared in cognitively impaired aged rats infused with either brain-derived neurotrophic factor (BDNF) or nerve growth factor (NGF). BDNF or NGF was infused into the dorsal hippocampus/third ventricle while animals were being trained on the Morris water maze. Training continued until all rats met a spatial learning criterion. Seven weeks later, they were tested for retention of the task, and sacrificed for assessment of hippocampal high-affinity choline uptake (HACU) or hypothalamic biogenic amine levels. NGF, but not BDNF, improved spatial learning rate in aged rats and increased hippocampal choline uptake weeks after withdrawal of NGF. Although BDNF did not improve, spatial learning, it did induce a partial, long-term normalization of the elevated hypothalamic 5-HT levels observed in our aged rats. These data suggest that (1) intrahippocampal/intraventricular infusion of NGF can improve the learning rate of aged, spatial learning-impaired rats, and that this improvement in acquisition could be associated with increased hippocampal cholinergic activity, and (2) that the BDNF-induced normalization of hypothalamic 5-HT levels in aged rats was not sufficient to improve learning rate in aged, spatial learning-impaired rats.

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References

  1. Abdulla F., Abu-Bakra M., Calaminici M.-R., Stephenson J., and Sinden J. (1995) Importance of forebrain cholinergic and GABAergic systems to the age-related deficits in water maze performance of rats.Neurobiol. Aging 16, 41–52.

    PubMed  Article  CAS  Google Scholar 

  2. Alter C., Boylan C., Fritsche M., Jones B., Jackson C., Wiegand S., Lindsay R., and Hyman C. (1994) Efficacy of brain-derived neurotrophic factor and neurotrophin-3 on neurochemical and behavioral deficits associated with partial nigrostriatal dopamine lesions.J. Neurochem. 63, 1021–1032.

    Google Scholar 

  3. Decker M., Pelleymounter M., and Gallagher M. (1988) Effects of training on a spatial memory task on high affinity choline uptake in hippocampus and cortex in young adult and aged rats.J. Neurosci.,8, 90–99.

    PubMed  CAS  Google Scholar 

  4. Falkenberg T., Mohammed A., Henriksson B., Persson H., Winblad B. and Lindefors N. (1992) Increased expression of brain-derived neurotrophic factor mRNA in rat hippocampus is associated with improved spatial memory and enriched environment.Neurosci. Lett.,138, 153–156.

    PubMed  Article  CAS  Google Scholar 

  5. Fischer W., Wictorin K., Bjorklund A., Williams L., Varon S. and Gage F. (1987) Amelioration of cholinergic neuron atrophy and spatial memory impairment in aged rats by nerve growth factor.Nature 329, 65–68.

    PubMed  Article  CAS  Google Scholar 

  6. Fischer W., Bjorklund A., Chen K., and Gage F. (1991) NGF improves spatial memory in aged rodents as a function of age.J. Neurosci.,11, 1889–1906.

    PubMed  CAS  Google Scholar 

  7. Fischer W., Sirevaag A., Wiegand S., Lindsay R., and Bjorklund A. (1994) Reversal of spatial memory impairments in aged rats by nerve growth factor and neurotrophins 3 and 4/5 but not by brain-derived neurotrophic factor.Proc. Natl. Acad. Sci. USA 91, 8607–8611.

    PubMed  Article  CAS  Google Scholar 

  8. Fisher R. A. (1949) The Design of Experiments. Edinburgh: Oliver and Boyd, Ltd.

    Google Scholar 

  9. Gage F., Chen K., Buzsaki G., and Armstrong D. (1988) Experimental approaches to age-related cognitive impairments.Neurobiol. Aging 9, 645–655.

    PubMed  Article  CAS  Google Scholar 

  10. Gallagher M., Burwell R., Kodsi M., McKinney M., Southerland S., Vella-Rountree L., and Lewis M. (1990) Markers for biogenic amines in the aged rat brain: relationship to decline in spatial learning ability.Neurobiol Aging 11, 507–514.

    PubMed  Article  CAS  Google Scholar 

  11. Hellweg R., Fischer W., Hock C., Gage F., Bjorklund A. and Thoenen H. (1990) Nerve growth factor levels and choline acetyltransferase activity in the brain of aged rats with spatial memory impairments.Brain Res. 537, 123–130.

    PubMed  Article  CAS  Google Scholar 

  12. Issa A., Rowe W., Gauthier S. and Meaney M. (1990) Hypothalamic-pituitary-adrenal activity in aged, cognitively impaired and cognitively unimpaired rats.J. Neurosci. 10, 3247–3254.

    PubMed  CAS  Google Scholar 

  13. Knusel B., Beck K., Winslow J., Rosenthal A., Burton L., Widmer H., Nikolics K., and Hefti F. (1992) Brain-derived neurotrophic factor administration protects basal forebrain cholinergic but not nigral dopaminergic neurons from degenerative changes after axotomy in the adult rat brain.J. Neurosci. 12, 4391–4402.

    PubMed  CAS  Google Scholar 

  14. Lapchak P. and Hefti F. (1992) BDNF and NGF treatment in lesioned rats: effects on cholinergic function and weight gain.NeuroReport 3, 405–408.

    PubMed  CAS  Google Scholar 

  15. Lapchak P., Araujo D., and Hefti F. (1993a) BDNF and trkB mRNA expression in the rat hippocampus following entorhinal cortex lesions.NeuroReport 4, 191–194.

    PubMed  CAS  Google Scholar 

  16. Lapchak P., Araujo D., and Hefti F. (1993b) Cholinergic regulation of hippocampal brain-derived neurotrophic factor mRNA expression: evidence from lesion and chronic cholinergic drug treatmend studies.Neuroscience 52, 575–585.

    PubMed  Article  CAS  Google Scholar 

  17. Lapchak P., Araujo D., Beck K., Finch C., Johnson S., and Hefti F. (1993c) BDNF and trkB mRNA expression in the hippocampal formation of aging rats.Neurobiol. Aging 14, 121–126.

    PubMed  Article  CAS  Google Scholar 

  18. Martin-Iverson M., Todd K., and Alter C. (1994) Brain-derived neurotrophic factor and neurotrophin-3 activate striatal dopamine and serotonin metabolism and related behaviors: interactions with amphetamine.J. Neurosci. 14, 1262–1270.

    PubMed  CAS  Google Scholar 

  19. Masana Y., Wanaka A., Kato H., Asai T., and Tohyama M. (1993) Localization of trkB mRNA in postnatal brain development.J. Neurosci. Res. 35, 468–479.

    PubMed  Article  CAS  Google Scholar 

  20. Morse J., Wiegand S., Anderson K., You Y., Cai N., Carnahan J., Miller J., DiStefano P., Altar C., Lindsay R., and Alderson R. (1993) Brain-derived neurotrophic factor (BDNF) prevents the degeneration of medial septal cholinergic neurons following fimbria transection.J. Neurosci. 13, 4146–4156.

    PubMed  CAS  Google Scholar 

  21. Nakamura S. and Ishihara T. (1989) Region selective increase in activities of CNS cholinergic marker enzymes during learning of memory tasks in aged rats.Pharmacol. Biochem. Behav. 34, 805–810.

    PubMed  Article  CAS  Google Scholar 

  22. Nilsson O., Strecker R., Daszuta A., and Bjorklund A. (1988) Combined cholinergic and serotonergic denervation of the forebrain produces severe deficits in a spatial learning task in the rat.Brain Res. 453, 235–246.

    PubMed  Article  CAS  Google Scholar 

  23. Nilsson O., Brundin P., and Bjorklund A. (1990) Amelioration of spatial memory impairment by intrahippocampal grafts of mixed septal and raphe tissue in rats with combined cholinergic and serotonergic denervation of the forebrain.Brain. Res. 515, 193–206.

    PubMed  Article  CAS  Google Scholar 

  24. Palkovits M., Brownstein M., Kizer J., Saavedra J., and Kopin I. (1976) Effects of stress on serotonin concentration and tryptophan hydroxylase activity of brain nuclei.Neuroendocrinology 22, 298–304.

    PubMed  Article  CAS  Google Scholar 

  25. Pallage V., Toniolo G., Will B. and Hefti F. (1986) Long-term effects of nerve growth factor and neural transplants on behavior of rats with medial septal lesions.Brain Res. 386, 197–208.

    PubMed  Article  CAS  Google Scholar 

  26. Paxinos G and Watson C. (1986)The Rat Brain in Stereotaxic Coordinates. Academic, London.

    Google Scholar 

  27. Pelleymounter M., Cullen M., and Wellman C. (1955) Characteristics of BDNF-induced weight loss.Exper. Neurol. 131, 229–238.

    Article  Google Scholar 

  28. Phillips H., Hains J., Laramee G., Rosenthal A. and Winslow J. (1990) Widespread expression of BDNF but not NT-3 by target areas of basal forebrain cholinergic neurons.Science 250, 290–294.

    PubMed  Article  CAS  Google Scholar 

  29. Phillips H., Hains J., Armanini M., Laramee G., Johnson S. and Winslow J. (1991) BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer’s disease.Neuron 7, 695–702.

    PubMed  Article  CAS  Google Scholar 

  30. Rapp P., Rosenberg R., and Gallagher M. (1987) An evaluation of spatial information processing in aged rats.Behav. Neurosci. 101, 3–12.

    PubMed  Article  CAS  Google Scholar 

  31. Riekkinen P., Miettinen R., Sirvio J., Aaltonen M. and Riekkinen P. (1990) The correlation of passive avoidance deficit in aged rat with the loss of nucleus basalis choline acetyltransferase-positive neurons.Brain Res. Bull. 25, 415–417.

    PubMed  Article  Google Scholar 

  32. Rylett R., Goddard S., Schmidt B., and Williams L. (1993) Acetylcholine synthesis and release following continuous intracerebral administration of NGF in adult and aged Fischer-344 rats.J. Neurosci. 13, 3956–3963.

    PubMed  CAS  Google Scholar 

  33. Sapolsky R., Krey L. and McEwen B. (1983) The adrenocortical stress-response in the aged male rat: impairment of recovery from stress.Exp. Gerontol. 18, 55–65.

    PubMed  Article  CAS  Google Scholar 

  34. Sherman K., Zigmond M., and Hanin I. (1978) High affinity choline uptake in striatum and hippocampus: Differential effects of treatments which release acetylcholine.Life Sci. 23, 1863–1870.

    PubMed  Article  CAS  Google Scholar 

  35. Simon J., Atweh S., and Kuhar M. (1976) Sodium-dependent high affinity choline uptake: A regulatory step in the synthesis of acetylcholine.J. Neurochem. 26, 909–922.

    PubMed  Article  CAS  Google Scholar 

  36. Siuciak J., Boylan C., Fritchie M., Altar C., and Lindsay R. (1996) BDNF increases monoaminergic activity in rat brain following intracerebroventricular or intraparenchymal administration.Brain Research 710, 11–20.

    PubMed  Article  CAS  Google Scholar 

  37. Studer L., Spenger C., Seiler R., Altar C., Lindsay R., and Hyman C. (1995) Comparison of the effects of the neurotrophins on the morphological structure of dopaminergic neurons in cultures of rat substantia nigra.Eur. J. Neurosci. 7, 223–233.

    PubMed  Article  CAS  Google Scholar 

  38. Widmer H., Knusel B., and Hefti F. (1993) BDNF protection of basal forebrain cholinergic neurons after axotomy: complete protection of p75NGFR-positive cells.Neuroreport 4, 363–366.

    PubMed  CAS  Article  Google Scholar 

  39. Williams L. (1991) Exogenous nerve growth factor stimulates choline acetyltransferase activity in aging Fischer 344 rats.Neurobiol. Aging 12, 39–46.

    PubMed  Article  CAS  Google Scholar 

  40. Williams L., Rylett R., Ingram D., Joseph J., Moises H., Tang A., and Mervis R. (1993) NGF affects the cholinergic neurochemistry and behavior of aged rats.Prog. Brain Res. 98, 251–256.

    PubMed  Article  Google Scholar 

  41. Williams L., Cummins V., Welcher A., Cullen M. and Pelleymounter M. (1994) Age-related alterations in trk-B mRNA expression that correlate with memory impairment.Soc. Neurosci Abstract 109, 1.

    Google Scholar 

  42. Yan Q., Matheson C., Sun J., Radeke M., Feinstein S., and Miller J. (1994) Distribution of intracerebral ventricularly administered neurotrophisn in rat brain and its correlation with Trk receptor expression.Exp. Neurol. 127, 23–36.

    PubMed  Article  CAS  Google Scholar 

  43. Zhou X.-F., Parada L., Soppet D., and Rush R. (1993) Distribution of trkB tyrosine kinase immunoreactivity in the rat central nervous system.Brain Res. 622, 63–70.

    PubMed  Article  CAS  Google Scholar 

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Correspondence to Mary Ann Pelleymounter.

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Pelleymounter, M.A., Cullen, M.J., Baker, M.B. et al. The effects of intrahippocampal BDNF and NGF on spatial learning in aged long evans rats. Molecular and Chemical Neuropathology 29, 211–226 (1996). https://doi.org/10.1007/BF02815003

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Index Entries

  • BDNF
  • NGF
  • water maze
  • hippocampus
  • hypothalamus
  • high-affinity choline uptake
  • serotonin
  • cognitive impairment
  • aging
  • spatial learning