title: Grafting of nerve growth factor-producing fibroblasts reduces behavioral deficits in rats with lesions of the nucleus basalis magnocellularis.
abstract: Rats received bilateral lesions of the nucleus basalis magnocellularis by infusion of biotenic acid. Two weeks after the lesion, a suspension of genetically modified primary rat fibroblasts was grafted dorsal to the nucleus basalis magnocellularis (2 x 10(5) cells per side). The fibroblasts were either infected with the gene for human beta-nerve growth factor or Escherichia coli beta-galactosidase. The nerve growth factor-producing fibroblasts released 67 ng nerve growth factor/10(5) cells per day in vitro. Two weeks after implantation of the fibroblasts, spatial learning was tested in the Morris water-maze. Nerve growth factor-producing fibroblasts, but not beta-galactosidase-producing fibroblasts ameliorated the deficit in acquisition of the water-maze task. In addition, spatial acuity was improved to near-normal levels by the nerve growth factor-producing grafts. Choline acetyltransferase activity in cortical areas and hippocampus was not affected by the nerve growth factor-producing grafts. Both grafted groups showed a similar reduction in the level of dopamine, but not homovanillic acid or 3-methoxytyramine, in the frontal cortex. Levels of norepinephrine, epinephrine and serotonin and their metabolites in the neocortex and hippocampus were not affected by the lesion or the grafts. Nerve growth factor-producing grafts increased the size of remaining nerve growth factor-receptor (p75) immunoreactive neurons in the nucleus basalis magnocellularis by 25%. Nucleus basalis magnocellularis lesions reduced the integrated optic density of choline acetyltransferase-positive fiber staining in the ventral neocortex by 46%, but nerve growth factor-producing grafts restored this area to 86% of control. These data suggest that nerve growth factor-producing grafts can cause a marked behavioral improvement, probably through the partial restoration of the lesioned projection from nucleus basalis magnocellularis to neocortex.
authors.affiliation: Department of Neurosciences, University of California, San Diego.
authors.forename: A J
authors.initials: AJ
authors.lastname: Dekker
authors.forename: J
authors.initials: J
authors.lastname: Winkler
authors.forename: J
authors.initials: J
authors.lastname: Ray
authors.forename: L J
authors.initials: LJ
authors.lastname: Thal
authors.forename: F H
authors.initials: FH
authors.lastname: Gage
mesh_terms: D000818:Animals; D001679:Biogenic Amines / Q000378:metabolism*; D002478:Cells, Cultured; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000637:transplantation; D005625:Frontal Lobe / Q000378:metabolism*; D005822:Genetic Vectors; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D007051:Ibotenic Acid; D007858:Learning / Q000502:physiology*; D008297:Male; D009414:Nerve Growth Factors / Q000096:biosynthesis*; D009847:Olivary Nucleus / Q000502:physiology*; D010296:Parietal Lobe / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D012867:Skin / Q000166:cytology; D001616:beta-Galactosidase / Q000032:analysis / Q000096:biosynthesis
chemical_list: D001679:Biogenic Amines; D009414:Nerve Growth Factors; D007051:Ibotenic Acid; D002795:Choline O-Acetyltransferase; D001616:beta-Galactosidase