This proposal will test the hypothesis that nerve growth factor (NGF) is a neurotrophic factor for cholinergic neurons of the forebrain. In an attempt to characterize the actions of NGF on these cells, the P.I. has found that NGF promotes survival of cholinergic septo-hippocampal neurons of adult rats after destruction of their processes by transection of the fimbria. Furthermore, preliminary findings indicate that NGF stimulates survival and fiber growth of cholinergic neurons in culture. Planned experiments aim at thoroughly investigating these previously undiscovered effects of NGF and at characterizing the conditions necessary for them to occur. Studies will be carried out in vivo, on young and aged adult rats with lesions of the septo- hippocampal cholinergic pathway, and in vitro, on cultured cholinergic neurons from fetal rat brains. In addition, an immunohistochemical method has recently been developed by the P.I. for the visualization of NGF receptors in the rat brain. Findings obtained so far, and which were limited to telen- and diencephalon, indicate that NGF receptors are selectively located on forebrain cholinergic neurons. Planned experiments aim at substantiating this selective localization of NGF receptors and at differentiating between a localization in cholinergic cells and afferent terminals. Furthermore, it is proposed to map NGF receptors in the entire rat brain. The proposed studies will help to establish whether NGF is a neurotrophic factor for forebrain cholinergic neurons. Furthermore, the studies have implications for Alzheimer's disease which is associated with a selective loss of cholinergic neurons in the basal forebrain. The proposed studies concern survival and function of a neuronal population selectively affected in Alzheimer's disease and the effects of a neurotrophic factor for these neurons.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS022933-01A2
Application #
3405764
Study Section
Neurology B Subcommittee 1 (NEUB)
Project Start
1987-09-01
Project End
1990-08-31
Budget Start
1987-09-01
Budget End
1988-08-31
Support Year
1
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Type
Schools of Medicine
DUNS #
City
Miami
State
FL
Country
United States
Zip Code
33101
Qiao, X; Chen, L; Gao, H et al. (1998) Cerebellar brain-derived neurotrophic factor-TrkB defect associated with impairment of eyeblink conditioning in Stargazer mutant mice. J Neurosci 18:6990-9
Alexi, T; Hughes, P E; Knusel, B et al. (1998) Metabolic compromise with systemic 3-nitropropionic acid produces striatal apoptosis in Sprague-Dawley rats but not in BALB/c ByJ mice. Exp Neurol 153:74-93
Knusel, B; Gao, H; Okazaki, T et al. (1997) Ligand-induced down-regulation of Trk messenger RNA, protein and tyrosine phosphorylation in rat cortical neurons. Neuroscience 78:851-62
Gao, H; Qiao, X; Hefti, F et al. (1997) Elevated mRNA expression of brain-derived neurotrophic factor in retinal ganglion cell layer after optic nerve injury. Invest Ophthalmol Vis Sci 38:1840-7
Hughes, P E; Alexi, T; Hefti, F et al. (1997) Axotomized septal cholinergic neurons rescued by nerve growth factor or neurotrophin-4/5 fail to express the inducible transcription factor c-Jun. Neuroscience 78:1037-49
Qiao, X; Hughes, P E; Venero, J L et al. (1996) NT-4/5 protects against adrenalectomy-induced apoptosis of rat hippocampal granule cells. Neuroreport 7:682-6
Qiao, X; Hefti, F; Knusel, B et al. (1996) Selective failure of brain-derived neurotrophic factor mRNA expression in the cerebellum of stargazer, a mutant mouse with ataxia. J Neurosci 16:640-8
Knusel, B; Gao, H (1996) Neurotrophins and Alzheimer's disease: beyond the cholinergic neurons. Life Sci 58:2019-27
Venero, J L; Hefti, F; Knusel, B (1996) Trophic effect of exogenous nerve growth factor on rat striatal cholinergic neurons: comparison between intraparenchymal and intraventricular administration. Mol Pharmacol 49:303-10
Knusel, B; Kaplan, D R; Hefti, F (1996) Intraparenchymal NGF injections in adult and aged rats induce long-lasting Trk tyrosine phosphorylation. Exp Neurol 139:121-30

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