Abstract

Subpopulations of rats show a significant decline in learning and memory during the aging process which is not attributable to sensory, motor or motivational deficits. The basal forebrain cholinergic system is also impaired in these behaviorally impaired aged rats. In addition, evidence supports a decline in Nerve Growth Factor (NGF) and NGF receptors and their respective mRNAs in aged animals. Further, high voltage EEG spindles (HVS) in the neocortex which can disrupt cognitive function are increased dramatically with aging and are controlled in part through cholinergic neurons in the basal forebrain. Finally, the inserted form of the amyloid precursor protein (APP-751) which is regulated in part by NGF is abnormally expressed in the aged, behaviorally impaired rats. We wish to determine whether and/or which of these physiological markers of aging are causally linked to the age related learning and memory deficits. To test the generalizability of these results we will repeat the experiments in several rat strains, and will expand the learning test repertoire. We have shown that chronic infusions of the NGF can have a positive influence of retention in the learning task of the aged impaired animals, and that grafts of fetal basal forebrain tissue to the brains of the aged impaired animals have an ameliorative effect on acquisition in the same learning task. In the present set of experiments we propose to test the influence of NGF infusions, intracerebral rafts of fetal basal forebrain and a combination of NGF and intracerebral grafting on the physiological parameters described above in an attempt to determine whether any of these parameters are influenced by the treatments which have ameliorative influences on aspects of aged related behavioral impairments. These experiments are designed to test experimental therapeutic protocols in behaviorally impaired aged animals, and to determine the functional relationship between cholinergic activity, NGF function, and expression of the APP.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG006088-08
Application #
2049437
Study Section
Neurology B Subcommittee 2 (NEUB)
Project Start
1985-07-01
Project End
1996-01-31
Budget Start
1994-02-15
Budget End
1995-01-31
Support Year
8
Fiscal Year
1994
Total Cost
Indirect Cost

  Institution

Name
University of California San Diego
Department
Neurosciences
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093

  Publications

Jessberger, Sebastian; Gage, Fred H (2008) Stem-cell-associated structural and functional plasticity in the aging hippocampus. Psychol Aging 23:684-91
Lein, Edward S; Callaway, Edward M; Albright, Thomas D et al. (2005) Redefining the boundaries of the hippocampal CA2 subfield in the mouse using gene expression and 3-dimensional reconstruction. J Comp Neurol 485:1-10
Pizzo, Donald P; Paban, Veronique; Coufal, Nicole G et al. (2004) Long-term production of choline acetyltransferase in the CNS after transplantation of fibroblasts modified with a regulatable vector. Brain Res Mol Brain Res 126:1-13
Markakis, Eleni A; Palmer, Theo D; Randolph-Moore, Lynne et al. (2004) Novel neuronal phenotypes from neural progenitor cells. J Neurosci 24:2886-97
Lein, Ed S; Zhao, Xinyu; Gage, Fred H (2004) Defining a molecular atlas of the hippocampus using DNA microarrays and high-throughput in situ hybridization. J Neurosci 24:3879-89
Klassen, Henry; Imfeld, Karen L; Ray, Jasodhara et al. (2003) The immunological properties of adult hippocampal progenitor cells. Vision Res 43:947-56
Rhodes, Justin S; van Praag, Henriette; Jeffrey, Susan et al. (2003) Exercise increases hippocampal neurogenesis to high levels but does not improve spatial learning in mice bred for increased voluntary wheel running. Behav Neurosci 117:1006-16
Vallieres, Luc; Campbell, Iain L; Gage, Fred H et al. (2002) Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6. J Neurosci 22:486-92
Zhao, X; Lein, E S; He, A et al. (2001) Transcriptional profiling reveals strict boundaries between hippocampal subregions. J Comp Neurol 441:187-96
Palmer, T D; Willhoite, A R; Gage, F H (2000) Vascular niche for adult hippocampal neurogenesis. J Comp Neurol 425:479-94

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