What factors regulate neuronal plasticity in the mature brain and spinal cord? This question is at the center of research that seeks to promote the ability of the central nervous system (CNS) to recover from injury resulting from stroke, trauma or degenerative disease. Axonal growth and synapse formation can occur in the mature CNS. The mechanisms underlying such growth, however, are not clear. Damage to the basal forebrain of the rat (brain regions that are known to be affected in Alzheimer's disease) results in the growth of vascular autonomic fibers (sympathetic axons) into the hippocampal formation, a response that is significantly reduced in the aged animal. This example of axonal growth within the young rat is preceded by an increase in the amount of Nerve Growth Factor (NGF) in the region where growth occurs. However, we have demonstrated that global infusion of exogenous NGF is not sufficient to induce sympathetic ingrowth in the presence of septal fibers suggesting that local elevation of NGF may be required to elicit sprouting. Two of the goals over the next five years are to determine whether local availability of NGF within the hippocampal formation determines the topography of sympathetic ingrowth and whether septal lesions alter the growth-promoting ability of hippocampal tissue sections when used as a substrate in culture. A third goal is to determine whether the age-related decline in sympathetic sprouting is due to reduced trophic factor induction following septal denervation and/or alterations in tissue substrate properties. This arises from our finding that there is no age-related decline in total NGF activity in the rat hippocampal formation. The fourth goal is to determine the responsivity of aged sympathetic neurons to exogenous NGF to test the hypothesis that reduced sprouting is partly due to reduced responsiveness of aged sympathetic neurons to NGF. All of the experiments are designed to reveal information regarding the factors that regulate axonal growth within the mature and aging nervous system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS017131-12A1
Application #
2263154
Study Section
Neurology B Subcommittee 2 (NEUB)
Project Start
1994-09-01
Project End
1998-08-30
Budget Start
1994-09-01
Budget End
1995-08-31
Support Year
12
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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Pettigrew, D B; Levin, L; Crutcher, K A (2000) Sympathetic neurite growth on central nervous system sections is region-specific and unaltered by aging. Neurobiol Aging 21:629-38
Shafer, A J; Crutcher, K A; Isaacson, L G (2000) Remodeling of adult sensory axons in the superior cervical ganglion in response to exogenous nerve growth factor. Brain Res 864:252-62
Kuchel, G A; Crutcher, K A; Naheed, U et al. (1999) NGF expression in the aged rat pineal gland does not correlate with loss of sympathetic axonal branches and varicosities. Neurobiol Aging 20:685-93
Walsh, G S; Krol, K M; Crutcher, K A et al. (1999) Enhanced neurotrophin-induced axon growth in myelinated portions of the CNS in mice lacking the p75 neurotrophin receptor. J Neurosci 19:4155-68
Walsh, G S; Krol, K M; Kawaja, M D (1999) Absence of the p75 neurotrophin receptor alters the pattern of sympathosensory sprouting in the trigeminal ganglia of mice overexpressing nerve growth factor. J Neurosci 19:258-73
Isaacson, L G; Crutcher, K A (1998) Uninjured aged sympathetic neurons sprout in response to exogenous NGF in vivo. Neurobiol Aging 19:333-9
Isaacson, L G; Mareska, M; Nixdorf, W et al. (1997) Dose-dependent response of mature cerebrovascular axons in vivo following intracranial infusion of nerve growth factor. Neurosci Lett 222:21-4
Kawaja, M D; Crutcher, K A (1997) Sympathetic axons invade the brains of mice overexpressing nerve growth factor. J Comp Neurol 383:60-72
Isaacson, L G; Billieu, S C (1996) Increased perivascular norepinephrine following intracerebroventricular infusion of NGF into adult rats. Exp Neurol 139:54-60

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