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. That axonal growth and synapse formation can occur in the mature CNS has been established beyond doubt. 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. This example of axonal growth within the mature mammalian brain is preceded by an increase in the amount of Nerve Growth Factor (NGF) in the hippocampal tissue. However, there is disagreement in the literature concerning the degree, specificity and duration of the increase in NGF depending on whether a biological or immunological assay was used to detect NGF. One of the goals of the research in this application is to identify the causes of these discrepancies by applying both types of assays to the same tissue sample. In addition to testing the role that endogenous NGF has in this sprouting response, experiments are proposed to determine whether exogenous NGF delivered into the rat brain, either by way of infusion or by implanting polymer containing NGF, can elicit or later such growth. Also, the possibility that changes in substrate-bound growth factors play a role in sympathetic ingrowth will be tested by using sections of the brain as substrates for neurite growth in tissue culture. These experiments include determining whether septal denervation makes hippocampal tissue more permissive as a substrate for neurite outgrowth in tissue culture as well as electron microscopic studies to identify the tissue elements that regenerating axons are associated with in such cultures. Recent results indicate that the poor regenerative growth normally observed in mature CNS tissue may be due to the presence of growth-inhibiting factors associated with CNS white matter. Additional experiments are proposed to examine the growth-promoting ability of gray and white matter regions of the mature and developing rat CNS using the same tissue culture assay. All of the experiments are designed to identify the conditions that permit or prevent axonal growth within the mature mammalian brain.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurology B Subcommittee 2 (NEUB)
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University of Cincinnati
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Kudwa, A E; Shoemaker, S E; Crutcher, K A et al. (2002) Evidence for reduced accumulation of exogenous neurotrophin by aged sympathetic neurons. Brain Res 948:24-32
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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