Characterization of the cytokine-neurotrophic cascade associated with neurotoxin-induced plasticity of dopaminergic neurons in young and middle-aged mice.
Item
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Title
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Characterization of the cytokine-neurotrophic cascade associated with neurotoxin-induced plasticity of dopaminergic neurons in young and middle-aged mice.
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Identifier
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AAI9830722
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identifier
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9830722
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Creator
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Ho, Angela.
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Contributor
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Adviser: Mariann Blum
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Date
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1998
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biology, Neuroscience | Health Sciences, Toxicology
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Abstract
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The aim of this thesis is to examine the cytokine-neurotrophic cascade associated with plasticity of dopaminergic neurons and factors that may be responsible for age-related decline in axonal sprouting. Striatal implantation of interleukin-1 (IL-1), an immune response-generated cytokine, can stimulate compensatory axonal sprouting in the denervated striatum from remaining dopaminergic afferents of parkinsonian animals. We have investigated whether IL-1's beneficial effects are mediated by the induction of dopaminergic neurotrophic factors derived from astroglia. Among the factors studied, a selective upregulation of basic fibroblast growth factor (bFGF) synthesis by IL-1 was observed suggesting that bFGF could be the putative factor mediating IL-1-induced dopaminergic sprouting. We next sought to determine whether IL-1 and trophic factor activities are associated with spontaneous dopaminergic sprouting in the denervated striatum of young mice following a neurotoxin challenge of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which selectively destroys midbrain dopaminergic neurons. Young mice displayed a greater increase in IL-1{dollar}\alpha{dollar} synthesis in the denervated striatum, which remained elevated for several weeks, in contrast to middle-aged mice which exhibited a modest induction for a week. Moreover, the induction of IL-1 {dollar}\alpha{dollar} synthesis was region specific, for no changes were seen in the midbrain in either age group despite glial activation. Surprisingly, no changes in bFGF or any other astroglia-derived neurotrophic factors were observed in the denervated striatum subsequent to the induction of IL-1. Unlike a stab injury in which activated microglia are the main source of IL-1{dollar}\alpha{dollar} and the induction is detected within several hours, a later onset of IL-1{dollar}\alpha{dollar} induction in reactive astrocytes following a neurotoxin-induced brain injury was observed. We found that both microglia and astroglia can be stimulated to synthesize different cytokine/neurotrophic factor profiles depending on the type of injury. To address whether growth-inhibitory substrates may further underlie the age-associated decline in dopaminergic sprouting after MPTP, we examined the expression of the extracellular matrix inhibitory molecule chondroitin-sulfate proteoglycan (CSPG) in the denervated striatum of young and middle-aged mice. We found that while young mice displayed a transient increase of CSPG immunoreactivity, a sustained induction of CSPG was observed in middle-aged mice, which may contribute to the reduced axonal plasticity with age.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
