Andrews, Tim; (1993) The role of targets and growth factors in neuronal ageing. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The aim of this thesis has been to use morphological techniques to study the influence of targets, growth factors and presynaptic activity in neuronal ageing. I have used immunohistochemical and histochemical methods to investigate changes in the innervation in blood vessels from the cerebral, portal, cardiac and caudal circulation of the rat through development and ageing. These studies showed that neurodegeneration is not a general phenomenon of ageing perivascular nerves. However, significant amounts of neurodegeneration were seen on the middle cerebral artery (MCA) and the tail vein (TV). Intracellular injection techniques were developed to allow analysis of the dendritic arbors of the same neurones whose axons had been investigated. A preliminary study showed that, in accordance with other studies the dendritic arbors of sympathetic neurones in the SCG increase in length and complexity during postnatal development. However, in old age significant neurodegeneration of dendrites was observed. Furthermore contrary to previous studies, we show that the number of primary dendrites on SCG neurones decreases during postnatal development and ageing. Using retrograde tracing in combination with intracellular injection, I showed that the dendritic arbors of sympathetic neurones projecting to different targets demonstrated striking target-specificity. Furthermore, changes in dendritic geometry of these neurones during development and ageing were again target- specific. The ability of aged sympathetic neurones to respond to increased synaptic activity was investigated. The ability of aged neurones to upregulate tyrosine hydroxylase (TH) and neuropeptide Y was either slowed or abolished. Data shows that TH levels and TH activity are differentially regulated. Furthermore, evidence is provided to show that TH activity can be upregulated by nonsynaptic mechanisms. The ability of degenerating aged neurones to respond to exogenous nerve growth factor (NGF) was tested in vivo. Aged neurones are able to increase both their dendritic and axonal arbors in response to NGF. The pattern of regrowth innervation of the axonal arbors from aged neurones after NGF treatment was typical of the plexus found in young rats, providing evidence that variable NGF levels may cause the neurodegenerative changes we have observed. Dendritic regrowth was also observed in response to NGF treatment of the target tissue. However, reduced plasticity of response was shown by the inability of these neurones to induce new dendritic branches.

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