Due to the increased longevity and improved medical care in the western societies during the last decades, the incidence of age-related neurodegenerative disorders, such as Alzheimer's and Parkinson's disease, has increased significantly. Since the etiology of neurodegenerative disorders is largely unknown, and there is no effective treatment strategy for either of these disorders to date, studies of factors that might influence neural plasticity during aging, and degenerative disease are greatly needed. In the present application, the applicant proposes to investigate the role of neurotrophic factors on the plasticity of central noradrenergic neurons during aging, by utilizing intraocular double and triple transplants of variable age and application of different growth factors. Specifically, they will explore the relationship between noradrenergic innervation and two different neurotrophic factors, glial cell line-derived neurotrophic factor (GDNF) and neurotrophin-3 (NT-3), in the hippocampal formation during development and aging to evaluate whether these two factors play a role in the neuroplasticity of this transmitter system. GDNF and NT-3 dependency of locus coeruleus noradrenergic neurons will be investigated both by cross-grafting of tissues between intact and null-mutated GDNF or NT-3 knockout mice, and by administration of these trophic factors to aged transplants of brainstem tissue in rats. The use of intraocular brain tissue transplants for these experiments enables them to create so called "young-old chimeras", where the neuron and target age can be varied independently, and it also allows them to study maturation of the transmitter pathway in neurotrophic factor knockout strains that otherwise do not survive past birth. It is the applicant s career goal for this period to learn molecular biology methods, in order to apply in situ hybridization techniques to her laboratory. In addition, she would like to become proficient in the image analysis techniques involved in quantitative analysis of mRNA distribution in tissues, and to learn all the principles behind null mutation of targeted genes in mice, and cross-transplantation between mice.

K02AG000796

1997-08-15

2002-07-31