ANALYSIS OF FACTORS PREVENTING CNS NEURON DEATH IN VIVO

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Degeneration of cholinergic and non-cholinergic neurons in the septal-basal forebrain region has been observed in a number of disease states such as Alzheimer's disease and Parkinsonism-dementia. Although it is uncertain what factors are responsible for this cell death, it has been proposed that neurodegenerative changes resulting from CNS injuries or associated with some aging disorders, such as Alzheimer's disease, result from the loss of target-derived neuronotrophic factors. This hypothesis is consistent with recent studies which indicate that neuronotrophic factors released in response to selective lesions of the adult mammalian CNS promote the survival of CNS and PNS neurons in culture and influence the survival of transplanted neurons. Thus, the long-term objectives of this proposed research are to develop in vivo experimental preparations for the identification of specific trophic substances and cellular environments that prevent age related cell death and influence neuronal survival following lesions in the mature mammalian CNS. The experimental model system to be employed in these studies is the septal projection to the hippocampal formation. The specific aims of the present proposal are to utilize intracephalic neural transplants in conjunction with a variety of lesion paradigms and the intraventricular or systemic administration of proposed trophic substances in order to identify experimental manipulations that: 1) prevent retrograde degeneration of cholinergic and non-cholinergic septal neurons following complete bilateral transections of the fornix/fimbria and 2) promote the survival of these neuronal populations in aged individuals. Specific neuronal populations within the septal region and their afferent projections will be identified using a variety of neuroanatomical techniques employing retrograde and anterograde axonal tracing procedures, acetylcholinesterase histochemistry, immunocytochemical identification of cholinergic and gabaergic neurons, and biochemical assay procedures. Data from the proposed research will provide insight into molecular factors and cellular environments that influence the survival of cholinergic and non-cholinergic septal neurons within the mature and aged mammalian CNS. These results should prove beneficial for evaluating whether the loss of target-derived trophic factors may be involved in the neuronal degeneration observed following neural injuries and during aging of the CNS. Moreover, these results will provide insight into possible treatment therapies that may promote cell survival in the adult mammalian CNS.