The overall goal is to identify the neuropathological basis for the memory disorders of Alzheimer's disease (AD) and other age-related dementias. In particular, the role of the cholinergic basal forebrain in relation to other CNS structures implicated in the neuropathology of Alzheimer's disease will be assessed in the rhesus monkey as part of the development of an animal model of AD.
The specific aims of the project are: 1) to assess the effects of damage to the entorhinal cortex, amygdala or locous coeruleus (LC), alone or in combination with the basal forebrain on a series of memory and learning tasks sensitive to the memory disorders of AD. This will help determine if the entorhinal area, amygdala and LC act synergistically with the basal forebrain to produce anterograde memory impairments similar to those seen in AD. 2) To assess the effects of entorhinal, amygdals and LC lesions, alone or in combination with lesions of the basal forebrain on the postoperative retention of preoperatively learned tasks. The pattern of retrograde loss will be compared to that found after basal forebrain lesions alone as well as that seen in patients with AD. 3) The progression of cognitive dysfunction, presumably reflecting ongoing neuropathology may be due to the process of anterograde and retrograde transneuronal degeneration. In order to test this hypothesis, the long-term behavioral and anatomical consequences of basal forebrain damage will be assessed. 4) To assess histochemically the extent of cholinergic and/or noradrenergic depletion in selected sites in the limbic system and cerebral cortex following lesions of the basal forebrain and/or locus coeruleus. This would constitute an important step in identifying the role of the basal forebrain and locus coeruleus in the cognitive impairments of AD. 5) To assess the efficacy of neuronal transplantation in restoring normal anatomical and neurochemical relationships and to correlate these results with any improvements in learning or memory function.
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