Cholinergic Lesions and Age-Related Cognitive Impairment

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DESCRIPTION (provided by applicant): Alzheimer's-related dementia and age-associated cognitive decline are due, in part, to a loss of cholinergic projections to the hippocampus and frontal cortex. Despite many years of study, the specific cognitive processes that are affected by damage to basal forebrain cholinergic projections, and the degree to which the loss of cholinergic projections contributes to age-related cognitive decline, are not well understood. Recently we showed that aged ovariectomized rats are substantially impaired in the acquisition of a simple delayed matching-to-position (DMP) T-maze task. In addition, we have shown that intraseptal injection of the selective immunotoxin 192 IgG-saporin (SAP) into young adult rats produces a severe impairment in acquisition of the DMP task in both male and female rats, similar to the deficit observed in aged rats. Our preliminary studies suggest that the deficit produced by SAP is due to the selective loss of cholinergic, and not GABAergic, neurons in the basal forebrain, and that performance correlates with cholinergic innervation in the hippocampus and frontal cortex. In addition, the data suggest that the deficit in DMP acquisition produced by SAP is not due primarily to a deficit in spatial working memory. The goals of this proposal are (1) to identify the specific cholinergic projections and their targets that are responsible for the SAP-induced deficit in DMP acquisition, (2) to identify specific cognitive processes that are affected by the SAP lesions and that underlie the deficit in DMP acquisition, and (3) to evaluate how the deficits produced by SAP relate to deficits associated with age-related cognitive decline. Experiments 1 and 2 will use microinjections of SAP along with histochemical and biochemical assays to identify specific basal forebrain cholinergic projections in both males and females that are responsible for the sizeable SAP-induced deficit in DMP acquisition observed. Experiments 3a and 3b will use a modified version of the DMP task to determine whether SAP-lesioned animals and aged animals (both males and females) show a deficit in the ability to adopt a place vs. a response learning strategy to acquire the task. In addition, these same animals will be tested using two additional tasks, a negative patterning task that will test configural association learning, and a 12-arm radial arm maze task that will assess working and reference memory. By comparing the same animals across all of these tasks, it will be possible to identify specific cognitive processes that are affected by the SAP lesions in males and females, and to identify those cognitive deficits produced by intraseptal injections of SAP that reflect deficits also observed in the aged animals.