In humans, declarative memory and olfactory functioning are vulnerable to decline with advanced age. Changes in cholinergic basal forebrain neurons have been implicated in age-related cognitive decline, but recent data demonstrates that this projection system is not solely responsible such impairments. Co-distributed GABAergic neurons, which make up approximately half of the projections to these temporal lobe structures and that have been implicated in spatial/declarative memory in young subjects, have yet to be carefully studied in relation to cognitive decline. The proposed experiments will test the hypothesis that dysfunction of both the cholinergic and GABAergic projections from basal forebrain to cortical targets contribute to the decline of mnemonic processes associated with advanced age and test whether these projections are indeed necessary for such abilities. Young (5-7 mo) and aged (22-24 mo) Fischer 344 rats will be trained on the Morris water maze, which is sensitive to age-related decline, to identify individual differences in cognitive abilities. Using quantitative neuroanatomical techniques, behaviorally characterized rats will be co-labeled with two phenotypic markers to identify either cholinergic or GABAergic (Aim 1) neurons. Integrative stereological/confocal microscopy will be used to determine if cholinergic and or GABAergic basal forebrain neurons lose phenotypic expression, change morphology, and/or degenerate as a function of age and/or cognitive impairment (Specific Aim 1). Second, we will use pharmacological therapies directed at the cholinergic and/or GABAergic transmitter systems in an attempt to reverse cognitive dysfunction in Fischer 344 rats (Specific Aim 2). Finally, it will be determined if, as our Preliminary Data suggest, basal forebrain cholinergic and/or GABAergic afferents to hippocampus are indeed critical to olfactory discrimination learning and spatial learning, both of which are compromised in aging (Specific Aim 3). This overarching hypothesis to be tested in this proposal is that dysfunction of both basal forbrain cholinergic and GABAergic neurons contribute to learning and memory deficits that are associated with advanced age. Additionally, the results of these experiments could provide novel pharmacological approaches to combat the escalating problem of age-related cognitive decline. ? ? ?
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