The Nicotinic Cholinergic System and Cognitive Aging

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The cholinergic system has been shown to be the primary neurotransmitter system responsible for cognitive symptoms in dementia. While therapeutic benefits are clear in dementia, what remains uncertain is the role that the cholinergic system in general and the nicotinic system specifically plays in cognition in healthy non-demented older adults (referred to as cognitive aging in this application). This is critical because the expansion of the healthy aging population will nonetheless show declines in cognition that fall short of dementia but still impact functional abilities, independence, and financial decision making. Understanding the effects of age-related functional changes on the nicotinic system will elucidate one neurochemical mechanism underlying age-related changes in cognition and will provide information about how nicotinic dysfunction affects cognition in healthy older adults. Prior research has shown that the nicotinic system has a roll in attention and memory in healthy adults. More recently, with the increased use of brain functional magnetic resonance imaging (fMRI) in combination with psychopharmacological manipulations, data patterns have emerged that further define the role of the nicotinic system in cognition, aging, and dementia. We propose that nicotinic system changes are responsible for age differences in working memory task performance and brain activation. We can observe the functioning of the nicotinic system by examining brain activation patterns in response to nicotinic blockade and stimulation. Increased medial frontal gyrus (MFG) activation has been shown in older adults compared to younger adults. We propose that temporary antagonism of the nicotinic system will model this “older pattern” of impaired performance and increased MFG activation. We hypothesize that older adults will have greater performance impairments and increased MFG activation compared to younger adults after nicotinic blockade. We also propose that nicotinic stimulation will result in “younger patterns” of better performance and decreased MFG activation. We hypothesize that nicotinic stimulation will improve performance and this improvement will be greater for older adults compared to younger adults. We will also observe decreased MFG activation that will be greater for older adults compared to younger adults. These data will further the understanding of one neurochemical mechanism involved in normal aging and how brain activation patterns relate to receptor function. As the search continues for safe and effective cognitive enhancers, it will be important to understand the role of the nicotinic system in cognitive aging and whether nicotinic mechanisms have the potential to benefit cognition in healthy adults.