Neural Mechanisms of Cognitive Decline in Aging

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DESCRIPTION (provided by applicant): Accumulating evidence indicates that during normal aging, executive functions supported by the prefrontal cortex are among the earliest and most severely impaired cognitive abilities. Executive functions, which include attention, working memory, and cognitive flexibility, are essential to the successful guidance of adaptive behavior and to higher-order aspects of cognition such as decision making. Disruption of corticolimbic g- aminobutyric acid (GABA)ergic inhibitory circuits can have profound consequences for executive function, and preliminary data indicate that prefrontal cortical GABAergic systems are dysregulated in normal aging. Our long term goal is to understand how age-related alterations in forebrain inhibitory circuitry affect executive functions, and to identify potential therapeutic targets that can be exploited to improve cognition in aged individuals. Important to this goal, we have found that there are robust individual differences in the effects of normal aging on executive function, such that some aged subjects are impaired on an attentional set shifting test of cognitive flexibility whereas others are impaired on a delayed response test of working memory. Moreover, our preliminary data suggest that these distinct forms of executive dysfunction are linked to differences in patterns of GABAergic signaling. Building on our extensive preliminary data, the objective of this proposal is to determine how altered GABAergic signaling within the prefrontal cortex affects executive function and whether this signaling can be manipulated to attenuate age-related executive impairments. Our central hypothesis is that individual differences in prefrontal cortical GABAergic signaling underlie distinct forms of executive dysfunction within aging populations. The rationale for the proposed work is that by understanding how altered inhibitory signaling in prefrontal cortex contributes to different forms of executive dysfunction, we will be well-positioned to begin to develop intervention strategies that will allow tailored and more efficacious treatments for executive decline that accompanies aging. Using an integrative approach in which we combine behavioral assays with molecular, electrophysiological, anatomical, and pharmacological studies in Fischer 344 rats, we will test our central hypothesis by: 1) determining if individual differences in prefrontal cortical GABAergic signaling contribute to different forms of age-related executive dysfunction; 2) determining if compromised regulation and activation of prefrontal cortical interneurons contributes to age-related executive dysfunction; and 3) determining if altered GABAergic signaling and executive dysfunction in aging contribute to impairments in decision making. We will employ an innovative approach which both considers individual differences and employs the evaluation of multiple subcomponents of executive function. The findings from the proposed studies will be significant because the information gained will provide foundational knowledge necessary to develop tailored treatments for remediating executive decline and promoting quality of life and independence across the full lifespan.