Molecular and physiological determinants of age-related working memory decline



 DESCRIPTION (provided by applicant): Successes in improving somatic and peripheral health outpace our ability to protect brain health later in life. With advanced age, memory complaints become more frequent and severe and the manifestation of cognitive dysfunction poses a threat to the personal independence and well-being of our growing senior citizen population. Working memory, the ability to hold and manipulate information "in mind", is widely known to decline with age although the neural changes within the prefrontal cortex that underlie this decline remain poorly defined. Most neural models of working memory support that persistent excitation of pyramidal neurons is required for the maintenance of information in working memory stores. Co-distributed GABAergic interneurons also play an important role in sculpting pyramidal network activity and providing specificity for the to-be-remembered information. As such, it is not surprising that shifts in excitatory and inhibitory signaling dynamcs that occur in a number of diseases have profound consequences for working memory abilities. Preliminary data from our laboratory indicates that aging is accompanied by cell-type specific alterations in both prefrontal cortical GABA(B) receptor and NMDA receptor signaling. Our long-term goal is to understand both the causative factors and cognitive consequences of these signaling alterations within PFC and to use this information to identify novel intervention strategies that can optimize cognitive function across the full lifespan. Our rationale is that thee receptors are particularly vulnerable to cellular insults that accompany the aging process (e.g., oxidative stress or excessive glucocorticoid exposure) and that compromised signaling at GABA(B) and NMDA receptors in the aged PFC could markedly alter excitatory-inhibitory dynamics required for normal cognition. This project will, therefore, use a rat model of impaired working memory to test the hypotheses that 1) altered signaling at NMDA and GABA(B) receptors contributes to age-related decline of working memory abilities and 2) that chronic variable stress that mimics age-related hypothalamic-pituitary- adrenal axis dysfunction is sufficient to produce both working memory impairment and alterations in GABA(B) and NMDA receptors. Using a multidisciplinary approach that integrates rigorous behavioral/cognitive analysis with biochemical, electrophysiological and pharmacological techniques we will test our hypotheses by 1) determining if NMDAR dysfunction contributes to impaired working memory in aged rats; 2) determining how changes in GABA(B) and NMDA receptor signaling on prefrontal cortical pyramidal neurons and interneurons contribute to age-related working memory impairment; and 3) determining the contribution of stress and glucocorticoid signaling to age-related changes in GABA(B) and NMDA receptors and working memory abilities. Findings from this proposal will be significant because they will provide a critical foundation for developing ne therapeutic approaches to both prevent and reverse age-related cognitive decline. Furthermore, the proposed research will afford the applicant significant technical, conceptual and professional training in support of his stated career goals and objectives.