Neurogenesis and Memory Network Dynamics during Normal Aging

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 DESCRIPTION (provided by applicant): By the year 2020 the number of Americans over the age of 65 is projected to reach 55 million. It is therefore imperative that the ability of these individuals to live independently is preserved for reasons of personal dignity as well as the financial and public-health consequences that result from the necessity of long-term care. Unfortunately, even in the absence of significant neuropathology, a large proportion of elderly people will experience memory decline that will interfere with their instrumental activities of daiy living. The hippocampus is critical for memory and is subject to dysfunction during aging. Importantly, the dentate gyrus subregion of the hippocampus is one of only two brain regions in which new neurons are born and integrated into existing neural circuits; a process referred to as neurogenesis. Neurogenesis declines with age, but it is not known how this contributes to cognitive impairments. Although neurogenesis could have vital functions for normal memory, there is a fundamental gap in our knowledge of how this process impacts neuronal networks both within the dentate gyrus as well as in the brain regions that receive direct input from this structure. Moreover, to date, there is not a single report of the in vivo physiological characteristics of dentate gyrus neurons in aged animals. The long-term goal of the proposed research plan is to pinpoint disruptions in the neural circuits of old animals that can then be restored through therapeutic or behavioral interventions to reduce cognitive impairments in the elderly. The objective in this particular application is to determine how neurogenesis levels impact hippocampal-dependent behaviors and the dynamics of neural networks within the dentate gyrus and its primary efferent target, CA3. The central hypothesis is that the integration of newborn neurons is critical for dynamic hippocampal representations needed to support complex behaviors. The rationale for the proposed research is that understanding the functional importance of neurogenesis and how dentate gyrus and CA3 cellular activity dynamics are impacted by lower numbers of newborn neurons could direct clinical treatments for cognitive deficits associated with aging that are going to become more prevalent as the number of elderly people in the U.S. continues to grow. The hypothesis will be tested with 2 specific aims: 1) identify how age- related neurogenesis decline impact dentate gyrus circuit dynamics, and 2) quantify the impact of age- associated functional changes in the dentate gyrus on CA3. These aims will be achieved through the use of high-channel count neural recordings that allow single-cell activity to be monitored from up to hundreds of neurons across multiple brain regions simultaneously in behaving rats. This is an innovative approach that optimizes power for detecting neural-behavioral relationships.