Identifying new mechanisms of long-term memory formation

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Project Summary/Abstract One debilitating feature of aging is the loss of cognitive abilities, especially memory decline. Alzheimer’s disease reduces the healthspan of patients, resulting in a loss of independence and social relationships. The disease is also financially burdensome to patients and society. Despite the increase in the prevalence of Alzheimer’s disease, the mechanisms that underlie aberrant memory function are unclear, making the treatment of memory decline challenging. It is well established that the CREB transcription factor is required for long-term memory; however, not all factors involved in CREB-dependent long-term memory formation are known yet. Identifying factors upstream and downstream in the CREB cascade could reveal new mechanisms for the treatment and reversal of Alzheimer’s disease and other dementias. To identify new candidates that function within the CREB pathway and regulate long-term memory consolidation, this proposal will examine the role of specific nuclear factors (Aim 1), small non-coding RNAs (Aim 2), and glial factors (Aim 3) in CREB- dependent long-term memory. Nuclear factors regulate gene transcription, so identifying which factors modulate memory formation is critical. Small RNAs regulate gene expression transcriptionally and post- transcriptionally, but their function in adult neurons and, in turn memory, has not been tested. Glia have recently been implicated in memory, but how they support memory consolidation is largely unexplored. We are using the well-established aging model system C. elegans to determine where and how these factors function to regulate memory with age. Our lab has shown that the memory machinery, including the CREB requirement for long-term memory consolidation, is conserved in C. elegans and we developed behavioral assays to test learning and short-term and long-term associative memory. C. elegans serves as a powerful system to investigate the molecular mechanisms of memory. There are ample genetic tools available, and, with the worm’s simple nervous system, mechanisms by which candidate genes regulate memory can be easily probed. By using behavioral assays, tissue-specific isolation techniques, and transcriptomic approaches, these experiments will determine where and how specific nuclear factors, small RNAs, and glial factors function within the CREB pathway to regulate memory formation with age. This proposal examines multiple facets of CREB-dependent long-term memory and will identify new candidates and pathways required for memory formation. These findings could lead to better therapeutics for reversing or treating age-related cognitive decline in cases of neurodegenerative disease, including Alzheimer’s. The proposed research plan will provide the applicant with extensive training in behavioral, molecular, and tissue-specific transcriptomic approaches to study memory with age. The training in these techniques and the proposed individualized mentorship plan will ensure the applicant is prepared for a career as an independent investigator, studying mechanisms of memory and age-related cognitive decline.