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.