C. elegans, like humans, experience cognitive functional declines with age, but the cause of these declines are not yet known. We propose to identify age-related changes in neuronal function, and to distinguish those changes that are functionally deleterious from those that may be an adaptive response to aging. In our first Aim, we will identify the genes required for long-term associative memory (LTAM) that change with age and with decreased function, and rescue function with age through manipulation of candidate genes.
Our second Aim focuses on the identification of the cells involved in LTAM, and the characterization of their roles in the LTAM process. Furthermore, we will assess changes in cellular function with age. Finally, we will compare changes during normal aging to pathological changes in two C. elegans models of dementia. Comparisons with models of dementia will distinguish healthy from pathological age-dependent changes. Through these studies, the contributions of specific components to functional cognition will be used to identify the best targets of therapeutic intervention to treat cognitive decline with age.

Public Health Relevance

In our work, we propose to use the model organism C. elegans to discover genes whose changes in function are correlated with decline in cognitive ability with age. We have designed a test of long-term memory in this organism, and observe that the animals lose their ability to remember with age. Using this test and various molecular tools, we can study the genes and cells responsible for loss of memory with age and in neurodegenerative disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZAG1-ZIJ-5 (M2))
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Wagster, Molly V
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Princeton University
Schools of Arts and Sciences
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Arey, Rachel N; Murphy, Coleen T (2017) Conserved regulators of cognitive aging: From worms to humans. Behav Brain Res 322:299-310
Kaletsky, Rachel; Lakhina, Vanisha; Arey, Rachel et al. (2016) The C. elegans adult neuronal IIS/FOXO transcriptome reveals adult phenotype regulators. Nature 529:92-6
Li, Ling-Bo; Lei, Haoyun; Arey, Rachel N et al. (2016) The Neuronal Kinesin UNC-104/KIF1A Is a Key Regulator of Synaptic Aging and Insulin Signaling-Regulated Memory. Curr Biol 26:605-15
Lakhina, Vanisha; Arey, Rachel N; Kaletsky, Rachel et al. (2015) Genome-wide functional analysis of CREB/long-term memory-dependent transcription reveals distinct basal and memory gene expression programs. Neuron 85:330-45
Wang, Juan; Kaletsky, Rachel; Silva, Malan et al. (2015) Cell-Specific Transcriptional Profiling of Ciliated Sensory Neurons Reveals Regulators of Behavior and Extracellular Vesicle Biogenesis. Curr Biol 25:3232-8
Stein, Geneva M; Murphy, Coleen T (2014) C. elegans positive olfactory associative memory is a molecularly conserved behavioral paradigm. Neurobiol Learn Mem 115:86-94
Tepper, Ronald G; Ashraf, Jasmine; Kaletsky, Rachel et al. (2013) PQM-1 complements DAF-16 as a key transcriptional regulator of DAF-2-mediated development and longevity. Cell 154:676-690
Stein, Geneva M; Murphy, Coleen T (2012) The Intersection of Aging, Longevity Pathways, and Learning and Memory in C. elegans. Front Genet 3:259
Rizki, Gizem; Iwata, Terri Naoko; Li, Ji et al. (2011) The evolutionarily conserved longevity determinants HCF-1 and SIR-2.1/SIRT1 collaborate to regulate DAF-16/FOXO. PLoS Genet 7:e1002235
Liu, Gang; Rogers, Jason; Murphy, Coleen T et al. (2011) EGF signalling activates the ubiquitin proteasome system to modulate C. elegans lifespan. EMBO J 30:2990-3003

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