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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG034446-04
Application #
8309207
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5 (M2))
Program Officer
Wagster, Molly V
Project Start
2009-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$288,171
Indirect Cost
$107,369
Name
Princeton University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08544
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
Arey, Rachel N; Murphy, Coleen T (2016) Conserved regulators of cognitive aging: From worms to humans. Behav Brain Res :
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
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 154:676-90
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
Kauffman, Amanda; Parsons, Lance; Stein, Geneva et al. (2011) C. elegans positive butanone learning, short-term, and long-term associative memory assays. J Vis Exp :

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