Sleep benefits the nervous system but the mechanisms underlying its restorative and neuroprotective properties are unknown. This understanding is important: without a circuit, cellular and molecular understanding we limit our ability to address disorders, such as Alzheimer's disease, that are exacerbated by lack of sleep or to devise treatments based on sleep's benefits. By examining and manipulating the most compact circuit that requires sleep to consolidate memory, we hope to decipher the molecular and cellular rules by which sleep enhances the performance of a neural network. Rules employed by a simple circuit are likely to be followed by cells within circuit modules that are linked together to form the much more complicated neural network of a human brain. We will utilize the anatomic simplicity and optical malleability of the C. elegans olfactory circuit to test hypotheses designed to elucidate the rules by which sleep acts to promote memory. Specifically, we will:
Aim 1. Test the hypothesis that sleep is required for olfactory memory consolidation in a C. elegans classical conditioning model. We will examine sleep in animals that have been conditioned to avoid butanone. We will test the hypothesis that sleep is correlated with the strength of the memory and that it is both necessary and sufficient to promote memory consolidation. We will identify the cells that are required for sleep post training. These studies will lay the groundwork for understanding if sleep occurs post training and whether it is indeed necessary and sufficient to promote memory consolidation.
Aim 2. Identify the synaptic basis of memory consolidation during sleep. First, we will observe the synapses via GRASP Then, using light-driven tools to activate or inactivate the animals during the consolidation period, we will test memory consolidation. We will then ask if visible markers for connections between cells are altered. These would provide the first study with synaptic resolution in a live animal of a memory trace being consolidated by sleep. Upon completion of these aims, we will have a conceptual, molecular, cellular, and circuit framework to understand how sleep alters the cell's function to benefit memory storage and thus behavioral fitness. The impact of this study is that it will ultimately inform study and treatment of disorders of sleep and memory and harness sleep's benefits to tackle aging and neurodegeneration.

Public Health Relevance

How sleep benefits the nervous system is unknown and specifically how it affects memory consolidated is still a mystery. Our lab is the first, to our knowledge, to have discovered that C. elegans require sleep after a spaced learning task in order to consolidate memory. Thus, we propose to leverage this anatomically simple, transparent organism to understand how this enigmatic yet beneficial process of sleep affects memory. The rules employed by a simple circuit are likely to be followed by cells within the circuit modules that link together to form the much more complicated neural network of a human brain.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
3R01DC005991-11A1S2
Application #
9920425
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sullivan, Susan L
Project Start
2004-12-05
Project End
2023-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
11
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Anatomy/Cell Biology
Type
Schools of Dentistry/Oral Hygn
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
O'Halloran, Damien M; Altshuler-Keylin, Svetlana; Zhang, Xiao-Dong et al. (2017) Contribution of the cyclic nucleotide gated channel subunit, CNG-3, to olfactory plasticity in Caenorhabditis elegans. Sci Rep 7:169
Cho, Christine E; Brueggemann, Chantal; L'Etoile, Noelle D et al. (2016) Parallel encoding of sensory history and behavioral preference during Caenorhabditis elegans olfactory learning. Elife 5:
He, Chao; Altshuler-Keylin, Svetlana; Daniel, David et al. (2016) The cyclic nucleotide gated channel subunit CNG-1 instructs behavioral outputs in Caenorhabditis elegans by coincidence detection of nutritional status and olfactory input. Neurosci Lett 632:71-8
Juang, Bi-Tzen; Ludwig, Anna L; Benedetti, Kelli L et al. (2014) Expression of an expanded CGG-repeat RNA in a single pair of primary sensory neurons impairs olfactory adaptation in Caenorhabditis elegans. Hum Mol Genet 23:4945-59
Juang, Bi-Tzen; Gu, Chen; Starnes, Linda et al. (2013) Endogenous nuclear RNAi mediates behavioral adaptation to odor. Cell 154:1010-1022
Krzyzanowski, Michelle C; Brueggemann, Chantal; Ezak, Meredith J et al. (2013) The C. elegans cGMP-dependent protein kinase EGL-4 regulates nociceptive behavioral sensitivity. PLoS Genet 9:e1003619
O'Halloran, Damien M; Hamilton, O Scott; Lee, Jin I et al. (2012) Changes in cGMP levels affect the localization of EGL-4 in AWC in Caenorhabditis elegans. PLoS One 7:e31614
Swarbrick, Alexander; Woods, Susan L; Shaw, Alexander et al. (2010) miR-380-5p represses p53 to control cellular survival and is associated with poor outcome in MYCN-amplified neuroblastoma. Nat Med 16:1134-40
Kaye, Julia A; Rose, Natalie C; Goldsworthy, Brett et al. (2009) A 3'UTR pumilio-binding element directs translational activation in olfactory sensory neurons. Neuron 61:57-70
O'Halloran, Damien M; Altshuler-Keylin, Svetlana; Lee, Jin I et al. (2009) Regulators of AWC-mediated olfactory plasticity in Caenorhabditis elegans. PLoS Genet 5:e1000761