The goal of our research is to elucidate the molecular machinery underlying sleep and to define the role of sleep in the consolidation of long-term memory. Sleep is involved in many physiological processes, and disturbances in sleep are a hallmark of many diseases, including neurodegenerative disorders such as Alzheimer's disease, in which memory deficits are prominent. An understanding of the relation between sleep dysfunction and memory loss may help us to better define the pathophysiology of these diseases. We are interested in bridging past behavioral studies, which have shown that sleep is needed for the consolidation of memory, with current knowledge about the molecular mechanisms underlying memory storage. Mice are an ideal system with which to explore the relationship between sleep and memory consolidation. Our recent work has used genetic and pharmacological approaches in mice to demonstrate that protein kinase A (PKA) activity is critically important for long-term memory storage. There are striking parallels between the effects of sleep deprivation and the effects of pharmacological manipulation of the PKA signaling pathway on the consolidation of memory. Both sleep deprivation and inhibition of PKA disrupt the consolidation of memory only at discrete times following training and these times vary depending on the strength of the training protocol. Based on this, we propose to examine the role of the cAMP/PKA/CREB signaling pathway in the behavioral effects of sleep deprivation on hippocampus-dependent tasks in mice.
In Specific Aim 1, we will determine the effects of total sleep deprivation as well as rapid eye movement (REM) and non-REM (NREM) sleep deprivation on contextual fear conditioning, a single-trial hippocampus-dependent learning task in mice.
Specific Aim 2 will focus on biochemical and molecular assays to directly measure changes in PKA activity and phospho-CREB levels in the hippocampus after sleep deprivation and contextual fear conditioning.
Specific Aim 3 will investigate the hypothesis that sleep may modulate memory storage through the prominent cholinergic flux to the hippocampus that occurs during REM sleep.
In Specific Aim 4, we will examine sleep architecture in mice with genetic alterations in the cAMP/PKA/CREB signaling pathway to test the hypothesis that memory consolidation deficits in these mice are due to altered patterns of sleep. The broad-based experimental design of this proposal, using genetic, pharmacological, electrophysiological and behavioral approaches, will bring us closer to an understanding of the molecular and biochemical processes underlying sleep and enable us to define the role that sleep plays in memory consolidation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG018199-04
Application #
6509748
Study Section
Special Emphasis Panel (ZHL1-CSR-R (S1))
Program Officer
Monjan, Andrew A
Project Start
1999-09-30
Project End
2004-06-30
Budget Start
2002-07-01
Budget End
2004-06-30
Support Year
4
Fiscal Year
2002
Total Cost
$237,750
Indirect Cost
Name
University of Pennsylvania
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Hernandez, Pepe J; Abel, Ted (2011) A molecular basis for interactions between sleep and memory. Sleep Med Clin 6:71-84
Hellman, Kevin; Hernandez, Pepe; Park, Alice et al. (2010) Genetic evidence for a role for protein kinase A in the maintenance of sleep and thalamocortical oscillations. Sleep 33:19-28
Kelly, M P; Stein, J M; Vecsey, C G et al. (2009) Developmental etiology for neuroanatomical and cognitive deficits in mice overexpressing Galphas, a G-protein subunit genetically linked to schizophrenia. Mol Psychiatry 14:398-415, 347
Favilla, Christopher; Abel, Ted; Kelly, Michele P (2008) Chronic Galphas signaling in the striatum increases anxiety-related behaviors independent of developmental effects. J Neurosci 28:13952-6
Kelly, Michele P; Cheung, York-Fong; Favilla, Christopher et al. (2008) Constitutive activation of the G-protein subunit Galphas within forebrain neurons causes PKA-dependent alterations in fear conditioning and cortical Arc mRNA expression. Learn Mem 15:75-83
Hellman, Kevin; Abel, Ted (2007) Fear conditioning increases NREM sleep. Behav Neurosci 121:310-23
Kelly, Michele P; Isiegas, Carolina; Cheung, York-Fong et al. (2007) Constitutive activation of Galphas within forebrain neurons causes deficits in sensorimotor gating because of PKA-dependent decreases in cAMP. Neuropsychopharmacology 32:577-88
Keeley, Michael B; Wood, Marcelo A; Isiegas, Carolina et al. (2006) Differential transcriptional response to nonassociative and associative components of classical fear conditioning in the amygdala and hippocampus. Learn Mem 13:135-42
Hussain, Rifat J; Stumpo, Deborah J; Blackshear, Perry J et al. (2006) Myristoylated alanine rich C kinase substrate (MARCKS) heterozygous mutant mice exhibit deficits in hippocampal mossy fiber-CA3 long-term potentiation. Hippocampus 16:495-503
Bourtchouladze, Rusiko; Patterson, Susan L; Kelly, Michele P et al. (2006) Chronically increased Gsalpha signaling disrupts associative and spatial learning. Learn Mem 13:745-52

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