Sleep loss produces deficits in hippocampal synaptic plasticity and hippocampus-dependent memory storage. However, the molecular and cellular mechanisms that underlie these effects of sleep deprivation remain unclear. Several studies have suggested that protein synthesis pathways are altered during sleep and after periods of sleep deprivation. None however have previously described in mechanistic detail how protein synthesis is altered with sleep or sleep deprivation, nor how these alterations regulate memory formation. In this proposal, we will explore the protein synthesis regulatory role of mammalian target of rapamycin (mTOR) signaling during sleep and sleep-mediated memory consolidation. The experiments proposed will develop tools to analyze mTOR signaling in the brain and will provide direct evidence for a novel role of mTOR signaling in sleep-dependent memory consolidation. In this application, two Specific Aims are proposed that use novel genetic approaches to study how sleep deprivation affects the mTOR signaling pathway that results in reduced translation. To directly test the role of mTOR signaling - and the role of 4E-BP activity in particular - in sleep deprivation-induced impairments, we will use a viral-expression approach in Specific Aim 1 to determine if expressing wild-type 4E-BP in the hippocampus is sufficient to restore memory and plasticity deficits induced by sleep deprivation. This approach will allow for carefully timed and cell type- and brain region-specific expression of 4E-BP with sleep deprivation. Finally, in Specific Aim 2 we will use a viral approach to determine if expressing phosphorylation-defective 4E-BP in the hippocampus will mimic the effects of sleep deprivation. Importantly, these experiments will allow us to determine if mTOR signaling plays a functional role in the memory and plasticity deficits observed with sleep loss.

Public Health Relevance

Sleep deprivation is a significant public health issue in our society with millions of people obtaining insufficient sleep that greatly affects quality of life. Additionally, many people who have psychiatric and neurodegenerative disorders, including depression, schizophrenia, and Alzheimer's disease, suffer from sleep loss. This proposal seeks to explore the potential of the mTOR signaling pathway to reverse the negative impact of sleep deprivation on cognition, which promises to lead to the development of novel therapeutic approaches to alleviate the cognitive deficits associated with sleep loss.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32MH099730-01A1
Application #
8717169
Study Section
Special Emphasis Panel (ZRG1-F02B-D (20))
Program Officer
Li, Ingrid Y
Project Start
2014-04-01
Project End
2016-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$57,794
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