Abstract

Poor sleep quality or disrupted sleep, due to reasons such as sleep disorders, psychiatric disturbances, or aging, are associated with impairments in cognitive function. Deficits in learning and memory that can result from disrupted sleep have recurring and profound impacts on daily function. Understandably, unraveling the common molecular mechanisms between sleep disturbances and neurocognitive impairments ? which may lead to new therapeutic approaches to alleviate these outcomes ? is of great importance. Our project is designed to test the overall hypothesis that kynurenic acid (KYNA), an astrocyte-derived metabolite of the kynurenine pathway (KP) of tryptophan metabolism, represents a key molecular link between sleep disturbances and cognitive dysfunction. We will examine, in rats, a) the mechanisms linking sleep deprivation (SD) and increased KYNA formation; b) the role of KYNA in connecting sleep dysfunction and cognitive deficits; and c) the therapeutic value of KYNA synthesis inhibition to overcome cognitive deficits after SD. A newly developed specific inhibitor of kynurenine aminotransferase II (KAT II), the main enzyme responsible for KYNA formation, will be used as an experimental tool to mechanistically test the hypothesis. There are three specific aims to test our hypothesis.
Aim #1 : To examine the dynamics of KP metabolism in the brain, liver, and blood after SD. Working hypothesis: Peripheral changes in kynurenine pathway metabolism drive increased KYNA formation in the hippocampus after SD.
Aim #2 : To investigate the impact of up- and down- regulation of KYNA formation on sleep architecture. Working hypothesis: Elevations in KYNA adversely impact sleep and targeted inhibition of KAT II can improve sleep quality.
Aim #3 : To evaluate the impact of KYNA synthesis inhibition in attenuating hippocampal-mediated cognitive dysfunction and improving sleep quality after SD. Working hypothesis: Inhibition of KAT II serves as an efficacious strategy to overcome sleep loss-induced cognitive dysfunction. Successful completion of these experiments will define causal relationships between KP metabolism, sleep disturbances, and hippocampal-mediated cognitive functions. The proposed research will advance our understanding of common molecular mechanisms between sleep disturbances and neurocognitive impairments, paving the way for novel therapies to alleviate these outcomes.

Public Health Relevance

Nearly half of all Americans report poor or insufficient sleep that afflicts their daily activities at least once a week. These cycles of poor sleep are associated with impairments in cognitive function, including deficits in learning and memory. Unraveling the underlying mechanisms between sleep disturbances and neurocognitive impairments ? which may lead to new therapeutic approaches to alleviate these outcomes? is of great importance. The following proposal is designed to test the novel hypothesis that kynurenic acid represents a key molecular link between sleep disturbances and cognitive dysfunction.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS102209-04
Application #
9664008
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
He, Janet
Project Start
2018-09-01
Project End
2022-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost

  Institution

Name
University of South Carolina at Columbia
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041387846
City
Columbia
State
SC
Country
United States
Zip Code
29208