Several theories concerning sleep function posit that sleep serves to maintain, repair or consolidate synapses. Several lines of evidence support these theories but, to date, there has been no direct test of these hypotheses. An independent large literature relates long-term memory tasks to synaptic plasticity. Further, a few studies have demonstrated a clear influence of sleep on memory consolidation and of learning tasks on sleep. However, there are heretofore, no studies of the influence of sleep on synaptic plasticity despite the theoretical foundation for such studies and the fact that the necessary molecular tools and mouse models are now available. To test the general hypothesis that sleep has a role in synaptic plasticity we will use a non-cognitive stimulus (a unilateral whisker cut) and a cognitive stimulus (a spatial learning test) to induce synaptic plasticity in the somatosensory cotex and the hippocampus respectively. The effects of sleep loss and excess sleep in these experimental paradigms on the magnitude and rates of change of a variety of molecular markers of synaptic plasticity will be determined. The markers to be analyzed represent six classes of molecules necessary for synaptic remodeling; extracellular matrix proteins, cell adhesion molecules, growth factors, neurotransmission related proteins, cytoskeletal and associated proteins and transcription factors. Three strains of mice will be used, AKR/J, acallosal mice and a transgenic strain carrying the lac-Z gene coupled to a promoter dependent upon the presence of nuclear factor Kappa B. In addition to quantifying the changes in the molecular markers of synaptic plasticity in extracts of small areas of the brain, we will also determine the specific location of cell types in which these molecules change in response to sleep manipulation using histochemistry, immunocytochemistry and in situ hybridization histochemistry. Expected results will provide the foundations for the experimental verification of sleep function.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064245-05
Application #
6527310
Study Section
Special Emphasis Panel (ZHL1-CSR-R (S1))
Program Officer
Twery, Michael
Project Start
1999-09-30
Project End
2004-08-31
Budget Start
2002-09-01
Budget End
2004-08-31
Support Year
5
Fiscal Year
2002
Total Cost
$346,275
Indirect Cost
Name
Pennsylvania State University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Wright, John W; Yamamoto, Brent J; Harding, Joseph W (2008) Angiotensin receptor subtype mediated physiologies and behaviors: new discoveries and clinical targets. Prog Neurobiol 84:157-81
Wright, John W; Mizutani, Shigehiko; Harding, Joseph W (2008) Pathways involved in the transition from hypertension to hypertrophy to heart failure. Treatment strategies. Heart Fail Rev 13:367-75
Jenkins, Joe B; Omori, Takenori; Guan, Zhiwei et al. (2006) Sleep is increased in mice with obesity induced by high-fat food. Physiol Behav 87:255-62
Guan, Zhiwei; Fang, Jidong (2006) Peripheral immune activation by lipopolysaccharide decreases neurotrophins in the cortex and hippocampus in rats. Brain Behav Immun 20:64-71
Tang, Xiangdong; Xiao, Jihua; Parris, Brian S et al. (2005) Differential effects of two types of environmental novelty on activity and sleep in BALB/cJ and C57BL/6J mice. Physiol Behav 85:419-29
Guan, Zhiwei; Vgontzas, Alexandros N; Omori, Takenori et al. (2005) Interleukin-6 levels fluctuate with the light-dark cycle in the brain and peripheral tissues in rats. Brain Behav Immun 19:526-9
Wright, John W; Harding, Joseph W (2004) The brain angiotensin system and extracellular matrix molecules in neural plasticity, learning, and memory. Prog Neurobiol 72:263-93
Guan, Zhiwei; Peng, Xuwen; Fang, Jidong (2004) Sleep deprivation impairs spatial memory and decreases extracellular signal-regulated kinase phosphorylation in the hippocampus. Brain Res 1018:38-47
Feng, Pingfu; Guan, Zhiwei; Yang, Xiaoping et al. (2003) Impairments of ERK signal transduction in the brain in a rat model of depression induced by neonatal exposure of clomipramine. Brain Res 991:195-205
Wright, John W; Reichert, Jennifer R; Davis, Christopher J et al. (2002) Neural plasticity and the brain renin-angiotensin system. Neurosci Biobehav Rev 26:529-52

Showing the most recent 10 out of 11 publications