Proposed studies will assess hypotheses related to a fundamental biological problem, how sleep affects brain structure and plasticity. We will examine the processes of adult hippocampal neurogenesis (AN) and the expression of genes and proteins facilitating AN. We showed that sleep deprivation strongly inhibits proliferation of new cells and the percentage of new cells showing mature neuronal properties. We now propose to study effects of sleep fragmentation and REM deprivation on AN and to evaluate a prediction of delayed functional effects of sleep fragmentation. AN is regulated by a cascade of proteins, including phosphorylated cyclic AMP response element binding protein (pCREB) and brain-derived neurotrophic factor (BDNF). Our pilot data shows that 48 hrs sleep deprivation depresses hippocampal expression of BDNF as well as synapsin-1, a vesicular protein induced by BDNF. In neocortex plasticity-related genes are expressed during wake. Brain protein synthesis is increased during sleep. These findings suggest that wake and sleep states play distinct roles in support of brain functions and plasticity. We will assess the following model: The light/sleep phase provides the milieu for gene translation and protein synthesis, including cell proliferation. REM sleep is required for protein docking and stabilization. However, the interactions of wake and sleep and the effects of sleep fragmentation and REM deprivation on proliferation gene expression and protein synthesis in hippocampus have not been studied. We will separately analyze the light phase sleep arid dark phase wake periods and determine effects of sleep fragmentation and REM deprivation. Cell proliferation will be studied by the bromodeoxyuridine (BrdU) method. Gene expression in hippocampus is assessed by RT-PCR. We propose to restore proliferation, during sleep fragmentation and to suppress proliferation during sleep by local changes in BDNF. Our studies utilize a new, well-controlled, non-stressful method of sleep deprivation, the intermittent treadmill. Dependent variables will be correlated with sleep parameters and delta EEG activity during sleep. Much evidence shows that suppression of AN could be critically involved in the neuro- and cognitive pathology associated with aging and with prevalent human diseases, including major depressive disorder, and obstructive sleep apnea. Chronic sleep fragmentation and restriction are common to these conditions. ? ? ?

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Biological Rhythms and Sleep Study Section (BRS)
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Beckel-Mitchener, Andrea C
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University of California Los Angeles
Schools of Arts and Sciences
Los Angeles
United States
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Methippara, M; Mitrani, B; Schrader, F X et al. (2012) Salubrinal, an endoplasmic reticulum stress blocker, modulates sleep homeostasis and activation of sleep- and wake-regulatory neurons. Neuroscience 209:108-18
Kostin, A; Rai, S; Kumar, S et al. (2011) Nitric oxide production in the perifornical-lateral hypothalamic area and its influences on the modulation of perifornical-lateral hypothalamic area neurons. Neuroscience 179:159-69
Rai, S; Kumar, S; Alam, M A et al. (2010) A1 receptor mediated adenosinergic regulation of perifornical-lateral hypothalamic area neurons in freely behaving rats. Neuroscience 167:40-8
Alam, M N; Kumar, S; Suntsova, N et al. (2010) GABAergic regulation of the perifornical-lateral hypothalamic neurons during non-rapid eye movement sleep in rats. Neuroscience 167:920-8
Methippara, Melvi; Bashir, Tariq; Suntsova, Natalia et al. (2010) Hippocampal adult neurogenesis is enhanced by chronic eszopiclone treatment in rats. J Sleep Res 19:384-93
Sportiche, N; Suntsova, N; Methippara, M et al. (2010) Sustained sleep fragmentation results in delayed changes in hippocampal-dependent cognitive function associated with reduced dentate gyrus neurogenesis. Neuroscience 170:247-58
Meerlo, Peter; Mistlberger, Ralph E; Jacobs, Barry L et al. (2009) New neurons in the adult brain: the role of sleep and consequences of sleep loss. Sleep Med Rev 13:187-94
Methippara, Melvi M; Bashir, Tariq; Kumar, Sunil et al. (2009) Salubrinal, an inhibitor of protein synthesis, promotes deep slow wave sleep. Am J Physiol Regul Integr Comp Physiol 296:R178-84
Suntsova, N; Kumar, S; Guzman-Marin, R et al. (2009) A role for the preoptic sleep-promoting system in absence epilepsy. Neurobiol Dis 36:126-41
Methippara, M M; Alam, M N; Kumar, S et al. (2008) Administration of the protein synthesis inhibitor, anisomycin, has distinct sleep-promoting effects in lateral preoptic and perifornical hypothalamic sites in rats. Neuroscience 151:1-11

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