The long-term objective of this research is to further our understanding of brainstem cellular, molecular, and network mechanisms of REM sleep regulation. Specifically, the goal of this renewal application is to investigate the involvement of pedunculopontine tegmentum (PPT) intracellular signaling mechanisms in the regulation of REM sleep. The central hypothesis of this proposal is that REM sleep is regulated by a balance of cellular mechanisms in the PPT;specifically, in the PPT, REM sleep is induced by the activation of cAMP- dependent protein kinase A (PKA), and REM sleep is suppressed by the induction of wakefulness caused by activation of Ca2????dependent protein kinase II (CaMKII) and/or mitogen-activated protein kinase (MAPK).
Three specific aims have been designed to systematically test this hypothesis: 1. Identify the neurotransmitter phenotype(s) of cells in the PPT whose activation induces REM sleep. To achieve this goal, state-dependently activated PPT cells will be identified by c-fos and pCREB expression, and their neurochemical identity will be determined by the immunocytochemical labeling of choline acetyltransferase (ChAT) and GABA. 2. Test the hypothesis that the activation of PKA in the PPT induces REM sleep. This goal will be achieved by quantifying the levels of PPT PKA activity after different amounts of REM sleep and by microinjecting a selective cAMP-PKA activation inhibitor into the PPT to block the homeostatic drive for REM sleep. 3. Test the hypothesis that CaMKII and MAPK activation in the PPT terminates REM sleep by inducing wakefulness. This goal will be achieved by measuring the levels of PPT CaMKII and MAPK activity at varying amounts of wakefulness and REM sleep and by applying inhibitors of CaMKII and MAPK activation into the PPT while quantifying their effects on the architecture of spontaneous as well as rebound REM sleep. All of these experiments will be performed on adult, freely moving rats. Preliminary data provide a rationale for each specific aim and demonstrate feasibility. This proposal addresses, at the mechanistic level, the general question in basic neurobiology: how is REM sleep regulated? Importantly, identification of the intracellular signaling molecules involved in the regulation of REM sleep may lead to the design of a future generation of drugs to treat REM sleep disorders as well as a variety of serious medical conditions that are exacerbated by disrupted REM sleep, such as narcolepsy/cataplexy, restless legs syndrome, endogenous depression, schizophrenia, Alzheimer's, and Huntington's disease.

Public Health Relevance

The goal of this research is to identify the intracellular signaling molecules involved in the normal regulation of rapid eye movement (REM) sleep. Recent evidence indicates that novel compounds designed to modify intracellular transduction pathways have therapeutic potential for endogenous depression, cancer, hypothermia, and pathological aggregation of platelets. Similarly, identification of the intracellular molecules involved in normal regulation of REM sleep may lead to the design of a future generation of drugs to treat REM sleep disorders as well as a variety of serious medical conditions that are exacerbated by disrupted REM sleep, such as narcolepsy/cataplexy, restless legs syndrome, endogenous depression, schizophrenia, Alzheimer's, and Huntington's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH059839-14
Application #
8247816
Study Section
Biological Rhythms and Sleep Study Section (BRS)
Program Officer
Vicentic, Aleksandra
Project Start
1999-04-01
Project End
2013-06-30
Budget Start
2012-04-01
Budget End
2013-06-30
Support Year
14
Fiscal Year
2012
Total Cost
$341,859
Indirect Cost
$131,484
Name
Boston University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Knapp, Clifford M; Ciraulo, Domenic A; Datta, Subimal (2014) Mechanisms underlying sleep-wake disturbances in alcoholism: focus on the cholinergic pedunculopontine tegmentum. Behav Brain Res 274:291-301
Siwek, Donald F; Knapp, Clifford M; Kaur, Gurcharan et al. (2014) Dorsal subcoeruleus nucleus (SubCD) involvement in context-associated fear memory consolidation. Exp Brain Res 232:1535-45
Datta, Subimal; O'Malley, Matthew W (2013) Fear extinction memory consolidation requires potentiation of pontine-wave activity during REM sleep. J Neurosci 33:4561-9
O'Malley, Matthew W; Fishman, Rachel Lea; Ciraulo, Domenic A et al. (2013) Effect of five-consecutive-day exposure to an anxiogenic stressor on sleep-wake activity in rats. Front Neurol 4:15
Desarnaud, Frank; Macone, Brian W; Datta, Subimal (2011) Activation of extracellular signal-regulated kinase signaling in the pedunculopontine tegmental cells is involved in the maintenance of sleep in rats. J Neurochem 116:577-87
Macone, Brian W; O'Malley, Matthew; Datta, Subimal (2011) Sharing stressful experiences attenuates anxiety-related cognitive and sleep impairments. Behav Brain Res 222:351-6
Datta, Subimal; O'Malley, Matthew W; Patterson, Elissa H (2011) Calcium/calmodulin kinase II in the pedunculopontine tegmental nucleus modulates the initiation and maintenance of wakefulness. J Neurosci 31:17007-16
Datta, Subimal; Desarnaud, Frank (2010) Protein kinase A in the pedunculopontine tegmental nucleus of rat contributes to regulation of rapid eye movement sleep. J Neurosci 30:12263-73
Huang, Max P; Radadia, Kushan; Macone, Brian W et al. (2010) Effects of eszopiclone and zolpidem on sleep-wake behavior, anxiety-like behavior and contextual memory in rats. Behav Brain Res 210:54-66
Datta, Subimal (2010) Cellular and chemical neuroscience of mammalian sleep. Sleep Med 11:431-40

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