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 molecular mechanisms within the cholinergic cell compartment of the pedunculopontine tegmentum (CCC-PPT) and dorsal subcoeruleus nucleus (SubCD) with respect to their roles in homeostatic regulation of REM sleep. The central hypothesis of this proposal is that homeostatic regulation of REM sleep and phasic pontine- wave (P-wave) activity are actively regulated by the interaction between brain-derived neurotrophic factor (BDNF) receptors (tropomyosin-related kinase B [TrkB]) and extracellular signal-regulated kinase1/2 (ERK1/2) signaling in the CCC-PPT and SubCD.
Three specific aims have been designed to systematically test this hypothesis: 1. Test the hypothesis that during selective REM sleep deprivation, increased slow-wave sleep and increased expression of BDNF in the CCC-PPT are critical for the development of homeostatic drive for REM sleep, and under the same conditions, increased BDNF expression in the SubCD is critical for the homeostatic regulation of P-wave activity. This goal will be achieved by measuring homeostatic drive-associated changes in BDNF levels in the CCC-PPT, SubCD, and in a number of control areas at different intensities of increased REM sleep homeostatic drive. 2. Test the hypothesis that the interaction between BDNF TrkB receptors and ERK1/2 signaling in the CCC-PPT is critical for the homeostatic regulation of REM sleep, and that this same interaction in the SubCD is critical for the homeostatic regulation of P-wave activity. To test this hypothesis, at the beginning of a selective REM sleep deprivation period we will apply a BDNF TrkB receptor inhibitor, ERK1/2 activation inhibitor, or vehicle control into either the CCC-PPT or SubCD of rats, in order to block the increased homeostatic drive for REM sleep. 3. Test the hypothesis that, in heterozygous BDNF knockout (BDNF+/-) rats, decreased BDNF production in the CCC-PPT attenuates homeostatic regulation of REM sleep, and decreased BDNF production in the SubCD attenuates homeostatic regulation of P-wave activity. To test this hypothesis, at the beginning of the selective REM sleep deprivation period we will apply BDNF either into the CCC-PPT or SubCD of BDNF+/- rats. All of these experiments will be performed on adult, freely moving rats. We believe that the results of these studies will extend the leading edge of knowledge on the basic neurobiological mechanisms of REM sleep regulation. Also, for the first time, these results will launch a new area of investigation aimed at understanding the localized cellular and molecular mechanisms of homeostatic regulation of individual physiological signs of REM sleep. We believe that the results of these studies will shed light on the neuro-pathological mechanisms of REM sleep homeostatic regulatory dysfunctions in a number of psychiatric and neurological disorders (e.g., endogenous depression, schizophrenia, Alzheimer's, Huntington's, Parkinson's, and stroke), and will help us to design therapeutic interventions to eliminate these dysfunctions.

Public Health Relevance

Deficits in the homeostatic regulation of rapid eye movement (REM) sleep and/or activities of its individual physiological sign generators are associated with a number of neurological and psychiatric disorders, which collectively affect large segments of our population. This research is devoted to understanding the cellular and molecular mechanisms that are involved in the homeostatic regulation of REM sleep and one specific physiological sign of REM sleep, pontine-wave (P-wave) activity. Because very little to nothing is presently known about the cellular and molecular mechanisms that homeostatically regulate REM sleep and P-wave generator activity, this work has the potential to pioneer development of novel therapeutic approaches for REM sleep homeostatic regulation deficits seen in endogenous depression, schizophrenia, stroke, Alzheimer's, Huntington's, and Parkinson's diseases among others.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH059839-15
Application #
8494150
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Vicentic, Aleksandra
Project Start
1999-04-01
Project End
2018-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
15
Fiscal Year
2013
Total Cost
$409,250
Indirect Cost
$159,250
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Oliver 2nd, Michael D; Datta, Subimal; Baldwin, Debora R (2017) Wellness among African-American and Caucasian students attending a predominantly White institution. J Health Psychol :1359105317694484
Geist, Phillip A; Dulka, Brooke N; Barnes, Abigail et al. (2017) BNDF heterozygosity is associated with memory deficits and alterations in cortical and hippocampal EEG power. Behav Brain Res 332:154-163
Oliver, Michael D; Datta, Subimal; Baldwin, Debora R (2017) A sympathetic nervous system evaluation of obesity stigma. PLoS One 12:e0185703
Barnes, Abigail K; Koul-Tiwari, Richa; Garner, Jennifer M et al. (2017) Activation of brain-derived neurotrophic factor-tropomyosin receptor kinase B signaling in the pedunculopontine tegmental nucleus: a novel mechanism for the homeostatic regulation of rapid eye movement sleep. J Neurochem 141:111-123
Barnes, Abigail K; Smith, Summer B; Datta, Subimal (2017) Beyond Emotional and Spatial Processes: Cognitive Dysfunction in a Depressive Phenotype Produced by Long Photoperiod Exposure. PLoS One 12:e0170032
Datta, Subimal; Oliver, Michael D (2017) Cellular and Molecular Mechanisms of REM Sleep Homeostatic Drive: A Plausible Component for Behavioral Plasticity. Front Neural Circuits 11:63
Totty, Michael S; Chesney, Logan A; Geist, Phillip A et al. (2017) Sleep-Dependent Oscillatory Synchronization: A Role in Fear Memory Consolidation. Front Neural Circuits 11:49
Datta, Subimal; Knapp, Clifford M; Koul-Tiwari, Richa et al. (2015) The homeostatic regulation of REM sleep: A role for localized expression of brain-derived neurotrophic factor in the brainstem. Behav Brain Res 292:381-92
Datta, Subimal (2015) Mysteries of pedunculopontine nucleus physiology: Towards a deeper understanding of arousal and neuropsychiatric disorders. Sleep Sci 8:53-5
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

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