CELLULAR AND NEUROCHEMICAL MECHANISMS OF REM SLEEP

Summary

Principal Investigator: Subimal Datta
Affiliation: Boston University
Country: USA
Abstract: DESCRIPTION: (adapted from applicant's abstract) The long term objective of this application is to elucidate the cellular and neurochemical mechanisms of REM sleep. More, specifically, the goal is to contribute to the existing, yet incomplete, body of knowledge on the regulation of the PPT cholinergic cell activity in relation to the generation and maintenance of REM sleep. A clearer understanding of PPT cell regulation mechanisms will move the field of sleep research closer to the development of effective treatments for human REM disorders, such as narcolepsy, cataplexy, excessive daytime sleepiness, and those REM disorders associated with psychiatric and neurological conditions such as depression and Alzheimer's disease. The central hypothesis of this proposal is that PPT cholinergic cells are stimulated via specific glutamate receptors to induce REM sleep. To test this hypothesis systematically, there are four specific aims: 1. Determine the optimal dosage of L-Glutamate in the PPT to induce the maximum amount of REM sleep. The optimal dosage will be determined by making discrete microinjections of one of five different doses of L-Glutamate or control vehicle directly into the PPT cholinergic compartment while quantifying the effects of REM sleep. 2. Identify the glutamate receptor subtype(s) that is involved in exogenous L-glutamate-microinjection-induced REM sleep. This goal will be achieved by microinjecting specific glutamate receptor antagonists directly into the PPT cholinergic cell compartment to block the REM sleep inducing effect of the optimal dose of exogenous L-glutamate. 3. Identify which glutamate receptor type, if any, is involved in the maintenance of REM sleep by endogenous glutamate. This goal will be achieved by making discrete microinjections of specific antagonists or control vehicle alone into the PPT cell compartment while quantifying changes in REM sleep. 4. Test the hypothesis that activation of REM-on and Wake- REM-on cells of the PPT cell compartment by specific glutamate receptors is causal for the generation of REM sleep. This aim will be achieved by applying the REM sleep suppressing glutamate receptor antagonist to identified REM-on and Wake-REM-on PPT cells while recording single cell unitary activity in freely moving rats. The pharmacological identification of glutamate receptors involved with PPT-modulated REM sleep regulation will be an important step toward future experiments to elucidate the molecular mechanisms of REM sleep generation.
Funding Period: 1999-04-01 - 2003-03-31
more information: NIH RePORT

Top Publications

  1. pmc Pontine-wave generator activation-dependent memory processing of avoidance learning involves the dorsal hippocampus in the rat
    Subimal Datta
    Sleep and Cognitive Neuroscience Laboratory, Department of Psychiatry and Program in Behavioral Neuroscience, Boston University School of Medicine, Boston, MA 02118, USA
    J Neurosci Res 80:727-37. 2005
  2. pmc Identification of cholinergic and non-cholinergic neurons in the pons expressing phosphorylated cyclic adenosine monophosphate response element-binding protein as a function of rapid eye movement sleep
    S Datta
    Laboratory of Sleep and Cognitive Neuroscience, Boston University School of Medicine, 85 East Newton Street, Suite M 902, Boston, MA 02118, USA
    Neuroscience 163:397-414. 2009
  3. pmc Improvement of two-way active avoidance memory requires protein kinase a activation and brain-derived neurotrophic factor expression in the dorsal hippocampus
    Subimal Datta
    Sleep and Cognitive Neuroscience Laboratory, Department of Psychiatry, Boston University School of Medicine, 85 East Newton Street, Suite M 902, Boston, MA, 02118, USA
    J Mol Neurosci 38:257-64. 2009
  4. pmc Rapid eye movement (REM) sleep homeostatic regulatory processes in the rat: changes in the sleep-wake stages and electroencephalographic power spectra
    J L Shea
    Sleep and Cognitive Neuroscience Laboratory, Department of Psychiatry, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA
    Brain Res 1213:48-56. 2008
  5. pmc Activation of phasic pontine-wave generator in the rat: a mechanism for expression of plasticity-related genes and proteins in the dorsal hippocampus and amygdala
    Subimal Datta
    Sleep and Cognitive Neuroscience Laboratory, Department of Psychiatry, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA
    Eur J Neurosci 27:1876-92. 2008
  6. pmc The relationship between anxiety and sleep-wake behavior after stressor exposure in the rat
    Robert Ross Maclean
    Sleep and Cognitive Neuroscience Laboratory, Department of Psychiatry, Boston University School of Medicine, 85 E Newton St M 902, Boston, MA 02118, USA
    Brain Res 1164:72-80. 2007
  7. pmc Neurobiological mechanisms for the regulation of mammalian sleep-wake behavior: reinterpretation of historical evidence and inclusion of contemporary cellular and molecular evidence
    Subimal Datta
    Sleep and Cognitive Neuroscience Laboratory, Department of Psychiatry and Behavioral Neuroscience, Boston University School of Medicine, Boston, MA 02118, USA
    Neurosci Biobehav Rev 31:775-824. 2007
  8. ncbi Activation of pedunculopontine tegmental PKA prevents GABAB receptor activation-mediated rapid eye movement sleep suppression in the freely moving rat
    Subimal Datta
    Sleep and Cognitive Neuroscience Lab, Dept of Psychiatry, Boston Univ School of Medicine, M 902, 715 Albany St, Boston, MA 02118, USA
    J Neurophysiol 97:3841-50. 2007
  9. pmc Electrotonic coupling in the nucleus SubCoeruleus. Focus on "evidence for electrical coupling in the SubCoeruleus (SubC) nucleus"
    Matthew Ennis
    J Neurophysiol 97:2579. 2007
  10. ncbi Activation of pedunculopontine tegmental protein kinase A: a mechanism for rapid eye movement sleep generation in the freely moving rat
    Ram S Bandyopadhya
    Sleep and Cognitive Neuroscience Laboratory, Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts 02118, USA
    J Neurosci 26:8931-42. 2006

Scientific Experts

  • Subimal Datta
  • Subhash Saha
  • Edward C Stack
  • J L Shea
  • Matthew Ennis
  • Robert Ross Maclean
  • Ram S Bandyopadhya
  • Jagadish Ulloor
  • Frank Desarnaud
  • Donald F Siwek
  • T Aspevik
  • T Mochizuki
  • A A Bjorkum
  • V Sagvaag

Detail Information

Publications15

  1. pmc Pontine-wave generator activation-dependent memory processing of avoidance learning involves the dorsal hippocampus in the rat
    Subimal Datta
    Sleep and Cognitive Neuroscience Laboratory, Department of Psychiatry and Program in Behavioral Neuroscience, Boston University School of Medicine, Boston, MA 02118, USA
    J Neurosci Res 80:727-37. 2005
    ..The results also provide evidence that under mnemonic pressure, the dorsal hippocampus may not be involved directly in regulating the sleep-wake cycle...
  2. pmc Identification of cholinergic and non-cholinergic neurons in the pons expressing phosphorylated cyclic adenosine monophosphate response element-binding protein as a function of rapid eye movement sleep
    S Datta
    Laboratory of Sleep and Cognitive Neuroscience, Boston University School of Medicine, 85 East Newton Street, Suite M 902, Boston, MA 02118, USA
    Neuroscience 163:397-414. 2009
    ..Moreover the results indicate that during REM sleep, PPT intracellular PKA activation and a transcriptional cascade involving pCREB occur exclusively in the cholinergic neurons...
  3. pmc Improvement of two-way active avoidance memory requires protein kinase a activation and brain-derived neurotrophic factor expression in the dorsal hippocampus
    Subimal Datta
    Sleep and Cognitive Neuroscience Laboratory, Department of Psychiatry, Boston University School of Medicine, 85 East Newton Street, Suite M 902, Boston, MA, 02118, USA
    J Mol Neurosci 38:257-64. 2009
    ..Together, these findings suggest that the PKA activation and BDNF expression in the DH-CA3 is essential for the improvement of TWAA memory...
  4. pmc Rapid eye movement (REM) sleep homeostatic regulatory processes in the rat: changes in the sleep-wake stages and electroencephalographic power spectra
    J L Shea
    Sleep and Cognitive Neuroscience Laboratory, Department of Psychiatry, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA
    Brain Res 1213:48-56. 2008
    ..These findings suggest that the REM sleep homeostatic process involves increased delta- and decreased theta-frequency wave activities in the cortical EEG...
  5. pmc Activation of phasic pontine-wave generator in the rat: a mechanism for expression of plasticity-related genes and proteins in the dorsal hippocampus and amygdala
    Subimal Datta
    Sleep and Cognitive Neuroscience Laboratory, Department of Psychiatry, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA
    Eur J Neurosci 27:1876-92. 2008
    ..These findings are discussed in relation to the role of P-wave generator activation for the REM sleep-dependent development and cognitive functions of the brain...
  6. pmc The relationship between anxiety and sleep-wake behavior after stressor exposure in the rat
    Robert Ross Maclean
    Sleep and Cognitive Neuroscience Laboratory, Department of Psychiatry, Boston University School of Medicine, 85 E Newton St M 902, Boston, MA 02118, USA
    Brain Res 1164:72-80. 2007
    ..Rather, individual anxiety may be exacerbated by disrupted sleep. To fully understand the relationship between anxiety and sleep-wake behavior, a more objective analysis of anxiety after stressor exposure is mandated...
  7. pmc Neurobiological mechanisms for the regulation of mammalian sleep-wake behavior: reinterpretation of historical evidence and inclusion of contemporary cellular and molecular evidence
    Subimal Datta
    Sleep and Cognitive Neuroscience Laboratory, Department of Psychiatry and Behavioral Neuroscience, Boston University School of Medicine, Boston, MA 02118, USA
    Neurosci Biobehav Rev 31:775-824. 2007
    ....
  8. ncbi Activation of pedunculopontine tegmental PKA prevents GABAB receptor activation-mediated rapid eye movement sleep suppression in the freely moving rat
    Subimal Datta
    Sleep and Cognitive Neuroscience Lab, Dept of Psychiatry, Boston Univ School of Medicine, M 902, 715 Albany St, Boston, MA 02118, USA
    J Neurophysiol 97:3841-50. 2007
    ..These findings suggest that the PPT GABA(B) receptor activation-mediated REM sleep regulating mechanism involves inactivation of cAMP-PKA signaling in the freely moving rat...
  9. pmc Electrotonic coupling in the nucleus SubCoeruleus. Focus on "evidence for electrical coupling in the SubCoeruleus (SubC) nucleus"
    Matthew Ennis
    J Neurophysiol 97:2579. 2007
  10. ncbi Activation of pedunculopontine tegmental protein kinase A: a mechanism for rapid eye movement sleep generation in the freely moving rat
    Ram S Bandyopadhya
    Sleep and Cognitive Neuroscience Laboratory, Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts 02118, USA
    J Neurosci 26:8931-42. 2006
    ..Together, these results provide the first evidence that the activation of the PPT intracellular PKA system is involved in the generation of REM sleep...
  11. ncbi Spatio-temporal activation of cyclic AMP response element-binding protein, activity-regulated cytoskeletal-associated protein and brain-derived nerve growth factor: a mechanism for pontine-wave generator activation-dependent two-way active-avoidance memor
    Jagadish Ulloor
    Sleep and Cognitive Neuroscience Laboratory, Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts 02118, USA
    J Neurochem 95:418-28. 2005
    ..These dynamic changes in cellular and molecular features provide considerable insight into the mechanisms of the P-wave generator activation-dependent memory consolidation process...
  12. ncbi Two-way active avoidance training-specific increases in phosphorylated cAMP response element-binding protein in the dorsal hippocampus, amygdala, and hypothalamus
    Subhash Saha
    Sleep and Cognitive Neuroscience Laboratory, Department of Psychiatry, and Program in Behavioural Neuroscience, Boston University School of Medicine, Building M 902, 715 Albany Street, Boston, MA 02118, USA
    Eur J Neurosci 21:3403-14. 2005
    ....
  13. pmc Novel role of brain stem pedunculopontine tegmental adenylyl cyclase in the regulation of spontaneous REM sleep in the freely moving rat
    Subimal Datta
    Sleep and Cognitive Neuroscience Laboratory, Department of Psychiatry, Boston University School of Medicine, M 902, 715 Albany St, Boston, Massachusetts 02118, USA
    J Neurophysiol 94:1928-37. 2005
    ..These findings suggest that activation of the cAMP-signaling pathway within the cholinergic cell compartment of the PPT is an intracellular biochemical/molecular step for generating REM sleep in the freely moving rat...
  14. pmc A novel role for calcium/calmodulin kinase II within the brainstem pedunculopontine tegmentum for the regulation of wakefulness and rapid eye movement sleep
    Edward C Stack
    Laboratory of Sleep and Cognitive Neurosciences, Boston University School of Medicine, Boston, Massachusetts, USA
    J Neurochem 112:271-81. 2010
    ....