Mechanisms Underlying the Cognitive Function of Sleep

Summary

Principal Investigator: Subimal Datta
Abstract: The long-term objective of this application is to identify the cellular and molecular mechanisms underlying the cognitive functions of sleep. Specifically, the goal of this renewal application is to investigate how the phasic pontine-wave (P-wave) generator and the hippocampus interact in sleep-dependent learning and memory processing in the rat. Clarifying the mechanisms of sleep-dependent learning and memory processing will advance the field of cognitive research toward the development of effective treatments for cognitive deficiencies associated with sleep disorders in humans. The central hypothesis of this proposal is that activation of phasic P-wave generating cells in the brainstem during REM sleep stimulates the post-synaptic cAMP/protein kinase A/cAMP response element binding protein (cAMP/PKA/CREB) pathway in the dorsal hippocampus as part of REM sleep-dependent memory processing. 3 specific aims have been designed to test this hypothesis systematically: 1. Determine whether the elimination of cells in the dorsal hippocampus attenuates 2-way active avoidance (TWAA) learning memory in post-sleep test trials. Cells will be lesioned by discrete microinjection of ibotenic acid into the CA1, CA3, and DG subfields of the dorsal hippocampus of different animals prior to TWAA training. After a sleep period, rats will be tested on the TWAA task and degrees of learning improvement will be compared between the specific subfield lesioned rats and sham lesioned rats. 2. Test the hypothesis that cAMP-dependent PKA activation in the dorsal hippocampus is involved in P-wave-generator-activation-dependent memory processing of TWAA learning. Effects of microinjecting a cAMP-dependent PKA inhibitor directly into the dorsal hippocampus to block P-wave generator activation will be measured with post-sleep TWAA testing to achieve this goal. 3. Test the hypothesis that P-wave generator activation increases phosphorylation of CREB (pCREB) and synthesis of activity-regulated cytoskeleton associated (Arc) protein in the dorsal hippocampus. Western blotting and immunocytochemical techniques will measure the levels of pCREB and Arc protein in the dorsal hippocampus. This proposal addresses, at the mechanistic level, the general question, what is the function of sleep? In addition, this research will propel sleep-dependent cognitive research toward treatments for cognitive impairments associated with jet lag, shift work, sleep deprivation and brainstem degenerative disorders.
Funding Period: 1996-07-01 - 2010-07-31
more information: NIH RePORT

Top Publications

  1. pmc Fear extinction memory consolidation requires potentiation of pontine-wave activity during REM sleep
    Subimal Datta
    Laboratory of Sleep and Cognitive Neuroscience, and Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts 02118, USA
    J Neurosci 33:4561-9. 2013
  2. pmc Cellular and chemical neuroscience of mammalian sleep
    Subimal Datta
    Laboratory of Sleep and Cognitive Neuroscience, Departments of Psychiatry, Neurology, and Neuroscience, Boston University School of Medicine, 85 East Newton Street, Suite M 902, Boston, MA 02118, USA
    Sleep Med 11:431-40. 2010
  3. pmc Sharing stressful experiences attenuates anxiety-related cognitive and sleep impairments
    Brian W Macone
    Laboratory of Sleep and Cognitive Neuroscience, Department of Psychiatry, Boston University School of Medicine, 85 East Newton Street, M 902, Boston, MA 02118, USA
    Behav Brain Res 222:351-6. 2011
  4. pmc Activation of extracellular signal-regulated kinase signaling in the pedunculopontine tegmental cells is involved in the maintenance of sleep in rats
    Frank Desarnaud
    Department of Laboratory of Sleep and Cognitive Neuroscience, Boston University School of Medicine, Boston, Massachusetts, USA
    J Neurochem 116:577-87. 2011
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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

Scientific Experts

  • Subimal Datta
  • Brian W Macone
  • Frank Desarnaud
  • Edward C Stack
  • J L Shea
  • Matthew Ennis
  • Robert Ross Maclean
  • Matthew O'Malley
  • Donald F Siwek
  • V Sagvaag
  • T Aspevik
  • A A Bjorkum
  • T Mochizuki

Detail Information

Publications15

  1. pmc Fear extinction memory consolidation requires potentiation of pontine-wave activity during REM sleep
    Subimal Datta
    Laboratory of Sleep and Cognitive Neuroscience, and Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts 02118, USA
    J Neurosci 33:4561-9. 2013
    ....
  2. pmc Cellular and chemical neuroscience of mammalian sleep
    Subimal Datta
    Laboratory of Sleep and Cognitive Neuroscience, Departments of Psychiatry, Neurology, and Neuroscience, Boston University School of Medicine, 85 East Newton Street, Suite M 902, Boston, MA 02118, USA
    Sleep Med 11:431-40. 2010
    ..I conclude this review by suggesting some potential future directions to further our understanding of the neurobiology of sleep...
  3. pmc Sharing stressful experiences attenuates anxiety-related cognitive and sleep impairments
    Brian W Macone
    Laboratory of Sleep and Cognitive Neuroscience, Department of Psychiatry, Boston University School of Medicine, 85 East Newton Street, M 902, Boston, MA 02118, USA
    Behav Brain Res 222:351-6. 2011
    ..While these results indicate the benefits and importance of companionship, the underlying mechanism of this phenomenon is yet to be elucidated...
  4. pmc Activation of extracellular signal-regulated kinase signaling in the pedunculopontine tegmental cells is involved in the maintenance of sleep in rats
    Frank Desarnaud
    Department of Laboratory of Sleep and Cognitive Neuroscience, Boston University School of Medicine, Boston, Massachusetts, USA
    J Neurochem 116:577-87. 2011
    ..Collectively, these results, for the first time, suggest that the increased ERK1/2 signaling in the PPT is associated with maintenance of sleep via suppression of wakefulness...
  5. 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
    ....
  6. 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...
  7. 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...
  8. 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...
  9. 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...
  10. 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...
  11. 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
    ....
  12. 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...
  13. 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
  14. 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...