The long-term objective of this application is to identify the cellular mechanisms underlying the cognitive function of sleep. Specifically, the goal is to investigate what role brainstem rapid eye movement (REM) sleep generating structures play in sleep-dependent learning in the rat. Clarifying the mechanisms of sleep-dependent learning and memory will move the field of cognitive research closer to the development of effective treatments for cognitive deficiencies associated with sleep disorders. The central hypothesis of this proposal is that activation of phasic P-wave generating cells in the dorsal part of the nucleus subcoeruleus is critical for sleep-dependent learning and memory processing. From this hypothesis, four testable questions have been generated: 1. After learning task training, does supplementary activation of the P-wave generator enhance information processing efficiency, resulting in improved learning? Immediately after a session of two-way active avoidance test trials, the P-wave generator will be directly activated by a discrete microinjection of carbachol. The effect of this supplementary activation will be examined in retest trials after a six hour period of undisturbed sleep. 2. Does the activation of the P-wave generator during REM sleep enhance a physiological process of memorization which naturally occurs during post-learning sleep? The procedure for testing this question is the same as that of question 1, except that these rats are REM sleep deprived for the six hour period between test and retest trials. 3. Does the elimination of cells in the P- wave generator attenuate learning abilities in post-sleep retest trials? P-wave generating cells will be directly eliminated by a discrete microinjection of kainic acid. The retest performance of these P-wave generating cell lesioned rats will be compared with that of the sham lesioned rats. 4. Is the increased density of P-waves during post-learning REM sleep due to the activation of P-wave generating cells? P-waves and single cell unitary activity of P-wave generating cells will be simultaneously recorded in freely moving rats after a session of learning trials. This proposal addresses at the mechanistic level, the general question, what is the function of sleep? and also promises to further sleep-dependent cognitive research in the direction toward treatments for cognitive impairments associated with jet lag, shift work, sleep deprivation and brainstem degenerative disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-3 (01))
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Mitler, Merrill
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Boston University
Schools of Medicine
United States
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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
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; 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
Stack, Edward C; Desarnaud, Frank; Siwek, Donald F et al. (2010) A novel role for calcium/calmodulin kinase II within the brainstem pedunculopontine tegmentum for the regulation of wakefulness and rapid eye movement sleep. J Neurochem 112:271-81
Datta, Subimal (2010) Cellular and chemical neuroscience of mammalian sleep. Sleep Med 11:431-40
Datta, Subimal; Siwek, Donald F; Huang, Max P (2009) Improvement of two-way active avoidance memory requires protein kinase a activation and brain-derived neurotrophic factor expression in the dorsal hippocampus. J Mol Neurosci 38:257-64
Datta, S; Siwek, D F; Stack, E C (2009) 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. Neuroscience 163:397-414
Shea, J L; Mochizuki, T; Sagvaag, V et al. (2008) Rapid eye movement (REM) sleep homeostatic regulatory processes in the rat: changes in the sleep-wake stages and electroencephalographic power spectra. Brain Res 1213:48-56
Datta, Subimal; Li, Guangmu; Auerbach, Sanford (2008) 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. Eur J Neurosci 27:1876-92

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