We hypothesize that the absence of NE in the forebrain during REM sleep and the spindle-rich transition to REM sleep (TR) allows for synaptic depotentiation underlying normal assimilation of new memories into the global memory network schema. Post-traumatic stress disorder is one condition associated with abnormally high noradrenergic tone, intense dreaming and intrusive memories. We hypothesize that an abnormal presence of norepinephrine (NE) during sleep prevents the important depotentiation process of normal memory consolidation and thus prevents novel memories from being integrated with familiar memories in the neocortical memory network. We will record from the hippocampus and LC simultaneously to determine whether hippocampal reactivation during non-REM sleep occurs differently in the absence of NE (i.e. during spindle production). We will examine hippocampal reactivation events for changes indicative of plasticity, like burst spike attenuation changes, Causal Entropy and Functional Clustering. We will examine spike firing patterns in relation to local electrical field potentials and expect to see familiar, already consolidated memories activated differently than novel memories as we have seen during REM sleep, and that such replay will be phase specific during non-REM sleep spindles just as they are phase specific to theta in REM sleep. We hypothesize that LC silence is necessary to generate spindles in the first place as well as for the synaptic strengthening and weakening effects of spindle-phase associated firing. To test the necessity for NE to be absent we will stimulate the LC at sub-arousal levels (~3 Hz) during sleep whenever we see spindles in the cortex or hippocampus through to the next awakening. We expect a marked reduction in the number of spindles generated, a loss of the depotentiation that hippocampal replay in non-REM sleep produces, and impaired memory consolidation especially for reversal tasks. This research will have strong implications for the development of effective strategies to selectively downscale synaptic networks reactivated during the dreaming and spindle stages of sleep the overly strong retention of which is debilitating in those unable to normalize and integrate their traumatic memories.

Public Health Relevance

Post traumatic stress disorder is associated with abnormally high noradrenergic tone, intense dreaming incorporating veridical elements of the traumatic memory and intrusive trauma recall. We hypothesize that an abnormal presence of norepinephrine (NE) from an overactive locus coeruleus (LC) during the transition to REM sleep and REM sleep states prevents the normal depotentiation processes of memory consolidation and thus prevents novel memories from being integrated with other familiar memories in the neocortical memory network. This research will look at normal LC and hippocampal activity profiles during post-learning memory consolidation and test whether an abnormal presence of NE during REM sleep and during the transition to REM (TR) prevents depotentiation necessary for reversal learning consolidation and extinction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH060670-12
Application #
8538501
Study Section
Special Emphasis Panel (ZRG1-IFCN-N (02))
Program Officer
Vicentic, Aleksandra
Project Start
2000-03-01
Project End
2017-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
12
Fiscal Year
2013
Total Cost
$315,439
Indirect Cost
$109,276
Name
University of Michigan Ann Arbor
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Walsh, Christine M; Booth, Victoria; Poe, Gina R (2011) Spatial and reversal learning in the Morris water maze are largely resistant to six hours of REM sleep deprivation following training. Learn Mem 18:422-34
Poe, Gina R; Walsh, Christine M; Bjorness, Theresa E (2010) Cognitive neuroscience of sleep. Prog Brain Res 185:1-19
Gross, Brooks A; Walsh, Christine M; Turakhia, Apurva A et al. (2009) Open-source logic-based automated sleep scoring software using electrophysiological recordings in rats. J Neurosci Methods 184:10-8
Reasor, Jonathan D; Poe, Gina R (2008) Learning and memory during sleep and anesthesia. Int Anesthesiol Clin 46:105-29
Wang, Jane X; Poe, Gina; Zochowski, Michal (2008) From network heterogeneities to familiarity detection and hippocampal memory management. Phys Rev E Stat Nonlin Soft Matter Phys 78:041905
Jablonski, Piotr; Poe, Gina R; Zochowski, Michal (2007) Structural network heterogeneities and network dynamics: a possible dynamical mechanism for hippocampal memory reactivation. Phys Rev E Stat Nonlin Soft Matter Phys 75:011912
Best, Janet; Diniz Behn, Cecilia; Poe, Gina R et al. (2007) Neuronal models for sleep-wake regulation and synaptic reorganization in the sleeping hippocampus. J Biol Rhythms 22:220-32
Waddell, Jack; Dzakpasu, Rhonda; Booth, Victoria et al. (2007) Causal entropies--a measure for determining changes in the temporal organization of neural systems. J Neurosci Methods 162:320-32
Booth, Victoria; Poe, Gina R (2006) Input source and strength influences overall firing phase of model hippocampal CA1 pyramidal cells during theta: relevance to REM sleep reactivation and memory consolidation. Hippocampus 16:161-73
Bjorness, Theresa E; Riley, Brett T; Tysor, Michael K et al. (2005) REM restriction persistently alters strategy used to solve a spatial task. Learn Mem 12:352-9

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