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Sleep and the Generalization Extinction of Conditioned Fear


The proposed experiments will explore the role of sleep in generalizing memory for the extinction of conditioned fear. We recently discovered this generalization effect in an unfunded but published pilot study. We now wish to further develop this line of research within the R21 grant mechanism. Extinction training represents the neurobehavioral basis of exposure therapy, which is a first-line treatment for post-traumatic stress disorder (PTSD) as well as other anxiety disorders. Generalization extends extinction learning from specifically extinguished cues to other, similar stimuli. Such generalization is essential to successful exposure therapy because the reduction of fearful responding to specific cues, achieved in treatment, must then be extended to the multiplicity of related stimuli encountered outside the therapist's office. Our research has demonstrated that normal overnight sleep promotes generalization of extinction learning. Conditioned responding was established to two previously neutral color stimuli using an electric shock, and skin conductance response (SCR) served as the dependent measure of conditioned responding. One of the CS+'s was then extinguished (CS+E) whereas the other remained unextinguished (CS+U). After a 12-hour delay with intervening sleep, not only did SCR remain reduced following presentations of the CS+E (extinction recall) but it was also reduced following CS+U presentations (extinction generalization). However, such generalization was not seen when the delay contained only waking. The proposed project will first confirm that it is indeed sleep that produces generalization by examining time-of-day factors that potentially confound this previous observation. A 24-hour delay will now follow conditioning and extinction after which the Sleep-first group, trained in the evening, will immediately sleep then spend a normal day's waking whereas the Wake-first group, trained in the morning, will begin their 24 hours with waking. Thus, the Sleep-first group will now be tested at the time-of-day that poorer extinction generalization was previously observed and the Wake-first group at the time-of-day when generalization was best. Sleep physiological correlates of memory consolidation are widely replicated phenomena. We therefore next propose to examine polysomnographic correlates of extinction generalization. Additionally we propose to quantify phasic events in sleep that have been associated with memory phenomena including rapid-eye-movement density in REM sleep and sleep spindle density in Stage 2 non-REM sleep, and examine their association with extinction generalization. PUBLIC HEALTH RELEVANCE: The proposed work will explore relationships between sleep and learning not to fear previously threatening stimuli. Results may have clinical implications for timing of exposure therapy sessions relative to sleep in a manner that maximizes generalization of therapeutic extinction learning in PTSD and other anxiety disorders. Additionally, results may suggest behavioral interventions and pharmacological strategies that can be applied to post-therapy sleep in order to preserve or enhance those aspects of sleep most beneficial for extinction generalization.

Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.