Sleep and the Generalization Extinction of Conditioned Fear

描述（由申请人提供）：所提出的实验将探索睡眠在概括记忆以消除条件性恐惧中的作用。我们最近在一项未受资助但已发表的试点研究中发现了这种泛化效应。我们现在希望在R21赠款机制内进一步发展这一系列研究。灭绝训练代表了暴露疗法的神经行为基础，暴露疗法是创伤后应激障碍（PTSD）和其他焦虑症的一线治疗方法。泛化将灭绝学习从特定的灭绝线索扩展到其他类似的刺激。这种概括对于成功的暴露疗法至关重要，因为在治疗中实现的对特定线索的恐惧反应的减少，必须扩展到治疗师办公室外遇到的多种相关刺激。我们的研究表明，正常的夜间睡眠促进了灭绝学习的泛化。使用电击对两种先前的中性颜色刺激建立条件反应，皮肤电导反应（SCR）作为条件反应的依赖性测量。其中一个CS+然后熄灭（CS+E），而另一个保持未熄灭（CS+U）。经过12小时的延迟与干预睡眠，不仅SCR保持降低后，介绍了CS+E（灭绝回忆），但它也减少后，CS+U介绍（灭绝泛化）。然而，这样的泛化时，延迟只包含清醒。该项目将首先通过检查可能混淆先前观察结果的时间因素来确认确实是睡眠产生泛化。24小时的延迟现在将遵循条件反射和消退，之后睡眠第一组，在晚上训练，将立即睡觉，然后度过正常的一天醒来，而醒来第一组，在早上训练，将开始他们的24小时醒来。因此，现在将在先前观察到较差的消退泛化的一天中的时间测试睡眠第一组，并且在泛化最好的一天中的时间测试唤醒第一组。睡眠与记忆巩固的生理相关性是被广泛复制的现象。因此，我们接下来建议检查多导睡眠图与灭绝泛化的相关性。此外，我们建议量化与记忆现象相关的睡眠阶段性事件，包括REM睡眠中的快速眼动密度和第2阶段非REM睡眠中的睡眠纺锤体密度，并检查它们与灭绝泛化的相关性。 公共卫生相关性：拟议的工作将探索睡眠和学习不害怕以前的威胁刺激之间的关系。结果可能具有临床意义的时间暴露治疗会话相对于睡眠的方式，最大限度地推广治疗性消退学习的创伤后应激障碍和其他焦虑症。此外，研究结果可能表明，行为干预和药理学策略可以应用于治疗后的睡眠，以保持或增强最有利于灭绝泛化的睡眠方面。

DESCRIPTION (provided by applicant): 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.