Sleep and the Generalization Extinction of Conditioned Fear

描述(申请人提供)：拟议的实验将探索睡眠在消除条件性恐惧的记忆中的作用。我们最近在一项没有资金但已发表的初步研究中发现了这种泛化效应。我们现在希望在R21拨款机制内进一步发展这方面的研究。消退训练代表了暴露疗法的神经行为学基础，这是治疗创伤后应激障碍(PTSD)和其他焦虑症的一线疗法。泛化将消退学习从特定的熄灭线索扩展到其他类似的刺激。这种泛化对于成功的暴露疗法是必不可少的，因为在治疗中实现的对特定线索的恐惧反应的减少，然后必须扩展到在治疗师办公室外遇到的多种相关刺激。我们的研究表明，正常的通宵睡眠促进了消亡学习的泛化。使用电击建立对两种先前中性颜色刺激的条件性反应，皮肤电导反应(SCR)作为条件反应的依赖测量。一只CS+‘S随后被扑灭(CS+E)，而另一只仍未熄灭(CS+U)。在12小时的延迟和睡眠干预后，不仅在CS+E(消退回忆)呈现后SCR保持下降，而且在CS+U呈现(消退概括)呈现后SCR也降低。然而，当延迟只包含唤醒时，这种概括就看不到了。拟议的项目将首先通过检查可能扰乱先前观察的时间因素来证实确实是睡眠产生了概括。条件反射和消退之后会有24小时的延迟，在此之后，在晚上训练的睡眠优先组将立即入睡，然后正常地度过一天的清醒时间，而在早上训练的第一睡眠组将从醒来开始他们的24小时。因此，睡眠优先组现在将在先前观察到较差的灭绝概括的一天中的时间进行测试，而唤醒第一组将在概括最好的一天中的时间进行测试。记忆巩固的睡眠生理关联是被广泛复制的现象。因此，我们下一步建议检查多导睡眠图与灭绝泛化的相关性。此外，我们建议量化睡眠中与记忆现象相关的阶段事件，包括快速眼动睡眠中的快速眼动密度和阶段2非快速眼动睡眠中的睡眠纺锤密度，并检验它们与灭绝概化的关系。 与公共健康相关：这项拟议的工作将探索睡眠和学习不害怕以前具有威胁性的刺激之间的关系。结果可能对与睡眠相关的暴露治疗疗程的时间安排具有临床意义，从而最大限度地推广创伤后应激障碍和其他焦虑症的治疗消退学习。此外，研究结果可能提出可应用于治疗后睡眠的行为干预和药理学策略，以保存或增强那些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.