Mechanisms of Stress-Enhanced Aversive Conditioning

描述(由申请人提供)：紧张的经历极大地促进了厌恶记忆的形成。因此，对这些记忆的回忆会触发夸张而持久的恐惧反应。在人类和实验动物中观察到的应激对厌恶学习的影响与创伤后应激障碍(PTSD)的发病机制有关。在这里，我们提出的假设是，在急性应激时触发的关键机制，但在应激源停止后以延迟的时间过程激活，是增强厌恶条件反射的主要介质。如果我们的假设被证明是正确的，那么导致精神病理的急性创伤性事件的影响，如创伤后应激障碍，可以通过后应激干预得到显著预防。由于应激情况的发生通常是不可预测的，因此对大脑神经递质系统进行逆行干扰的可能性对于预防应激增强的恐惧条件反射将具有特别重要的意义。对啮齿动物的研究表明，在应激暴露之前对谷氨酸受体进行药物阻断可以显著减弱应激的行为影响。不太清楚的是，在压力源终止后，类似的手法是否有效。这项建议的目的是详细描述应激在恐惧条件反射中的延迟效应，并试图通过应激后谷氨酸受体的失活来阻断这些效应。我们计划使用情境恐惧条件反射作为强健厌恶条件反射的模型。这项建议中涉及的机械性问题将确定谷氨酸受体类型(目标1)、学习过程(目标2)和下游谷氨酸能机制(目标3)，这些机制介导恐惧条件反射中延迟和持续的应激效应。这些发现的治疗意义将包括通过阻断特定的谷氨酸能机制来追溯和选择性地缓解应激增强的厌恶条件反射的新选择。我们的长期目标是确定压力对与创伤后应激障碍相关的内表型的后续习得和持久性影响的机制。在易受影响的人中，一个单一的应激事件有时就足以引发创伤后应激障碍(PTSD)和持久的恐惧。我们建议，这种恐惧症状的发展可以通过抑制压力后的谷氨酸受体来预防。如果这一假设得到实验证实，结果将为降低风险和二级预防与创伤后应激障碍相关的恐惧症状开辟新的治疗选择。

DESCRIPTION (provided by applicant): Stressful experiences significantly facilitate the formation of aversive memories. Consequently, the recall of these memories triggers exaggerated and persistent fear responses. The effects of stress on aversive learning, observed in humans as well as experimental animals, have been implicated in the pathogenesis of posttraumatic stress disorder (PTSD). Here we put forward the hypothesis that key mechanisms triggered during acute stress, but activated with a delayed time course after cessation of the stressor, are the main mediators of enhanced aversive conditioning. If our hypothesis proves correct, the effects of acute traumatic events leading to psychopathology, such as PTSD, could be significantly prevented by poststress interventions. Because the occurrence of stressful situations is commonly unpredictable, the possibility of retrograde interference with brain neurotransmitter systems would be of particular significance for the prevention of stress-enhanced fear conditioning. Studies with rodents have shown that pharmacological blockade of glutamate receptors prior to stress exposure significantly attenuates the behavioral effects of stress. It is less clear whether similar manipulations can be effective after the stressor has terminated. The objective of this proposal is to characterize in detail the delayed effects of stress on fear conditioning and attempt to block these effects by poststress inactivation of glutamate receptors. We plan to employ the contextual fear conditioning as a model of robust aversive conditioning. Mechanistic questions addressed in this proposal will identify the glutamate receptor type (Aim 1), learning process (Aim 2) and downstream glutamatergic mechanisms (Aim 3) mediating the delayed and persistent stress effects on fear conditioning. The therapeutic implications of the findings will encompass novel options to retroactively and selectively alleviate stress-enhanced aversive conditioning by blocking specific glutamatergic mechanisms. Our long-term goal is to identify the mechanisms mediating the effects of stress on subsequent acquisition and persistence of endophenotypes relevant for PTSD. In susceptible individuals, a single stressful event is sometimes sufficient to trigger posttraumatic stress disorder (PTSD) and lasting fear. We propose that the development of such fear symptoms can be prevented by inhibition of glutamate receptors in the aftermath of stress. If this hypothesis is experimentally confirmed, the results will open new therapeutic options for the risk reduction and secondary prevention of fear symptoms associated with PTSD.