Mechanisms of Stress-Enhanced Aversive Conditioning

描述（由申请人提供）：压力经历显著促进厌恶记忆的形成。因此，对这些记忆的回忆引发了夸大和持续的恐惧反应。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。在此，我们提出了一种假设，即在急性应激过程中触发的关键机制，在应激源停止后被延迟激活，是厌恶条件反射增强的主要介质。如果我们的假设被证明是正确的，急性创伤事件导致的精神病理，如创伤后应激障碍，可以通过应激后干预显著预防。由于压力情况的发生通常是不可预测的，因此对脑神经递质系统的逆行干扰的可能性对于预防压力增强的恐惧条件反射具有特别重要的意义。对啮齿动物的研究表明，在应激暴露前对谷氨酸受体进行药物阻断可显著减轻应激的行为影响。目前尚不清楚的是，在压力源终止后，类似的操作是否有效。本研究的目的是详细描述应激对恐惧条件反射的延迟效应，并试图通过应激后谷氨酸受体的失活来阻止这些效应。我们计划采用情境恐惧条件反射作为稳健厌恶条件反射的模型。在本提案中解决的机制问题将确定谷氨酸受体类型（Aim 1），学习过程（Aim 2）和下游谷氨酸能机制（Aim 3）介导延迟和持续应激对恐惧条件反射的影响。该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介导应激对PTSD相关内表型的后续获得和持续的影响的机制。在易感人群中，单一的压力事件有时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谷氨酸受体在压力后预防。如果这一假设在实验中得到证实，结果将为降低与PTSD相关的恐惧症状的风险和二级预防开辟新的治疗选择。

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.