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，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压力对厌恶性学习的影响与创伤后应激障碍（PTSD）的发病机制有关。在这里，我们提出了一个假设，即在急性应激过程中触发的关键机制，但在应激源停止后的延迟时间过程中激活，是增强厌恶性条件反射的主要介质。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学的影响，如创伤后应激障碍，可以显着预防应激后干预。由于压力情境的发生通常是不可预测的，因此对大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。对啮齿类动物的研究表明，在应激暴露前药理学阻断谷氨酸受体可显著减弱应激的行为效应。目前尚不清楚在压力源终止后，类似的操作是否有效。这个提议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断这些效应。我们计划采用情境恐惧条件反射作为一个强大的厌恶条件反射的模型。机制的问题，在这个建议中将确定谷氨酸受体类型（目的1），学习过程（目的2）和下游amatergic机制（目的3）介导的延迟和持续的压力对恐惧条件反射的影响。这些发现的治疗意义将包括通过阻断特定的神经元能机制来追溯性地和选择性地减轻压力增强的厌恶性条件反射的新选择。我们的长期目标是确定机制介导的影响，随后收购和持久性的内表型相关的创伤后应激障碍的压力。在易感个体中，一个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。我们认为，这种恐惧症状的发展可以通过抑制应激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.