Role of subunit composition of hippocampal N-Methyl-D-Aspartate (NMDA) receptors in the extinction of contextual fear

海马N-甲基-D-天冬氨酸（NMDA）受体亚基组成在情境恐惧消除中的作用

• 批准号: 193237260
• 负责人: Dr. Ivana Mesic, Ph.D.
• 金额: --
• 依托单位: Department of Psychiatry and Behavioral Sciences
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2012-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/193237260?language=en
• 关键词: Role; subunit; composition; hippocampal; Methyl

Fear-motivated learning forms a basis for anxiety disorders such as post-traumatic stress disorders. The knowledge how to treat such human diseases is based upon behavioral studies using Pavlovian fear conditioning. Here, a causal relationship between a neutral/conditioned and a negatively valenced/unconditioned stimulus is established inducing a fear response. Importantly, consecutive presentation of the neutral stimulus alone induces extinction of conditioned fear. However, extinction is not erasure of fear memory but a form of new learning. Learning is driven by detecting a mismatch between expected and experienced events. Hence, if there is a failure to form adequate shock expectations fear extinction is largely affected.One important brain region for fear conditioning and extinction is the hippocampus that is fundamental for processing the contextual aspect and expectation violation. On a molecular level, it was shown that during fear extinction the hippocampal extracellular signal-regulated kinase (ERK) is phosphorylated somatonuclearly. Importantly, in animal models, where adequate shock expectations are not established, the somatonuclear ERK-phosphorylation and fear extinction are prevented. The exact mechanism that triggers differential ERK-phosphorylaion patterns is not known.Phosphorylation of ERK highly depends on the upstream activation of N-Methyl-D-Aspartate (NMDA) receptors. These receptors are one of the major mediators of experience-dependent changes at the synapse underlying learning and memory. Specifically, the NMDA receptor subunit composition largely determines the compartmentalized activation of this signaling pathway. While some insight on this process has been gained by studying NR2 subunits, the role of the NR2 and NR3 subunits is largely unknown. Hence, the hypothesis of this application is that success or failure of contextual fear extinction is determined by the subunit composition of hippocampal NMDA receptors.

恐惧动机的学习构成了诸如创伤后应激障碍之类的焦虑症的基础。知识如何治疗这种人类疾病是基于使用Pavlovian恐惧调节的行为研究。在这里，建立了中性/条件和否定价值/无条件刺激之间的因果关系，诱导了恐惧反应。重要的是，单独的中性刺激的连续表示会导致条件恐惧的灭绝。但是，灭绝并不是擦除恐惧记忆，而是一种新学习的形式。学习是通过检测预期事件和经验丰富的事件之间的不匹配来驱动的。因此，如果未能形成充分的震惊期望，恐惧灭绝会在很大程度上受到影响。恐惧调节和灭绝的重要大脑区域是海马，这是处理上下文方面和违反期望的基础的海马。在分子水平上，结果表明，在恐惧灭绝期间，海马细胞外信号调节激酶（ERK）被磷酸化的体磷酸化。重要的是，在没有建立足够的冲击期望的动物模型中，可以防止种子核ERK-磷酸化和恐惧灭绝。触发差异ERK-磷酸磷酸化模式的确切机制尚不清楚。ERK的磷酸化高度取决于N-甲基-D-天冬氨酸（NMDA）受体的上游激活。这些受体是在学习和记忆的突触中依赖经验变化的主要介体之一。具体而言，NMDA受体亚基组成在很大程度上确定了该信号通路的分区激活。尽管通过研究NR2亚基获得了有关此过程的一些见解，但NR2和NR3亚基的作用在很大程度上是未知的。因此，该应用的假设是，情境恐惧灭绝的成功或失败取决于海马NMDA受体的亚基组成。