The role of the mTOR pathway in fear learning

mTOR 通路在恐惧学习中的作用

• 批准号: 371599-2009
• 负责人: Blundell, Jacqueline
• 金额: $ 1.97万
• 依托单位: Memorial University of Newfoundland
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=528287
• 关键词: role; mTOR; pathway; fear; learning

This research program investigates the molecular mechanisms underlying associative and non-associative fear memory. We have recently shown that the mammalian target of rapamycin (mTOR) pathway is critical to associative fear memory (Blundell et al., 2008). Using the classical fear conditioning paradigm in which an animal learns to associate a context with an aversive stimulus (in this case, a shock), we showed that a systemic injection of rapamycin, an inhibitor of the mTOR pathway, during consolidation (following fear training) or reconsolidation (following a reminder of the fearful event) blocked subsequent memory for the aversive event. While these data suggest that the mTOR pathway mediates associative fear memory, it is unknown if it also mediates stress-induced long lasting fear sensitization (e.g. following exposure to a predator), a non-associative fear memory. Thus, the primary goal of my proposed program of research is to determine if the mTOR pathway is not only critically involved in associative fear memory, but also stress-induced non-associative fear memory. This will be a first step in determining whether the molecular mechanisms underlying associative fear memory are similar to those underlying non-associative fear memories. A better understanding of the factors contributing to fear memories will provide valuable insight into the nature of pathological fear disorders such as posttraumatic stress disorder and phobias. Ultimately this knowledge will aid in the development of novel drugs to treat these disorders.

本研究计划探讨关联和非关联恐惧记忆的分子机制。 我们最近已经表明，雷帕霉素（mTOR）通路的哺乳动物靶标对于关联恐惧记忆是至关重要的（Blundell等人，2008年）。 使用经典的恐惧条件反射范式，其中动物学会将背景与厌恶刺激（在这种情况下，休克）联系起来，我们表明，在巩固（恐惧训练后）或再巩固（恐惧事件的提醒后）期间，全身注射雷帕霉素，mTOR通路的抑制剂，阻断了随后的厌恶事件记忆。 虽然这些数据表明mTOR通路介导了关联性恐惧记忆，但尚不清楚它是否也介导了应激诱导的持久恐惧敏化（例如，暴露于捕食者之后），即非关联性恐惧记忆。 因此，我提出的研究计划的主要目标是确定mTOR通路是否不仅与关联恐惧记忆密切相关，而且与压力诱导的非关联恐惧记忆密切相关。 这将是确定关联性恐惧记忆的分子机制是否与非关联性恐惧记忆的分子机制相似的第一步。 更好地理解恐惧记忆的因素将为病理性恐惧障碍（如创伤后应激障碍和恐惧症）的本质提供有价值的见解。 最终，这些知识将有助于开发治疗这些疾病的新药。