The role of the mTOR pathway in fear learning

本研究计划探讨联想性和非联想性恐惧记忆的分子机制。我们最近发现，雷帕霉素（mTOR）途径的哺乳动物靶点对联想恐惧记忆至关重要（Blundell et al., 2008）。利用经典的恐惧条件反射范式，动物学会将情境与厌恶刺激（在本例中是电击）联系起来，我们发现在巩固（在恐惧训练之后）或再巩固（在恐惧事件的提醒之后）期间，全身注射雷帕霉素（mTOR途径的抑制剂）会阻止对厌恶事件的后续记忆。虽然这些数据表明mTOR通路介导联想恐惧记忆，但尚不清楚它是否也介导应激诱导的持久恐惧敏化（例如，暴露于捕食者之后），一种非联想恐惧记忆。因此，我提出的研究项目的主要目标是确定mTOR通路是否不仅在联想恐惧记忆中起关键作用，而且在应激诱导的非联想恐惧记忆中也起关键作用。这将是确定联想恐惧记忆的分子机制是否与非联想恐惧记忆相似的第一步。更好地理解造成恐惧记忆的因素将为了解病理性恐惧障碍（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。

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.