Neural Mechanisms underlying associative and non-associative fear memories.

我的研究计划的长期目标是确定创伤事件(或恐惧记忆)记忆背后的神经机制。我的实验室和其他实验室的研究表明，哺乳动物雷帕霉素(MTOR)途径的靶点可能在恐惧记忆的形成、维持和持久性方面发挥关键作用。恐惧记忆可以发生在之前与应激源相关的环境中(称为关联性恐惧回忆录)，也可以在与应激源不同的环境中明显出现，这表明这些变化不是条件性的，而是非关联性恐惧(或恐惧敏感化)的衡量标准。在目前的建议中，关联性恐惧将使用经典的恐惧条件反射范式进行评估，根据该范式，动物将学习将新的背景(或线索)与厌恶的刺激(即轻微的脚部电击)联系起来。当再次暴露在与厌恶刺激相关的背景(或线索)中时，啮齿动物将表现出典型的物种恐惧行为(以僵硬衡量)。相比之下，非关联性恐惧将使用捕食者应激范式进行评估，在该范式中，啮齿动物暴露在猫面前。捕食者压力导致的高度唤醒(根据对声音惊吓的反应)和类似焦虑的行为的变化在不同于猫暴露的环境中是明显的，因此，是非联想恐惧的衡量标准。这项提议的主要目标是确定特定的大脑区域，以及mTOR通路的上游和下游分子靶点，这些分子靶点介导了关联性和非关联性恐惧记忆。我们将对关联性和非关联性恐惧记忆的分子机制进行比较。我也有独一无二的机会将我的实验室发现扩展到自然主义的捕食者-猎物环境。具体地说，我将研究野生鹿鼠捕食者应激下的神经变化。如果类似的分子靶点(即mTOR途径)在野外暴露于应激源后被激活，就像那些在实验室动物中因应激源而激活的那样，那么这将表明实验室研究具有生态学有效性。此外，这项具有创新性和潜在变革性的研究将为我们理解恐惧对大脑的影响提供一个新颖的、自然主义的维度。识别调节恐惧记忆过程的特定靶点将代表着在阐明恐惧记忆背后的分子机制方面的重大进展。归根结底，确定恐惧背后的神经机制可能有助于理解创伤后应激障碍和特定恐惧症等与压力相关的疾病的发展，以及推进治疗。

The long-term goal of my research program is to identify the neural mechanisms underlying memories of traumatic events (or fear memories). Work from my lab and others suggest that the mammalian target of rapamycin (mTOR) pathway may play a critical role in fear memory formation, maintenance, and persistence. Fear memories can occur in response to environments that were previously associated with the stressor (termed associative fear memoires) or can be apparent in environments different from the stressor, suggesting these changes are not conditioned, but rather are measures of non-associative fear (or fear sensitization). In the current proposal, associative fear will be assessed using the classical fear conditioning paradigm whereby an animal learns to associate a novel context (or cue) with an aversive stimulus (i.e., mild foot shock). Upon re-exposure to the context (or cue) associated with the aversive stimulus, rodents will show species-typical fear behaviors (measured as freezing). In contrast, non-associative fear will be assessed using the predator stress paradigm in which a rodent is exposed to a cat. Predator stress-induced changes in hyperarousal (as measured as response to acoustic startle) and anxiety-like behaviors are apparent in environments different from the cat exposure, and thus, are measures of non-associative fear. The main goal of this proposal is the identification of the specific brain areas, as well as the upstream and downstream molecular targets of the mTOR pathway that mediate associative and non-associative fear memories. Comparisons will be made between the molecular mechanisms underlying associative and non-associative fear memories. I also have the unique opportunity to extend my laboratory findings to a naturalistic predator-prey setting. Specifically, I will examine the neural changes underlying predator stress in wild trapped deer mice. If similar molecular targets (i.e., mTOR pathway) are activated following exposure to a stressor in the wild, as those activated in response to a stressor in laboratory animals, then this will indicate that laboratory studies have ecological validity. Moreover, this innovative and potentially transformative research will provide a novel and naturalistic dimension to our understanding of the effects of fear on the brain. Identification of the specific targets that mediate fear memory processes will represent a major advance in elucidating the molecular mechanisms that underlie fear memory. Ultimately, identifying the neural mechanisms underlying fear may contribute to understanding the development of, as well as advancing the treatment for stress-related disorders such as post-traumatic stress disorder and specific phobias.