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记忆（或恐惧记忆）的神经机制。我的实验室和其他人的工作表明，哺乳动物雷帕霉素靶蛋白（mTOR）通路可能在恐惧记忆的形成、维持和持续中发挥关键作用。恐惧记忆可以发生在以前与压力源相关的环境中（称为联想恐惧记忆），也可以在与压力源不同的环境中明显出现，这表明这些变化不是条件性的，而是非联想恐惧（或恐惧敏感化）的措施。在目前的建议中，将使用经典的恐惧条件反射范式来评估关联恐惧，其中动物学会将新的背景（或线索）与厌恶刺激（即，轻微的脚震）。在重新暴露于与厌恶刺激相关的背景（或线索）时，啮齿动物会表现出物种典型的恐惧行为（以冻结来衡量）。相比之下，非关联的恐惧将使用捕食者的压力范例，其中啮齿动物暴露于猫。捕食者的压力引起的变化，在过度觉醒（作为测量响应声惊吓）和焦虑样的行为是明显的，在不同的环境中，从猫暴露，因此，非关联的恐惧的措施。该提案的主要目标是识别特定的大脑区域，以及介导关联和非关联恐惧记忆的mTOR通路的上游和下游分子靶点。我们将比较关联性和非关联性恐惧记忆的分子机制。我也有独特的机会，将我的实验室发现扩展到自然主义的捕食者-猎物环境。具体来说，我将研究神经的变化潜在的捕食者压力野生被困鹿小鼠。如果相似的分子靶标（即，mTOR通路）在暴露于野生环境中的应激源后被激活，就像那些在实验室动物中响应应激源而被激活一样，那么这将表明实验室研究具有生态学有效性。此外，这项创新的、潜在的变革性研究将为我们理解恐惧对大脑的影响提供一个新颖的、自然的维度。介导恐惧记忆过程的特定靶标的鉴定将代表阐明恐惧记忆基础的分子机制的重大进展。最终，确定恐惧背后的神经机制可能有助于理解与压力相关的疾病的发展，以及促进治疗，如创伤后应激障碍和特定的恐惧症。

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.