Neural Mechanisms underlying associative and non-associative fear memories.

我的研究项目的长期目标是确定创伤事件（或恐惧记忆）记忆的神经机制。我的实验室和其他人的研究表明，哺乳动物雷帕霉素靶点（mTOR）通路可能在恐惧记忆的形成、维持和持久中起着关键作用。恐惧记忆可以在先前与压力源相关的环境中发生（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反射，而是非联想恐惧（或恐惧敏感化）的测量。在目前的建议中，联想恐惧将使用经典的恐惧条件反射范式进行评估，即动物学会将新环境（或线索）与厌恶刺激（即轻微的足部电击）联系起来。在再次暴露于与厌恶刺激相关的环境（或线索）时，啮齿动物将表现出物种典型的恐惧行为（以冻结为衡量标准）。相比之下，非联想恐惧将使用捕食者压力范式进行评估，其中啮齿动物暴露于猫。捕食者压力引起的过度觉醒的变化（通过对声音惊吓的反应来测量）和类似焦虑的行为在不同于猫暴露的环境中是明显的，因此，是非联想恐惧的测量。本研究的主要目标是确定特定的大脑区域，以及介导联想性和非联想性恐惧记忆的mTOR通路的上游和下游分子靶点。将比较联想性和非联想性恐惧记忆的分子机制。我也有一个独特的机会将我的实验室发现扩展到自然的捕食者-猎物环境中。具体来说，我将研究野生鹿困小鼠捕食者压力下的神经变化。如果类似的分子靶标（即mTOR通路）在暴露于野外应激源后被激活，就像那些在实验室动物中对应激源作出反应时被激活一样，那么这将表明实验室研究具有生态有效性。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而自然的维度。确定介导恐惧记忆过程的特定目标将是阐明恐惧记忆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创伤后应激障碍和特定恐惧症等压力相关疾病的发展，并促进其治疗。

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.