Neural Mechanisms underlying associative and non-associative fear memories.

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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.