Inhibition of mTOR kinase via rapamycin blocks persistent predator stress-induced hyperarousal

Fifield, Kathleen Elizabeth (2012) Inhibition of mTOR kinase via rapamycin blocks persistent predator stress-induced hyperarousal. Masters thesis, Memorial University of Newfoundland.

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Abstract

Traumatic, stressful life events are thought to trigger acquired anxiety disorders such as post-traumatic stress disorder (PTSD). PTSD is characterised by several symptoms including both associative and non-associative tear memories. It has been previously established that the mammalian target of rapamycin (mTOR) pathway plays a key role in associative fear memories: however, it is unknown whether this pathway attenuates non-associative fear memories (or fear sensitization). Thus, the goal of these experiments was to examine the role of mTOR in non-associative fear memories. In the current set of experiments, non-associative fear memories were produced by predator stress. Predator stress involves an acute, unprotected exposure of a rat to a cat which causes long-lasting non-associative fear memories expressed as generalized hyperarousal (manifested as increased startle response and anxiety-like behavior and measured in the elevated plus maze, hole board and light/dark box). Here, we show that rapamycin. When given before (Experiment I) or after (Experiment 2) stress, attenuated predator stress induced hyperarousal, lasting at least three weeks. In addition, rapamycin blocked a subset of anxiety-like behaviors. Furthermore, when re-exposed to the predator stress context, rapamycin-treated predator stressed rats showed increased activity compared to vehicle controls. These data suggest that rapamycin blocks consolidation of predator stress-induced non-associative and associative fear memories. In a second set of experiments, we examined the effects of rapamycin following reactivation (Experiment 3) and without reactivation (Experiment 4) of predator stress-induced fear memories on non-associative fear memories. A single, 10 minute re-exposure to the predator stress context was sufficient to extinguish predator stress -induced hyperarousal (Experiments 3, 4). Rapamycin blocked this extinction (Experiment 3). We also show that, consistent with previous data, rapamycin significantly reduced weight gain lasting at least four weeks (Experiments 1-4). Taken together with past research, our results indicate that mTOR regulation of protein translation is required for consolidation of both associative and non-associative fear memories. Overall, these data suggest that rapamycin, a drug already in clinical trials, may be a novel treatment for patients suffering from acquired anxiety disorders such as PTSD.

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