Evaluating the effects of systemic mTOR inhibition on fear memory processes in rodents with relevance to ameliorating PTSD-like symptoms

MacCallum, Phillip Edward (2025) Evaluating the effects of systemic mTOR inhibition on fear memory processes in rodents with relevance to ameliorating PTSD-like symptoms. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

In this dissertation, I use physical and psychogenic contextual fear conditioning procedures to study the role of the mechanistic target of rapamycin (mTOR) in memory processes and investigate its potential as a target for treating post-traumatic stress disorder (PTSD)-like symptoms in rodents. I determined that inhibiting both mTOR complex 1 and 2 with AZD2014 impairs the consolidation of a foot-shock induced contextual fear memory in mice similar to the mTORC1 inhibitor rapamycin, while inhibition of the mTORC1 downstream effector S6K1 with PF-4708671 does not. Using the same conditioning procedure, I found that rapamycin treatment three-hours, but not 12-hours, post-conditioning impairs the consolidation and persistence of contextual fear memory in mice. In support of earlier published work showing rapamycin impairs the consolidation of long-lasting contextual fear, hyperarousal, and anxiety-like behaviour in rats following a brief unprotected exposure to a cat, I show here, using immunohistochemistry, increased mTORC1 activation in the hippocampus and periaqueductal grey of rats shortly after this type of exposure. I also investigated the effects of psychogenic-only predator stress at inducing long-lasting behavioural changes via a model of mouse defensive behaviour previously unexplored for this purpose. Following a fully protected exposure to a rat, mice exhibited associative contextual fear and other non-associative fear and anxiety-like behaviours, with many of these behaviours weakened from post-exposure rapamycin treatment. In a different set of experiments using foot-shock conditioning, I reveal that rapamycin injected three- or 12-hours post-reactivation impairs the persistence of contextual fear memory, while the same treatment appears to induce a gradient effect against reconsolidation of the memory. Additionally, I demonstrate that two consecutive days of reactivation and rapamycin treatment maximizes abatement to recall foot-shock associated contextual memory through impaired reconsolidation in mice. Lastly, I show that the effects of rapamycin to consolidation and reconsolidation on contextual fear memory in mice does not interfere with the ability to subsequently learn and recall new auditory fear associations but protects against fear generalization. Collectively, these findings advance our neurobiological understanding of mTOR in memory processes and provide preclinical evidence on how to pharmacologically treat PTSD-like symptoms.

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