Time-dependent effects of rapamycin on consolidation of predator stress-induced hyperarousal.
Previous studies have indicated that rapamycin, a potent inhibitor of the mammalian target of rapamycin (mTOR) pathway, blocks consolidation of shock-induced associative fear memories. Moreover, rapamycin's block of associative fear memories is time-dependent. It is unknown, however, if rapamycin blocks consolidation of predator stress-induced non-associative fear memories. Furthermore, the temporal pattern of mTOR activation following predator stress is unknown. Thus, the goal of the current studies was to determine if rapamycin blocks consolidation of predator stress-induced fear memories and if so, whether rapamycin's effect is time-dependent. Male rats were injected systemically with rapamycin at various time points following predator stress. Predator stress involves an acute, unprotected exposure of a rat to a cat, which causes long-lasting non-associative fear memories manifested as generalized hyperarousal and increased anxiety-like behaviour. We show that rapamycin injected immediately after predator stress blocked consolidation of stress-induced startle. However, rapamycin injected 9, 24 or 48h post predator stress potentiated stress-induced startle. Consistent with shock-induced associative fear memories, we show that mTOR signalling is essential for consolidation of predator stress-induced hyperarousal. However, unlike shock-induced fear memories, a second, persistent, late phase mTOR-dependent process following predator stress actually dampens startle. Consistent with previous findings, our data support the potential role for rapamycin in treatment of stress related disorders such as posttraumatic stress disorder. However, our data suggest timing of rapamycin administration is critical.
Department of Psychology, Memorial University of Newfoundland, 232 Elizabeth Ave. , St. John's, Newfoundland, Canada A1B 3X9.
Kathleen
K
Fifield
Department of Psychology, Memorial University of Newfoundland, 232 Elizabeth Ave. , St. John's, Newfoundland, Canada A1B 3X9.
Mark
M
Hebert
Department of Psychology, Memorial University of Newfoundland, 232 Elizabeth Ave. , St. John's, Newfoundland, Canada A1B 3X9.
Kimberly
K
Williams
Department of Psychology, Memorial University of Newfoundland, 232 Elizabeth Ave. , St. John's, Newfoundland, Canada A1B 3X9.
Victoria
V
Linehan
Department of Psychology, Memorial University of Newfoundland, 232 Elizabeth Ave. , St. John's, Newfoundland, Canada A1B 3X9.
Jesse D
JD
Whiteman
Department of Psychology, Memorial University of Newfoundland, 232 Elizabeth Ave. , St. John's, Newfoundland, Canada A1B 3X9.
Phillip
P
Mac Callum
Department of Psychology, Memorial University of Newfoundland, 232 Elizabeth Ave. , St. John's, Newfoundland, Canada A1B 3X9. Electronic address: jblundell@mun.ca.
Jacqueline
J
Blundell
D000818:Animals; D001143:Arousal / Q000187:drug effects / Q000502:physiology; D001835:Body Weight / Q000187:drug effects; D002415:Cats; D008297:Male; D000069077:Memory Consolidation / Q000187:drug effects* / Q000502:physiology; D011235:Predatory Behavior; D011619:Psychotropic Drugs / Q000494:pharmacology*; D011897:Random Allocation; D020318:Rats, Long-Evans; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D013315:Stress, Psychological / Q000188:drug therapy* / Q000503:physiopathology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors
D011619:Psychotropic Drugs; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
Consolidation; Hyperarousal; Predator stress; Rapamycin; Startle; mTOR