Fifield Kathleen, Hebert Mark, Williams Kimberly, Linehan Victoria, Whiteman Jesse D, Mac Callum Phillip, Blundell Jacqueline
Department of Psychology, Memorial University of Newfoundland, 232 Elizabeth Ave. , St. John's, Newfoundland, Canada A1B 3X9.
Department of Psychology, Memorial University of Newfoundland, 232 Elizabeth Ave. , St. John's, Newfoundland, Canada A1B 3X9.
Behav Brain Res. 2015 Jun 1;286:104-11. doi: 10.1016/j.bbr.2015.02.045. Epub 2015 Mar 5.
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.
先前的研究表明，雷帕霉素作为哺乳动物雷帕霉素靶蛋白（mTOR）通路的强效抑制剂，可阻断休克诱导的联想性恐惧记忆的巩固。此外，雷帕霉素对联想性恐惧记忆的阻断具有时间依赖性。然而，雷帕霉素是否会阻断捕食者应激诱导的非联想性恐惧记忆的巩固尚不清楚。此外，捕食者应激后mTOR激活的时间模式也未知。因此，当前研究的目的是确定雷帕霉素是否会阻断捕食者应激诱导的恐惧记忆的巩固，如果是，雷帕霉素的作用是否具有时间依赖性。在捕食者应激后的不同时间点，对雄性大鼠进行全身注射雷帕霉素。捕食者应激涉及将大鼠急性、无保护地暴露于猫，这会导致持久的非联想性恐惧记忆，表现为全身性过度觉醒和焦虑样行为增加。我们发现，在捕食者应激后立即注射雷帕霉素可阻断应激诱导的惊吓反应的巩固。然而，在捕食者应激后9、24或48小时注射雷帕霉素会增强应激诱导的惊吓反应。与休克诱导的联想性恐惧记忆一致，我们表明mTOR信号传导对于捕食者应激诱导的过度觉醒的巩固至关重要。然而，与休克诱导的恐惧记忆不同，捕食者应激后第二个持续的晚期mTOR依赖性过程实际上会减弱惊吓反应。与先前的研究结果一致，我们的数据支持雷帕霉素在治疗创伤后应激障碍等应激相关疾病中的潜在作用。然而，我们的数据表明雷帕霉素给药的时机至关重要。
