Propranolol Decreases Fear Expression by Modulating Fear Memory Traces.
Propranolol Decreases Fear Expression by Modulating Fear Memory Traces.
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DOI：
10.1016/j.biopsych.2021.01.005
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发表时间：
2021-06-15
影响因子：
10.6
通讯作者：
Denny CA
中科院分区：
文献类型：
--
作者：
Leal Santos S;Stackmann M;Muñoz Zamora A;Mastrodonato A;De Landri AV;Vaughan N;Chen BK;Lanio M;Denny CA
创伤后应激障碍(PTSD)可在创伤性事件发生后发展，并导致高度的、不适当的恐惧和焦虑。尽管大约8%的美国人口患有创伤后应激障碍，但FDA只批准了两种药物来治疗它，两种药物的疗效都很有限。普萘洛尔是一种非选择性β肾上腺素能拮抗剂，已显示出减少夸大恐惧的效果，人们对使用它治疗恐惧障碍重新产生了兴趣。在这里，我们试图通过利用依赖活动的标记系统ArcCreERT2 x增强型黄色荧光蛋白(EYFP)小鼠来确定心得安减轻恐惧的机制。129S6/SvEv小鼠被给予4次电击情境恐惧条件反射(CFC)范式，然后立即或延迟情境再暴露。生理盐水或心得安是在第一次环境重新暴露之前或之后给予的。为了量化海马、前额叶和杏仁核的记忆痕迹，ArcCreERT2 x EYFP小鼠被给予延迟的情景再暴露，在再次情景再次暴露之前，注射生理盐水或心得安。普萘洛尔只有在延迟的情景再暴露之前给药才能减少恐惧表达。在ArcCreERT2 x EYFP小鼠中，心得安给药后，背侧齿状回和基底外侧杏仁核中的恐惧记忆痕迹受到影响。心得安显著改变了海马区、皮质区和杏仁核区之间的功能连接。这些数据表明，心得安可能通过改变网络相关活动和减弱最初创伤记忆痕迹的重新激活来减少恐惧表达。这项工作有助于理解去甲肾上腺素能药物作为创伤后应激障碍患者的治疗辅助手段。
Post-traumatic stress disorder (PTSD) can develop following a traumatic event and results in heightened, inappropriate fear and anxiety. Although approximately 8% of the United States population suffers from PTSD, only two drugs have been approved by the FDA to treat it, both with limited efficacy. Propranolol, a non-selective β-adrenergic antagonist, has shown efficacy in decreasing exaggerated fear, and there has been renewed interest in using it to treat fear disorders. Here, we sought to determine the mechanisms by which propranolol attenuates fear by utilizing an activity-dependent tagging system, the ArcCreERT2 x enhanced yellow fluorescent protein (eYFP) mice. 129S6/SvEv mice were administered a 4-shock contextual fear conditioning (CFC) paradigm followed by immediate or delayed context re-exposures. Saline or propranolol was administered either prior to or following the first context re-exposure. To quantify hippocampal, prefrontal and amygdalar memory traces, ArcCreERT2 x eYFP mice were administered a delayed context re-exposure with either a saline or propranolol injection prior to context re-exposure. Propranolol decreased fear expression only when administered prior to a delayed context re-exposure. Fear memory traces were affected in the dorsal dentate gyrus and basolateral amygdala following propranolol administration in the ArcCreERT2 x eYFP mice. Propranolol acutely altered functional connectivity between hippocampal, cortical, and amygdalar regions. These data indicate that propranolol may decrease fear expression by altering network correlated activity and by weakening the reactivation of the initial traumatic memory trace. This work contributes to the understanding of noradrenergic drugs as therapeutic aids for PTSD patients.
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影响因子：
2.7
作者：
Giustino TF;Fitzgerald PJ;Maren S
通讯作者：
Maren S
影响因子：
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作者：
Denny CA;Kheirbek MA;Alba EL;Tanaka KF;Brachman RA;Laughman KB;Tomm NK;Turi GF;Losonczy A;Hen R
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Maren, Stephen