Background

Posttraumatic stress disorder can develop after a traumatic event and results in heightened, inappropriate fear and anxiety. Although approximately 8% of the U.S. population is affected by posttraumatic stress disorder, only two drugs have been approved by the Food and Drug Administration to treat it, both with limited efficacy. Propranolol, a nonselective β-adrenergic antagonist, has shown efficacy in decreasing exaggerated fear, and there has been renewed interest in using it to treat fear disorders.

Methods

Here, we sought to determine the mechanisms by which propranolol attenuates fear by utilizing an activity-dependent tagging system, ArcCreER^T2 x eYFP mice. 129S6/SvEv mice were administered a 4-shock contextual fear conditioning paradigm followed by immediate or delayed context reexposures. Saline or propranolol was administered either before or after the first context reexposure. To quantify hippocampal, prefrontal, and amygdalar memory traces, ArcCreER^T2 x eYFP mice were administered a delayed context reexposure with either a saline or propranolol injection before context reexposure.

Results

Propranolol decreased fear expression only when administered before a delayed context reexposure. Fear memory traces were affected in the dorsal dentate gyrus and basolateral amygdala after propranolol administration in the ArcCreER^T2 x eYFP mice. Propranolol acutely altered functional connectivity between the hippocampal, cortical, and amygdalar regions.

Conclusions

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 patients with posttraumatic stress disorder.

中文翻译：

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普萘洛尔通过调节恐惧记忆痕迹来减少恐惧表达

背景

创伤后应激障碍可在创伤事件后发展，并导致高度的、不适当的恐惧和焦虑。尽管大约 8% 的美国人口受到创伤后应激障碍的影响，但美国食品和药物管理局仅批准了两种治疗该疾病的药物，两种药物的疗效均有限。普萘洛尔是一种非选择性的 β-肾上腺素能拮抗剂，已显示出降低过度恐惧的功效，并且人们对使用它来治疗恐惧症重新产生了兴趣。

方法

在这里，我们试图确定普萘洛尔通过利用活动依赖性标记系统 ArcCreER ^T2 x eYFP 小鼠减轻恐惧的机制。对 129S6/SvEv 小鼠进行 4 次休克情境恐惧调节范式，然后立即或延迟情境再暴露。在第一次环境再暴露之前或之后给予盐水或普萘洛尔。为了量化海马、前额叶和杏仁核的记忆痕迹，ArcCreER ^T2 x eYFP 小鼠在上下文再暴露之前用盐水或普萘洛尔注射延迟上下文再暴露。

结果

普萘洛尔只有在延迟背景再暴露之前给药时才会降低恐惧表达。^{在 ArcCreER T2} x eYFP 小鼠中施用普萘洛尔后，背齿状回和基底外侧杏仁核的恐惧记忆痕迹受到影响。普萘洛尔急剧改变了海马、皮质和杏仁核区域之间的功能连接。

结论

这些数据表明，普萘洛尔可能通过改变网络相关活动和削弱初始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。