Post-traumatic stress disorder (PTSD) is a mental health condition that is triggered by a stressful event, with symptoms including exaggerated startle response, intrusive traumatic memories and nightmares. The single prolonged stress (SPS) is a multimodal stress protocol that comprises a sequential exposure to physical restraint, forced swimming, predator scent and ether anesthesia. This procedure generates behavioral and neurobiological alterations that resemble clinical findings of PTSD, and thus it is commonly used to model the disease in rodents. Here, we applied c-fos mapping to produce a comprehensive view of stress-activated brain regions in mice exposed to SPS alone or to SPS after oral pretreatment with the serotonin-noradrenaline receptor dual modulator ACH-000029 or the α1-adrenergic blocker prazosin. The SPS protocol evoked c-fos expression in several brain regions that control the stress-anxiety response, including the central and medial amygdala, the bed nucleus of the stria terminalis, the pallidum, the paraventricular hypothalamus, the intermediodorsal, paraventricular and central medial thalamic nuclei, the periaqueductal gray, the lateral habenula and the cuneiform nucleus. These effects were partially blocked by pretreatment with prazosin but completely prevented by ACH-000029. Collectively, these findings contribute to the brain-wide characterization of neural circuits involved in PTSD-related stress responses. Furthermore, the identification of brain areas regulated by ACH-000029 and prazosin revealed regions in which SPS-induced activation may depend on the combined or isolated action of the noradrenergic and serotonergic systems. Finally, the dual regulation of serotonin and α1 receptors by ACH-000029 might represent a potential pharmacotherapy that can be applied in the peri-trauma or early post-trauma period to mitigate the development of symptoms in PTSD patients.

创伤后应激障碍（PTSD）是一种心理健康状况，由压力事件触发，症状包括惊吓反应过度，侵入性创伤性记忆和噩梦。单次长时间应激（SPS）是一种多模式应激方案，包括依序进行物理约束，强迫游泳，捕食者的气味和以太麻醉。此过程会产生类似于PTSD临床表现的行为和神经生物学改变，因此通常用于为啮齿动物疾病建模。在这里，我们应用c-fos作图来产生单独暴露于SPS或使用5-羟色胺-去甲肾上腺素受体双重调节剂ACH-000029或α1-肾上腺素能阻滞剂prazosin进行口服预处理后暴露于SPS的小鼠中应力激活的大脑区域的全面视图。SPS协议在控制压力-焦虑反应的几个大脑区域中引起c-fos表达，包括中枢杏仁核和中枢杏仁核，终末纹的床核，苍白球，下丘脑旁丘脑，中间间窦，室旁和中央丘脑中央核，导水管周围的灰色，外侧ha管和楔形核。这些作用被哌唑嗪预处理部分阻止，但被ACH-000029完全阻止。这些发现共同促进了与PTSD相关的应激反应相关的神经回路的全脑表征。此外，由ACH-000029和哌唑嗪调节的大脑区域的鉴定揭示了SPS诱导的激活可能取决于去甲肾上腺素能和血清素能系统的联合或孤立作用的区域。