Institute of Physiology I, Westfälische Wilhelms-University Münster, 48149 Münster, Germany.
Institute of Physiology I, Westfälische Wilhelms-University Münster, 48149 Münster, Germany.
Prog Neuropsychopharmacol Biol Psychiatry. 2021 Dec 20;111:110338. doi: 10.1016/j.pnpbp.2021.110338. Epub 2021 Apr 26.
Treatment resistance of anxiety-related disorders often arises from an inappropriate fear expression, impairment in fear extinction, and spontaneous return of fear. Stress exposure is considered a high risk factor for neuropsychiatric disorders, but understanding of the long-term consequences of stress is limited, particularly when it comes to treatment outcome. Therefore, studying the consequences of acute stress would provide critical information on the role of stress in psychopathology. In the present study, we investigated the effect of acute immobilization stress on anxiety-like behavior and on conditioned fear memory. Our results demonstrate that prior stress exposure had no effect on anxiety-related behavior, fear acquisition, as well as fear extinction compared to non-stressed controls, but resulted in significantly higher rates of freezing during recall of extinction, indicating a consolidation failure. Further, immunohistochemical analysis of the expression of the immediate early gene c-Fos after recall of extinction revealed increased neuronal activity in the posterior paraventricular nucleus of the thalamus (PVT) in previously stressed animals compared to non-stressed controls. These results indicate, firstly, that acute stress affects long-term fear memory even after successful extinction training, and secondly, a strong involvement of the PVT in maladaptive fear responses induced by prior stress. Thus, stress-induced changes in PVT neuronal activity might be of importance for the pathophysiology of stress-sensitive anxiety-related psychiatric disorders, since exposure to an earlier acute stressor could counteract the success of therapy.
焦虑相关障碍的治疗抵抗通常源于不适当的恐惧表达、恐惧消除受损和恐惧自发回归。应激暴露被认为是神经精神障碍的高风险因素，但对应激的长期后果的理解有限，特别是在治疗结果方面。因此，研究急性应激的后果将为应激在精神病理学中的作用提供关键信息。在本研究中，我们调查了急性束缚应激对焦虑样行为和条件性恐惧记忆的影响。我们的结果表明，与未应激对照相比，先前的应激暴露对焦虑相关行为、恐惧获得以及恐惧消除均无影响，但在回忆性消退时导致明显更高的冻结率，表明巩固失败。此外，在回忆性消退后，对即刻早期基因 c-Fos 的表达进行免疫组织化学分析显示，先前应激的动物的丘脑后室旁核（PVT）中的神经元活动增加，而未应激的对照则没有。这些结果表明，首先，急性应激会影响长期恐惧记忆，即使在成功的消退训练后也是如此，其次，PVT 强烈参与了先前应激引起的适应不良的恐惧反应。因此，PVT 神经元活动的应激诱导变化可能对应激敏感的焦虑相关精神障碍的病理生理学很重要，因为早期的急性应激暴露可能会抵消治疗的成功。
