Dept. of Pharmacology and Systems Physiology, University of Cincinnati, United States; Neuroscience Graduate Program, University of Cincinnati, United States.
Dept. of Pharmacology and Systems Physiology, University of Cincinnati, United States; VA Medical Center, Cincinnati, OH, 45221, United States.
Prog Neuropsychopharmacol Biol Psychiatry. 2019 Jun 8;92:378-386. doi: 10.1016/j.pnpbp.2019.02.007. Epub 2019 Feb 16.
Individuals with fear-associated conditions such as panic disorder (PD) and posttraumatic stress disorder (PTSD) display increased emotional responses to interoceptive triggers, such as CO inhalation, that signal a threat to physiological homeostasis. Currently, effector systems and mechanisms underlying homeostatic modulation of fear memory are not well understood. In this regard, the renin angiotensin system (RAS), particularly the angiotensin receptor type 1 (AT1R), a primary homeostatic regulatory target, has gained attention. RAS polymorphisms have been reported in PD and PTSD, and recent studies report AT1R-mediated modulation of fear extinction. However, contribution of AT1Rs in fear evoked by the interoceptive threat of CO has not been investigated. Using pharmacological, behavioral, and AT1R/ACE gene transcription analyses, we assessed central AT1R recruitment in CO-associated fear. CO inhalation led to significant AT1R and ACE mRNA upregulation in homeostatic regulatory regions, subfornical organ (SFO) and paraventricular nucleus (PVN), in a temporal manner. Intracerebroventricular infusion of selective AT1R antagonist, losartan, significantly attenuated freezing during CO inhalation, and during re-exposure to CO context, suggestive of AT1R modulation of contextual fear. Regional Fos mapping in losartan-treated mice post-behavior revealed significantly attenuated labeling in areas regulating defensive behavior, contextual fear, and threat responding; such as, the bed nucleus of stria terminalis, dorsal periaqueductal gray, hypothalamic nuclei, hippocampus, and prefrontal areas such as the prelimbic, infralimbic, and anterior cingulate cortices. Sub-regions of the amygdala did not show CO-associated AT1R regulation or altered Fos labeling. Collectively, our data suggests central AT1R recruitment in modulation of fear behaviors associated with CO inhalation via engagement of neurocircuits regulating homeostasis and defensive behaviors. Our data provides mechanistic insights into the interoceptive regulation of fear, relevant to fear related disorders such as PD and PTSD.
患有恐惧相关疾病（如惊恐障碍和创伤后应激障碍）的个体对提示生理内稳态受到威胁的内感受触发因素（如 CO 吸入）表现出更强的情绪反应。目前，尚不清楚调节恐惧记忆的内稳态的效应器系统和机制。在这方面，肾素血管紧张素系统（RAS），特别是血管紧张素受体 1（AT1R），作为主要的内稳态调节靶点，引起了人们的关注。已经在惊恐障碍和创伤后应激障碍中报道了 RAS 多态性，并且最近的研究报告了 AT1R 介导的恐惧消退的调节。然而，尚未研究 CO 引起的内感受威胁所诱发的恐惧中 AT1R 的作用。使用药理学、行为学和 AT1R/ACE 基因转录分析，我们评估了 CO 相关恐惧中中枢 AT1R 的募集。CO 吸入以时间依赖性方式导致内稳态调节区域（穹窿下器官[SFO]和室旁核[PVN]）中 AT1R 和 ACE mRNA 的显著上调。脑室注射选择性 AT1R 拮抗剂氯沙坦显著减弱 CO 吸入时的冻结，并且在重新暴露于 CO 环境时也减弱，提示 AT1R 调节情境恐惧。氯沙坦处理后的小鼠在行为后进行区域 Fos 映射显示，调节防御行为、情境恐惧和威胁反应的区域的标记显著减弱；如终纹床核、背侧periaqueductal 灰质、下丘脑核、海马和前额叶区域，如前扣带回皮质、下丘脑皮质和前扣带皮质。杏仁核的亚区没有显示出 CO 相关的 AT1R 调节或改变的 Fos 标记。总的来说，我们的数据表明，中枢 AT1R 的募集通过参与调节内稳态和防御行为的神经回路，调节与 CO 吸入相关的恐惧行为。我们的数据为 CO 吸入相关恐惧的内感受调节提供了机制见解，与惊恐障碍和创伤后应激障碍等恐惧相关障碍相关。
