Mental Health Service, VA Boston Healthcare System, West Roxbury, MA 02132, USA; Department of Psychiatry, Boston University School of Medicine, Boston, MA 02118, USA; Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA.
Research Service, VA Boston Healthcare System, West Roxbury, MA 02132, USA; Undergraduate Program in Neuroscience, Boston University, Boston, MA 02215, USA.
Brain Res Bull. 2022 Aug;186:106-122. doi: 10.1016/j.brainresbull.2022.05.006. Epub 2022 May 23.
Post-traumatic stress disorder (PTSD) is a trauma-related condition that produces distressing fear memory intrusions, avoidance behaviors, hyperarousal/startle, stress responses and insomnia. This review focuses on the importance of the orexin neural system as a novel mechanism related to the pathophysiology of PTSD. Orexinergic neurons originate in the lateral hypothalamus and project widely to key neurotransmitter systems, autonomic neurons, the hypothalamic-pituitary-adrenal (HPA) axis, and fear-related neural circuits. After trauma or stress, the basolateral amygdala (BLA) transmits sensory information to the central nucleus of the amygdala (CeA) and in turn to the hypothalamus and other subcortical and brainstem regions to promote fear and threat behaviors. Orexin receptors have a prominent role in this circuit as fear conditioned orexin receptor knockout mice show decreased fear expression while dual orexin receptor antagonists (DORAs) inhibit fear acquisition and expression. Orexin activation of an infralimbic-amygdala circuit impedes fear extinction while DORA treatments enhance it. Increased orexin signaling to the amygdalo-cortical-hippocampal circuit promotes avoidance behaviors. Orexin has an important role in activating sympathetic nervous system (SNS) activity and HPA axis stress responses. Blockade of orexin receptors reduces fear-conditioned startle responses. In PTSD models, individuals demonstrate sleep disturbances such as increased sleep latency and more transitions to wakefulness. Increased orexin activity impairs sleep by promoting wakefulness and reducing total sleep time while DORA treatments enhance sleep onset and maintenance. The orexinergic neural system provides important mechanisms for understanding multiple PTSD behaviors and provides new medication targets to treat this often persistent and debilitating illness.
创伤后应激障碍（PTSD）是一种与创伤相关的疾病，会产生痛苦的恐惧记忆入侵、回避行为、过度警觉/惊吓、应激反应和失眠。本综述重点介绍了孤啡肽神经递质系统作为与 PTSD 病理生理学相关的新机制的重要性。孤啡肽神经元起源于下丘脑外侧区，并广泛投射到关键神经递质系统、自主神经元、下丘脑-垂体-肾上腺（HPA）轴和与恐惧相关的神经回路。创伤或应激后，基底外侧杏仁核（BLA）将感觉信息传递到杏仁中央核（CeA），进而传递到下丘脑和其他皮质下及脑干区域，以促进恐惧和威胁行为。孤啡肽受体在该回路中具有突出作用，因为恐惧条件性孤啡肽受体敲除小鼠表现出恐惧表达减少，而双重孤啡肽受体拮抗剂（DORAs）则抑制恐惧获得和表达。孤啡肽激活杏仁下脚-杏仁核回路会阻碍恐惧消退，而 DORA 治疗则增强其作用。孤啡肽增加向杏仁皮质-海马回路的信号传递会促进回避行为。孤啡肽在激活交感神经系统（SNS）活动和 HPA 轴应激反应中具有重要作用。孤啡肽受体阻断会减少恐惧条件性惊吓反应。在 PTSD 模型中，个体表现出睡眠障碍，例如睡眠潜伏期延长和更多向觉醒状态的转变。孤啡肽活性增加会通过促进觉醒和减少总睡眠时间来破坏睡眠，而 DORA 治疗则会增强睡眠起始和维持。孤啡肽能神经递质系统为理解多种 PTSD 行为提供了重要机制，并为治疗这种常持续存在和使人衰弱的疾病提供了新的药物靶点。
