Exploring sex differences in the neural correlates of PTSD: Impact of oxytocin

描述(由申请人提供)：创伤后应激障碍(PTSD)是一种慢性和致残性障碍，可在暴露于创伤事件后发生。虐待儿童是导致创伤后应激障碍的主要原因之一。回避、过度唤醒和对事件的侵入性回忆的症状会一直持续到成年。尽管女性患创伤后应激障碍的可能性是男性的两倍多，但人们对导致男性患创伤后应激障碍风险和弹性差异的神经生物学因素知之甚少。杏仁核是一个边缘脑区域，在评估心理社会刺激的显着性方面发挥着关键作用。使用血氧水平依赖(BOLD)功能磁共振成像(FMRI)的研究发现，PTSD患者对恐惧面孔的图片表现出夸大的杏仁核反应。催产素(OT)是一种促进社会纽带、信任和冷静的神经肽。鼻腔注射催产素可减少杏仁核对恐惧表情的反应。值得注意的是，在杏仁核和OT系统之间的相互作用中已经发现了性别二型性。此外，还发现了OT系统对早期生活经历的敏感性的性别差异，表明OT可能是一个关键的神经生物学因素，突显了性别差异对创伤后应激障碍的风险和韧性。这项提案的广泛和长期目标是提供初步数据，指导R01应用程序探索1)神经肽和边缘脑活动之间的相互作用如何参与创伤后应激障碍的病理生理；2)边缘脑活动神经肽能调节的性别差异；以及3)这些差异如何赋予创伤后应激障碍的风险和韧性。为了实现这些目标，我们提出了三个具体目标。具体目标1：比较患有与童年创伤有关的创伤后应激障碍的男性(n=15)和女性(n=15)以及经历过童年创伤的有弹性的男性(n=15)和没有创伤后应激障碍(没有其他主要轴心I障碍)的女性(n=15)的杏仁核反应。具体目标2：在四个研究组之间，比较鼻腔注射催产素和安慰剂对杏仁核对恐惧面孔的反应。具体目的3：探讨四组大鼠血浆催产素水平与杏仁核反应之间的相互作用。所有受试者将在儿童创伤问卷中获得中到重度的分数，并有符合创伤后应激障碍诊断统计手册-IV标准A的童年创伤病史。杏仁核的反应将使用BOLD功能磁共振成像进行测量，所有女性都将在月经周期的早中期卵泡阶段进行扫描。在两次扫描之前，鼻腔注射OT或安慰剂将采用双盲交叉设计。服药前将采集血浆OT样本。对患有创伤后应激障碍的男性和女性进行比较，将有助于洞察创伤后应激障碍风险的神经生物学相关性中的性别差异。对有和没有创伤后应激障碍儿童虐待史的男性和女性进行比较，将提供有关韧性神经基础的性别差异的关键信息。

DESCRIPTION (provided by applicant): Posttraumatic stress disorder (PTSD) is a chronic and disabling disorder that can occur following exposure to a traumatic event. Child abuse is one of the leading causes of PTSD. Symptoms of avoidance, hyperarousal, and intrusive recollections of the event can persist into adulthood. Although, women are more than twice as likely as men to develop PTSD, little is known about the neurobiological factors that underlie sex differences in risk and resilience to PTSD. The amygdala is a limbic brain region that plays a critical role in evaluating the salience of psychosocial stimuli. Studies using blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) have found that individuals with PTSD show exaggerated amygdala responses to pictures of fearful faces. Oxytocin (OT) is a neuropeptide that promotes social bonding, trust and calmness. Intranasal administration of OT reduces amygdala responding to fearful faces. Of note, sexual dimorphisms in the interaction between the amygdala and the OT system have been found. In addition, sex differences in the sensitivity of the OT system to early life experiences have also been found and suggest that OT may be a critical neurobiological factor that underscores sex differences in risk and resilience to PTSD. The broad and long-term objectives of this proposal are to provide preliminary data that will guide an R01 application exploring 1) how interactions between neuropeptides and limbic brain activity are involved in the pathophysiology of PTSD 2) sex differences in neuropeptidergic regulation of limbic brain activity and 3) how these differences confer risk and resilience to PTSD. To meet these objectives we have proposed three specific aims. Specific Aim 1: To compare amygdala responding to fearful faces between men (n=15) and women (n=15) with PTSD related to childhood trauma; and resilient men (n=15) and women (n=15) without PTSD (free of other major Axis I disorders) who have experienced childhood trauma. Specific Aim 2: To compare intranasal OT versus placebo on amygdala responding to fearful faces between the four study groups. Specific Aim 3: To explore the interaction between plasma levels of oxytocin and amygdala responding between the four study groups. All subjects will have moderate to severe scores on the Childhood Trauma Questionnaire and a history of a childhood trauma that meets the Diagnostic Statistical Manual-IV Criterion A of PTSD. Amygdala responding will be measured using BOLD fMRI and all of the women will be scanned during the early to mid-follicular phase of their menstrual cycle. Intranasal OT or placebo will be administered in a double-blind, crossover design before each of two scanning sessions. Plasma OT samples will be collected prior to medication administration. Comparisons between men and women with PTSD will provide insight into sex differences in the neurobiologic correlates of risk in PTSD. Comparisons between men and women with a history of child abuse with and without PTSD will provide critical information regarding sex differences in the neural substrates of resilience.