Sex Differences in Fear Conditioning: Mechanisms of Risk and Resilience for PTSD

恐惧调节的性别差异：创伤后应激障碍的风险和复原力机制

• 批准号: 8813484
• 负责人: SABRA INSLICHT
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8813484
• 关键词: Accounting; Age; Area; Biological Markers; Blood specimen; Conditioned Stimulus; Conflict (Psychology); Data; Diagnosis; Discrimination; Epidemiology; Estrogens; Evaluation; Extinction (Psychology); Female; Fright; Functional disorder; Funding; Galvanic Skin Response; Gene Expression; Genes; Genetic Polymorphism; Goals; Gonadal Steroid Hormones; Grant; High Prevalence; Human; Image; In Vitro; Individual; Laboratories; Laboratory Study; Learning; Matched Group; Measures; Molecular; Nature; PACAPR-1 protein; Participant; Peptides; Phase; Play; Post-Traumatic Stress Disorders; Premenopause; Process; Publishing; Recovery; Recruitment Activity; Reporting; Research; Response Elements; Risk; Role; Safety; Severities; Sex Characteristics; Shock; Stimulus; Stress; Symptoms; Testing; Training; Trauma; Variant; Veterans; Vulnerable Populations; Woman; biological adaptation to stress; cohort; computer generated; conditioned fear; conditioning; effective therapy; experience; improved; in vivo; learning extinction; male; men; neuromechanism; novel; pituitary adenylate cyclase activating polypeptide; programs; proliferative phase Menstrual cycle; public health relevance; resilience; response; sex

The goal of this project is to characterize sex differences in mechanisms of fear extinction learning and retention that may account for differences in vulnerability for Posttraumatic Stress Disorder (PTSD) in women versus men. A mechanism proposed to account for recovery from traumatic stress is variability in the extinction of conditioned fear. While several studies have examined sex differences in fear conditioning and extinction in healthy individuals, it is notable that few studies have systematically examined sex differences in these measures in individuals with PTSD, which may represent a more vulnerable group. Our pilot data of individuals with PTSD suggest that women have increased fear conditioning and decreased extinction learning and recall, which may provide a mechanism that could explain the epidemiological findings. Another promising discovery that may explain differential vulnerability in some women is related to the peptide, pituitary adenylate cyclase-activating polypeptide (PACAP), which is a regulator of the stress response. Higher levels of PACAP have been associated with greater fear conditioning and PTSD presence and severity in women, but not men. Furthermore, estrogen modulates PACAP and has also been associated with enhanced extinction retention. However, PACAP has not been studied for potential effects on extinction. We propose to conduct a laboratory study of fear conditioning in male and female veterans with and without PTSD to establish whether there are sex differences in fear extinction learning and retention in PTSD. This study will also examine the role of PACAP in explaining PTSD group and sex differences in extinction ability. We will recruit medically healthy trauma-exposed PTSD+ and PTSD- male and pre-menopausal female veterans for participation in this study (n=108). Four age-matched groups (n=27 per group) will consist of: 1) PTSD+ female veterans; 2) PTSD- female veterans; 3) PTSD+ male veterans; 4) PTSD- male veterans. Participants will be trained in a 10-day fear conditioning task. On Day 1, they will be presented with computer- generated neutral images that are paired (CS+) or unpaired (CS-) with a mild electrical shock (US) and skin conductance responses will be assessed throughout. On Day 4, participants will undergo extinction training, in which they will be shown the images but will not receive shock. Participants will return on Day 11 for an evaluation of the durability of extinction. Blood samples will be drawn prior to each session to assess for levels of PACAP and estrogen. We predict that PTSD participants will have decreased fear extinction learning and retention compared to participants without PTSD. We also predict that men will have greater fear extinction learning and retention compared to women. Women with PTSD will have decreased extinction learning and retention compared to women without PTSD and men. We also predict that PACAP will be associated with decreased extinction learning and retention in women, but not in men. Among women, PACAP levels will be higher in PTSD+ participants compared to PTSD- participants. We will also explore whether lower PACAP accompanied by higher estrogen will be associated with greater extinction learning and retention. The ultimate goal of this research is to characterize sex differences in fear extinction processes in order to advance the identification of the pathophysiology of PTSD that may vary by sex and may be influenced by PACAP and sex hormones.

该项目的目的是表征性别差异在恐惧灭绝学习和 保留可能解释创伤后应激障碍脆弱性（PTSD）的差异 女人与男人。提议说明从创伤压力中恢复的一种机制是变异性 条件恐惧的灭绝。虽然几项研究检查了恐惧调节和 在健康个体中灭绝，值得注意的是，很少有研究系统地检查了性别差异 PTSD的个体中的这些措施可能代表一个更脆弱的群体。我们的试点数据 PTSD患者表明，妇女增加了恐惧调理和减少灭绝学习 并回想一下，这可能提供了一种可以解释流行病学发现的机制。另一个有希望的 可能解释某些女性差异脆弱性的发现与肽，垂体腺酸有关 环酶激活多肽（PACAP）是应力反应的调节剂。较高的PACAP 与女性的恐惧调节和PTSD的存在和严重程度相关，但与男性无关。 此外，雌激素调节PACAP，也与增强的灭绝保留率有关。 但是，尚未对PACAP进行对灭绝的潜在影响。 我们建议对有和没有的男女退伍军人进行一项实验室研究 PTSD确定PTSD中恐惧灭绝学习和保留是否存在性别差异。这 研究还将研究PACAP在解释PTSD组和性别差异在灭绝能力方面的作用。 我们将招募受医学健康的创伤暴露于PTSD+和PTSD-男性和绝经前女性 参加这项研究的退伍军人（n = 108）。四个年龄匹配的组（每组n = 27）将包括：1） PTSD+女退伍军人； 2）PTSD-女退伍军人； 3）PTSD+男性退伍军人； 4）PTSD-男性退伍军人。 参与者将接受为期10天的恐惧调节任务进行培训。在第1天，将向他们展示计算机 - 与轻度电击（US）和皮肤配对的中性图像（CS+）或未配对（CS-） 电导响应将在整个过程中进行评估。在第4天，参与者将接受灭绝培训， 它们将被向图像显示，但不会受到震惊。参与者将在第11天返回 评估灭绝的耐用性。每次会议之前将绘制血液样本，以评估水平 PACAP和雌激素。我们预测，PTSD参与者将减少恐惧灭绝学习和 与没有PTSD的参与者相比，保留率。我们还预测，男人会有更大的恐惧灭绝 与女性相比，学习和保留。具有PTSD的女性将减少灭绝学习和 与没有PTSD和男性的女性相比，保留。我们还预测PACAP将与 女性的灭绝学习和保留率下降，但男性的保留率不大。在女性中，PACAP水平将是 与PTSD参与者相比，PTSD+参与者的参与者更高。我们还将探索是否下pacap 伴随着较高的雌激素将与更大的灭绝学习和保留有关。最终 这项研究的目标是表征恐惧灭绝过程中的性别差异，以促进 鉴定可能因性别而异的PTSD的病理生理学，可能受到PACAP和性别的影响 激素。