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.

这个项目的目标是描述恐惧消退、学习和学习机制的性别差异。 保留可能是创伤后应激障碍(PTSD)易感性差异的原因 女人对男人。提出的一种解释创伤应激恢复的机制是 条件性恐惧的消退。虽然有几项研究考察了恐惧条件反射和性别差异 在健康个体中灭绝，值得注意的是，很少有研究系统地研究 这些措施适用于创伤后应激障碍患者，这可能代表着一个更脆弱的群体。我们的试点数据 患有创伤后应激障碍的人表示，女性恐惧条件反射增加，消亡学习减少。 和回忆，这可能提供一种机制，可以解释流行病学发现。另一个有希望的人 可能解释某些女性不同易感性的发现与一种名为脑下垂体腺苷的多肽有关 环化酶激活多肽(PACAP)，它是应激反应的调节因子。PACAP水平较高 在女性中与更大的恐惧条件作用、创伤后应激障碍的存在和严重性有关，但与男性无关。 此外，雌激素调节PACAP，也与增强消光保持有关。 然而，PACAP还没有被研究对物种灭绝的潜在影响。 我们建议对男性和女性退伍军人进行恐惧条件作用的实验室研究 目的：探讨创伤后应激障碍在恐惧消退、学习和保留方面是否存在性别差异。这 研究还将考察PACAP在解释创伤后应激障碍组和性别差异消退能力方面的作用。 我们将招募医学上健康的创伤暴露创伤后应激障碍+和创伤后应激障碍-男性和绝经前女性 参加本研究的退伍军人(n=108)。四个年龄匹配的小组(每组27人)将包括：1) 创伤后应激障碍+女性退伍军人；2)创伤后应激障碍--女性退伍军人；3)创伤后应激障碍+男性退伍军人；4)创伤后应激障碍--男性退伍军人。 参与者将接受为期10天的恐惧条件训练。在第一天，他们将被赠送电脑- 生成与轻度电击(US)和皮肤配对(CS+)或未配对(CS-)的中性图像 电导响应将在整个过程中进行评估。在第四天，参与者将接受灭绝训练， 他们将被展示图像，但不会受到电击。参与者将在第11天返回参加 评估物种灭绝的耐久性。将在每次治疗前抽取血样以评估血药浓度。 PACAP和雌激素。我们预测，创伤后应激障碍的参与者将减少恐惧消退学习和 保留率与没有创伤后应激障碍的参与者相比。我们还预测，人类将会有更大的恐惧灭绝 与女性相比，学习和保持能力更强。患有创伤后应激障碍的女性将减少灭绝学习和 与没有创伤后应激障碍的女性和男性相比。我们还预测，PACAP将与 女性的灭绝学习和保持能力下降，但男性没有。在女性中，PACAP水平将是 创伤后应激障碍+参与者比创伤后应激障碍参与者更高。我们还将探讨降低PACAP 伴随着更高的雌激素将与更大的消亡，学习和保持有关。终极的 本研究的目的是刻画恐惧消退过程中的性别差异，以促进 创伤后应激障碍的病理生理学鉴定可能因性别而异，并可能受PACAP和性别的影响 荷尔蒙。