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: 9794748
• 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 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9794748
• 关键词: Accounting; Age; Area; 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; Medical; Molecular; Nature; Participant; Peptides; Pharmacology; Phase; Play; Polypeptide Hormones; Post-Traumatic Stress Disorders; Premenopause; Process; Publishing; Recovery; Reporting; Research; Response Elements; Risk; Role; Safety; Severities; Sex Differences; Shock; Startle Reaction; Stimulus; Stress; Stress Tests; Symptoms; Training; Variant; Veterans; Vulnerable Populations; Woman; biological adaptation to stress; candidate marker; 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; receptor; recruit; resilience; response; sex; trauma exposure

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）： 该项目的目标是描述恐惧消退学习和保留机制中的性别差异，这可能解释女性与男性创伤后应激障碍（PTSD）脆弱性的差异。一种解释创伤性应激恢复的机制是条件性恐惧消退的可变性。虽然一些研究已经检验了健康个体的恐惧调节和消退方面的性别差异，但值得注意的是，很少有研究系统地检验了患有创伤后应激障碍的个体在这些指标上的性别差异，而创伤后应激障碍可能代表了一个更脆弱的群体。我们对患有创伤后应激障碍（PTSD）的个体进行的试点数据表明，女性的恐惧调节能力增强，消除学习和记忆能力下降，这可能提供了一种解释流行病学发现的机制。另一个有希望的发现可以解释一些女性的不同脆弱性，它与肽、垂体腺苷酸环化酶激活多肽（PACAP）有关，它是应激反应的调节剂。 PACAP 水平较高与女性（而非男性）更大的恐惧调节和 PTSD 存在及严重程度相关。此外，雌激素调节 PACAP，也与增强的消退保留有关。然而，尚未研究 PACAP 对灭绝的潜在影响。我们建议对患有和不患有 PTSD 的男性和女性退伍军人进行恐惧条件反射的实验室研究，以确定 PTSD 中的恐惧消退学习和保留是否存在性别差异。这项研究还将检验 PACAP 在解释 PTSD 群体和消退能力方面的性别差异中的作用。我们将招募身体健康、患有创伤后应激障碍（PTSD+）和创伤后应激障碍（PTSD-）的男性和绝经前女性退伍军人参与本研究（n=108）。四个年龄匹配组（每组 27 人）将包括： 1) PTSD+ 女性退伍军人； 2）PTSD——女性退伍军人； 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 天的恐惧调节任务的培训。第一天，他们将看到计算机生成的中性图像，这些图像与轻度电击（US）配对（CS+）或未配对（CS-），并且将在整个过程中评估皮肤电导反应。第四天，参与者将接受消退训练，他们将看到图像，但不会受到电击。参与者将于第 11 天返回，评估灭绝的持久性。每次治疗前都会抽取血样，以评估 PACAP 和雌激素的水平。我们预测，与没有 PTSD 的参与者相比，PTSD 参与者的恐惧消退学习和保留能力会下降。我们还预测，与女性相比，男性的恐惧消退学习和保留能力更强。与没有 PTSD 的女性和男性相比，患有 PTSD 的女性的消退学习和记忆能力会下降。我们还预测，PACAP 与女性的消退学习和保留能力下降有关，但与男性无关。在女性中，与 PTSD- 参与者相比，PTSD+ 参与者的 PACAP 水平更高。我们还将探讨较低的 PACAP 伴随较高的雌激素是否与更强的消退学习和记忆能力相关。这项研究的最终目标是描述恐惧消退过程中的性别差异，以促进对 PTSD 病理生理学的识别，该病理生理学可能因性别而异，并可能受到 PACAP 和性激素的影响。