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

描述(由申请人提供)： 该项目的目标是描述恐惧、消退、学习和保持机制中的性别差异，这可能解释女性与男性创伤后应激障碍(PTSD)易感性的差异。一种解释创伤应激恢复的机制是条件性恐惧消退的变异性。虽然有几项研究考察了健康个体在恐惧条件反射和消退方面的性别差异，但值得注意的是，很少有研究系统地研究创伤后应激障碍患者在这些指标上的性别差异，因为创伤后应激障碍患者可能代表着更脆弱的群体。我们对创伤后应激障碍患者的试点数据表明，女性恐惧条件反射增加，消亡学习和回忆减少，这可能提供了一种机制，可以解释流行病学的发现。另一项有希望的发现可能解释了一些女性的不同脆弱性，这与一种名为脑下垂体腺苷环化酶激活多肽(PACAP)的多肽有关，PACAP是应激反应的调节因子。在女性中，PACAP水平较高与更多的恐惧条件作用、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。我们建议对患有和不患有创伤后应激障碍的男性和女性退伍军人进行恐惧条件作用的实验室研究，以确定在创伤后应激障碍的恐惧消退、学习和保留方面是否存在性别差异。这项研究还将考察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-男性和绝经前女性退伍军人参加这项研究(n=108)。四个年龄匹配的组(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，他们将看到计算机生成的中性图像，这些图像是配对的(CS+)或不配对的(CS-)，并将在整个过程中评估皮肤电导反应。在第四天，参与者将接受灭绝训练，在训练中，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，评估物种灭绝的持久性。将在每次治疗前抽取血液样本，以评估PACAP和雌激素的水平。我们预测，与没有创伤后应激障碍的参与者相比，创伤后应激障碍参与者的恐惧消退、学习和保持能力将会降低。我们还预测，与女性相比，男性会有更大的恐惧、消亡、学习和保持。与没有创伤后应激障碍的女性和男性相比，患有创伤后应激障碍的女性将减少灭绝、学习和保持能力。我们还预测，PACAP将与女性学习和保持能力下降有关，但与男性无关。在女性中，创伤后应激障碍+参与者的PACAP水平将高于创伤后应激障碍参与者。我们还将探索低PACAP伴随高雌激素是否会与更大的消退、学习和保持相关。本研究的最终目的是刻画恐惧消退过程中的性别差异，以促进对创伤后应激障碍的病理生理学的识别。创伤后应激障碍的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。

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.