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: 10223177
• 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 2020-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10223177
• 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 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; traumatic stress

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持机制的性别差异，这可能是女性与男性在创伤后应激障碍（PTSD）脆弱性方面的差异。有一种机制被提出来解释从创伤性压力中恢复的原因，那就是条件性恐惧消退的变异性。虽然有几项研究已经研究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PTSD患者在这些措施中的性别差异，这可能代表了一个更脆弱的群体。我们对PTSD患者的试点数据表明，女性的恐惧条件反射增加，消退学习和回忆减少，这可能提供了一种机制，可以解释流行病学的发现。另一个有希望的发现可能解释了一些女性的差异脆弱性，这与肽有关，垂体腺苷酸环化酶激活多肽（PACAP），这是一种应激反应的调节剂。在女性中，较高水平的PACAP与更大的恐惧条件反射和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，也与增强的消光保留有关。然而，尚未研究PACAP对灭绝的潜在影响。我们建议进行一项实验室研究的恐惧条件反射的男性和女性退伍军人与创伤后应激障碍，以确定是否有性别差异，在恐惧消退学习和保留创伤后应激障碍。本研究还将探讨PACAP在解释PTSD组和性别差异中的作用。我们将招募医学上健康的创伤暴露的PTSD+和PTSD-男性和绝经前女性退伍军人参与本研究（n=108）。四个年龄匹配的组（每组n=27）将由以下组成：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天的恐惧条件反射任务培训。在第1天，将向他们展示计算机生成的中性图像，这些图像是配对的（CS+）或未配对的（CS-），伴有轻度电击（US），并将在整个过程中评估皮肤电导反应。在第4天，参与者将接受灭绝训练，在训练中，他们将看到图像，但不会受到电击。参与者将在第11天返回，以评估灭绝的持久性。每次治疗前将抽取血液样本，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记忆力会下降。我们还预测，与女性相比，男性将有更大的恐惧消退学习和记忆力。与没有PTSD的女性和男性相比，患有PTSD的女性的学习和记忆力下降。我们还预测，PACAP将与女性的消退学习和保持能力下降有关，但在男性中则不然。在女性中，PTSD+参与者的PACAP水平高于PTSD-参与者。我们还将探讨是否较低的PACAP伴随较高的雌激素将与更大的灭绝学习和保留。本研究的最终目标是描述恐惧消退过程中的性别差异，以促进对创伤后应激障碍病理生理学的鉴定，该病理生理学可能因性别而异，并且可能受到PACAP和性激素的影响。

项目成果

Gender Differences in Threat Biases: Trauma Type Matters in Posttraumatic Stress Disorder.

威胁偏见中的性别差异：创伤后应激障碍中的创伤类型很重要。

• DOI: 10.1002/jts.22439
• 发表时间: 2019
• 期刊: Journal of traumatic stress
• 影响因子: 3.3
• 作者: CowdenHindash,AlexandraH;Lujan,Callan;Howard,Meghan;O'Donovan,Aoife;Richards,Anne;Neylan,ThomasC;Inslicht,SabraS
• 通讯作者: Inslicht,SabraS

Sleep and hypothalamic pituitary adrenal axis responses to metyrapone in posttraumatic stress disorder.

• DOI: 10.1016/j.psyneuen.2017.12.002
• 发表时间: 2018-03
• 期刊: Psychoneuroendocrinology
• 影响因子: 3.7
• 作者: Inslicht SS;Rao MN;Richards A;O'Donovan A;Gibson CJ;Baum T;Metzler TJ;Neylan TC
• 通讯作者: Neylan TC

Randomized controlled experimental study of hydrocortisone and D-cycloserine effects on fear extinction in PTSD.

氢化可的松和D-环丝氨酸对PTSD恐惧灭绝的影响的随机对照实验研究。

• DOI: 10.1038/s41386-021-01222-z
• 发表时间: 2022-10
• 期刊: NEUROPSYCHOPHARMACOLOGY
• 影响因子: 7.6
• 作者: Inslicht, Sabra S.;Niles, Andrea N.;Metzler, Thomas J.;Lipshitz, Sa'ar L.;Otte, Christian;Milad, Mohammed R.;Orr, Scott P.;Marmar, Charles R.;Neylan, Thomas C.
• 通讯作者: Neylan, Thomas C.