Investigating the role of glucocorticoid function in PTSD

项目摘要：研究糖皮质激素功能在创伤后应激障碍中的作用 8-10%的人在经历创伤后会出现创伤后应激障碍（PTSD） 活动PTSD的一线药物干预在治疗衰弱方面只有22%的有效性 症状，包括与威胁相关的侵入性再体验和过度觉醒，以及与损失相关的情绪 麻木和快感缺失这些症状发生在创伤后立即发生，但在某些情况下会持续存在。 个体作为“未能控制生物应激反应”的特征PTSD。失调 PTSD中的生物应激反应表现为：1）皮质醇对 下丘脑-垂体-肾上腺（HPA）轴，以及2）外周皮质醇水平低与 更严重的损失相关症状。PTSD中皮质边缘连接的改变，这与增加 与威胁相关的症状，也与HPA轴失调有关。具体而言，低水平的 外周皮质醇与内侧前额叶皮质负功能连接减少相关 （mPFC）与杏仁核。临床前实验发现，增加局部糖皮质激素水平， 大脑重现了与威胁有关的行为，减少大脑糖皮质激素的产生减少了这种行为。 创伤后应激障碍样行为因此，我假设大脑皮质边缘区域的皮质醇水平是一个重要因素。 皮质边缘连接调节HPA轴负反馈的机制，导致 PTSD症状和相关的HPA轴失调。在目标1中，我将测量大脑糖皮质激素 在患有创伤后应激障碍的个体体内发挥作用。配备新型PET放射性示踪剂[18F]MOZAT，我将能够 来测量大脑中局部糖皮质激素的水平[18F]MOZAT与11 β-羟基类固醇酶结合 脱氢酶1型（11 β-HSD 1），它在大脑中再生皮质醇，因此可以用作标记物 大脑糖皮质激素的功能。脑皮质激素功能的临床前操作与临床 神经影像学研究表明，PTSD患者的11 β-HSD 1水平高于对照组。 创伤暴露对照组。在目标2中，我将把体内脑糖皮质激素功能与皮质边缘功能联系起来， 连通性。先前的研究表明mPFC-杏仁核功能连接的改变 和低外周皮质醇因此，脑糖皮质激素功能可能通过调节HPA轴的活性， 皮层边缘连接的能力。调查这种可能性可能会为广泛的大脑基底提供一个 观察到与PSTD症状相关的皮质边缘连接改变。在目标3中，我将在体内 大脑糖皮质激素功能的威胁和损失相关的症状的创伤后应激障碍。这条调查线将 揭示了11 β-HSD 1作为大脑药理学重新调整的可能靶点的潜力。 糖皮质激素水平和相关的皮质边缘连接，以改善PTSD症状。

Project Abstract: Investigating the role of glucocorticoid function in PTSD Post-traumatic Stress Disorder (PTSD) develops in 8-10% of individuals following experience of a traumatic event. First-line pharmacological interventions for PTSD are only 22% effective at treating the debilitating symptoms, which include threat-related intrusive re-experiencing and hyperarousal, and loss-related emotional numbing and anhedonia. These symptoms occur in the immediate aftermath of a trauma but persist in some individuals as the “failure to contain the biological stress response” that characterizes PTSD. Dysregulation of the biological stress response in PTSD is evidenced by 1) enhanced negative feedback cortisol onto the hypothalamic-pituitary-adrenal (HPA) axis, and 2) a correlation between low levels of peripheral cortisol with greater loss-related symptoms. Altered corticolimbic connectivity in PTSD, which has been related to increased threat-related symptoms, has also been associated with HPA axis dysregulation. Specifically, low levels of peripheral cortisol were correlated with reduced negative functional connectivity of medial prefrontal cortex (mPFC) with the amygdala. Preclinical experiments have found that increasing local levels of glucocorticoids in the brain recapitulated threat-related behavior and decreasing brain glucocorticoid production decreased this PTSD-like behavior. Thus, I hypothesize that local levels of cortisol in corticolimbic regions of the brain are a mechanism by which corticolimbic connectivity regulates negative feedback onto the HPA axis, resulting in PTSD symptoms and associated HPA axis dysregulation. In Aim 1, I will measure brain glucocorticoid function in vivo in individuals with PTSD. Equipped with a novel PET radiotracer [18F]MOZAT, I will be able to measure local glucocorticoid levels in the brain. [18F]MOZAT binds to the enzyme 11-hydroxysteroid dehydrogenase type 1 (11-HSD1), which regenerates cortisol in the brain and thus can be used as a marker of brain glucocorticoid function. Preclinical manipulation of brain glucocorticoid function and clinical neuroimaging studies indicate that 11-HSD1 levels will be higher in individuals with PTSD compared to trauma-exposed controls. In Aim 2, I will relate in vivo brain glucocorticoid function to corticolimbic connectivity. Previous work showed associations between altered mPFC-amygdala functional connectivity and low peripheral cortisol. Thus, brain glucocorticoid function may regulate HPA axis activity via modulation of corticolimbic connectivity. Investigating this possibility may provide a brain substrate for the extensive observations of altered corticolimbic connectivity related to PSTD symptoms. In Aim 3, I will relate in vivo brain glucocorticoid function to threat- and loss-related symptoms of PTSD. This line of investigation will shed light on the potential of 11-HSD1 as a possible target for pharmacological re-tuning of brain glucocorticoid levels and associated corticolimbic connectivity, to improve PTSD symptoms.