Exploring the Effects of Corticosteroids on the Human Hippocampus using Neurocognitive Testing and High-Resolution Brain Imaging

摘要 慢性皮质类固醇（CS）暴露与记忆和海马体的变化有关， 在人类和动物模型中。海马体有高浓度的糖皮质激素受体 （GCR），临床前文献表明CA 3区的顶树突缩短， 海马和减少的神经发生在齿状回（DG）后CS管理。在人类中， 压力和CS暴露都与陈述性记忆表现（一个过程）的下降有关。 由海马介导）。陈述性记忆障碍和海马萎缩的报道， 由于库欣病导致CS过度释放的患者，以及我们组接受 CS处方治疗这些发现对情绪障碍患者具有重要意义， 大部分患有重度抑郁症（MDD）的人显示出HPA轴激活的证据， 皮质醇，更重要的是，抗CS对HPA轴和陈述性记忆的影响。 因此，对皮质类固醇的耐药性似乎是MDD的结果。 我们先前的工作表明，接受处方CS的人记忆缺陷（例如，泼尼松）或 健康对照组短暂给予氢化可的松（皮质醇）。我们的试验数据表明， 氢化可的松的剂量与陈述性记忆的可逆性下降、任务相关记忆的减少有关。 海马激活，以及海马体积显著但可逆的减少。减少 女性海马体积较大，与血清皮质醇水平的增加相关。基于 这些数据，我们建议检查陈述性记忆的变化，以及使用最先进的高， 分辨率多模态神经成像，包括结构和功能（即，基于任务和静息状态）MRI， 在男性和女性健康对照组中，以及作为探索性目的的抑郁组中，给予3天 暴露于氢化可的松（160 mg/天）或安慰剂。这项研究将把临床前的发现转化为人类， 提供关于对皮质醇反应的可能性别差异的有价值的数据，并首次确定 特定的海马子区域（例如，CA 3/DG），对急性CS效应最敏感。使用 静息状态fMRI数据和全脑连接组学使用图论方法，我们将确定 皮质醇暴露对大脑功能网络的影响。此外，这将是第一项使用 神经成像，以比较抑郁症患者与对照组的大脑对CS的反应，并确定 抑郁症患者是否表现出海马体内的糖皮质激素抵抗。我们假设 海马对急性CS的反应在CA 3/DG子区最大，女性比女性大。 与对照组相比，抑郁症患者对CSs的海马反应迟钝。一 多学科研究团队在CS对大脑和海马子区域的影响方面拥有丰富的经验 神经影像学，和先前的研究合作史，将进行该项目。

Abstract Chronic corticosteroid (CS) exposure is associated with changes in memory and the hippocampus in both humans and in animal models. The hippocampus has a high concentration of glucocorticoid receptors (GCRs), and the pre-clinical literature demonstrates shortening of apical dendrites in the CA3 region of the hippocampus and decreased neurogenesis in the dentate gyrus (DG) following CS administration. In humans, both stress and CS exposure are associated with a decline in declarative memory performance (a process mediated by the hippocampus). Impairment in declarative memory and hippocampal atrophy are reported in patients with excessive CS release due to Cushing's disease, and, by our group, in patients receiving prescription CS therapy. These findings have important implications for patients with mood disorders, as a large subset of people with major depressive disorder (MDD) show evidence of HPA axis activation, elevated cortisol and, importantly, resistance to the effects of CSs on both the HPA axis and on declarative memory. Thus, resistance to corticosteroids appears to be a consequence of MDD. Our prior work has shown memory deficits in persons receiving prescription CSs (e.g., prednisone) or healthy controls briefly administered hydrocortisone (cortisol). Our pilot data suggest that 3-day administration of hydrocortisone is associated with reversible decline in declarative memory, decrease in task-related hippocampal activation, and a significant, but reversible, decrease in hippocampal volume. Decrease in hippocampal volume was greater in women and correlated with increases in serum cortisol levels. Based on these data, we propose to examine changes in declarative memory, as well as use state-of-the-art high- resolution multimodal neuroimaging, including structural and functional (i.e., task-based and resting state) MRI, in both men and women healthy controls, and, as an exploratory aim, a depressed group, given 3-day exposures to hydrocortisone (160 mg/day) or placebo. The study will translate preclinical findings to humans, provide valuable data on possible sex differences in the response to cortisol and, for the first time, identify specific hippocampal subfields (e.g., CA3/DG) in humans that are most sensitive to acute CS effects. Using resting state fMRI data and whole brain connectomics using graph theoretical approaches, we will determine the effects of cortisol exposure on functional brain networks. Furthermore, this will be the first study to use neuroimaging to compare the brain's response to CSs in people with depression vs. controls, and determine whether depressed people demonstrate glucocorticoid resistance within the hippocampus. We hypothesize that hippocampal response to acute CSs will be greatest in the CA3/DG subfield, greater in women than in men, and that depressed people will show a blunted hippocampal response to CSs compared to controls. A multidisciplinary research team with extensive experience in CS effects on the brain and hippocampal subfield neuroimaging, and a prior history of research collaboration, will conduct the project.