Exploring the role of neuroactive steroids in Tourette syndrome

摘要/项目摘要 多发性抽动症(TS)是一种以运动和发音为特征的致残性神经发育障碍。 由于我们对生物学基础的了解有限，现有的治疗策略仍然不能令人满意。 这种混乱的症状。本申请中提出的研究将探索以下两项潜在的机制 对TS的生物学特性了解最少，即其明显的男性优势和应激反应。 可接受性。我们小组的研究表明，TS的这些特征是由神经活性类固醇引起的， 一个牵涉到性和压力调节的调解人家庭。 典型的TS起病年龄为6-7岁，与肾上腺原始期、肾上腺成熟期特征相吻合。 以肾上腺神经活性类固醇的激增为特征，如脱氢表雄酮(DHEA)及其硫酸盐 (Dheas)。在初步研究中，我们发现DHEA加剧了TS动物模型中的抽动样反应。 有趣的是，在女性体内引发TS样反应所需的脱氢表雄酮剂量高于女性 男性，可能指出了TS的性别差异机制。 应激降低了TS患者抑制抽搐的能力，但其潜在机制仍不清楚。我们的 动物模型的研究表明，这一过程可能是由于神经活性类固醇异构体升高所致。 前额叶皮质的孕烯醇酮(AP)。通过抑制前额叶皮质抑制抽搐的能力，AP 促进抽动的执行。在一项初步研究中，我们发现抽动抑制是TS患者的一项众所周知的应激任务-- 增加AP唾液水平。此外，在另一项概念验证研究中，我们发现抑制AP 合成导致抽动的严重程度降低，并促进应激情况下抽动的自愿控制。 这些发现使我们假设TS患者的神经细胞成分发生了变化。 积极的类固醇特征，包括：1)男性TS患者基线脱氢表雄酮水平升高(S)，相关性 终生严重；以及2)急性应激反应中AP的夸大升高。 这项建议的两个目的将通过以下两个方面来验证这一假设：1)比较基线尿类固醇组的特征 对患有TS的男孩和女孩与未受影响的性别和年龄匹配的对照组进行比较；以及2)绘制动态图表 类固醇唾液体对抽动抑制的反应改变。这些研究将推动我们的联合国-- 了解TS的内分泌机制，并导致识别潜在的生物标志物 抽搐的严重程度和共病症状。从长远来看，这些研究的结果可能会为 开发治疗TS的新疗法，可能会降低抽搐的严重程度，并提高患者的反应性- 行为干预。

ABSTRACT / PROJECT SUMMARY Tourette syndrome (TS) is a disabling neurodevelopmental disorder characterized by motor and phonic tics. Available treatment strategies remain unsatisfactory, due to our limited knowledge of the biological foundations of this disorder. The studies proposed in this application will explore the mechanisms underlying two of the least well-understood biological characteristics of TS, namely its marked male predominance and stress sus- ceptibility. Studies from our group suggest that these features of TS are contributed by neuroactive steroids, a family of mediators implicated in sex and stress regulation. The typical age of onset of TS is 6-7 years, coinciding with adrenarche, a phase of adrenal maturation charac- terized by an upsurge in adrenal neuroactive steroids, such as dehydroepiandrosterone (DHEA) and its sulfate (DHEAS). In preliminary studies, we found that DHEA exacerbated tic-like responses in animal models of TS. Interestingly, the dose of DHEA needed to elicit TS-like responses in females is higher than those needed in males, possibly pointing to a mechanism of sex differences in TS. Stress reduces the ability of TS patients to suppress tics, but the underlying mechanisms remain unknown. Our studies in animal models indicate that this process may be due to the elevation of the neuroactive steroid allo- pregnanolone (AP) in the prefrontal cortex. By inhibiting the ability of the prefrontal cortex to suppress tics, AP promotes tic execution. In a pilot study, we found that tic suppression, a well-known stressful task in TS pa- tients, increases AP salivary levels. Furthermore, in another proof-of-concept study, we found that inhibiting AP synthesis led to a reduction in tic severity and facilitated voluntary control of tics in stressful situations. These findings lead us to hypothesize that TS patients exhibit alterations of the composition of their neuroac- tive steroid profiles, including: 1) an increase in baseline DHEA(S) levels in male TS patients, in correlation with lifetime severity; and 2) an exaggerated elevation in AP in response to acute stress. The two Aims of this proposal will test this hypothesis by: 1) comparing the baseline urinary steroidomic profile of TS-affected boys and girls with non-affected sex- and age-matched controls; and 2) charting the dynamic alterations in steroidomic salivary profiles in response to tic suppression. These studies will advance our un- derstanding of the endocrine mechanisms in TS and lead to the identification of potential biomarkers for the severity of tics and comorbid symptoms. In the long run, the results of these studies may open the way for the development of new therapies for TS that may reduce tic severity and increase patients' responsiveness to be- havioral interventions.