Exploring the role of neuroactive steroids in Tourette syndrome

摘要/项目总结 抽动秽语综合征（TS）是一种以运动和语音抽动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。本申请中提出的研究将探索两种潜在的机制， TS的生物学特征，即其显着的男性优势和压力的影响， 感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， 一个涉及性和压力调节的调解人家族。 TS的典型发病年龄为6-7岁，与肾上腺初发期一致，肾上腺初发期是肾上腺成熟的一个阶段。 其特征是肾上腺神经活性类固醇如脱氢表雄酮（DHEA）及其硫酸盐的激增 （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，在女性中引发TS样反应所需的DHEA剂量高于在女性中所需的剂量。 男性，可能指向TS性别差异的机制。 压力降低了TS患者抑制抽搐的能力，但其潜在机制尚不清楚。我们 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同种异体的升高， 前额叶皮层中的孕烷醇酮（AP）。通过抑制前额叶皮层抑制抽搐的能力， 促进抽搐执行。在一项初步研究中，我们发现，抽动抑制，一个众所周知的压力任务，在TS pa- 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 合成导致抽搐严重程度的降低，并促进在紧张情况下对抽搐的自愿控制。 这些发现使我们假设TS患者表现出其神经活性成分的改变， 有效的类固醇特征，包括：1）男性TS患者的基线DHEA（S）水平增加， 与终身严重性;和2）在AP反应急性应激夸张的升高。 本提案的两个目的将通过以下方式检验这一假设：1）比较基线尿类固醇特征 TS受影响的男孩和女孩与非受影响的性别和年龄匹配的对照;和2）绘制动态 对抽动抑制反应的类固醇唾液分布的改变。这些研究将促进我们的联合国- 了解TS的内分泌机制，并导致鉴定潜在的生物标志物， 抽搐和共病症状的严重程度。从长远来看，这些研究的结果可能会为 开发新的治疗TS的方法，可以降低抽搐的严重程度，并增加患者对... 口头发言。

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.