Exploring the role of neuroactive steroids in Tourette syndrome

探索神经活性类固醇在抽动秽语综合征中的作用

• 批准号: 10464500
• 负责人: Marco Bortolato
• 金额: $ 26.22万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10464500
• 关键词: 12 year old; Address; Adolescence; Adrenal Glands; Adult; Affect; Age; Age of Onset; Allopregnanolone; Animal Model; Behavioral; Biologic Characteristic; Biological; Biology; Child; Clinical; Clinical Research; Development; Disease; Dose; Endocrine; Exhibits; Family; Female; Foundations; Funding; Gilles de la Tourette syndrome; Hydrocortisone; Intervention; Investigation; Knowledge; Lead; Mass Spectrum Analysis; Measures; Mediator of activation protein; Metabolic Pathway; Metabolism; Motor; Names; Neurodevelopmental Disorder; Neurosecretory Systems; Participant; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Pilot Projects; Play; Positioning Attribute; Predisposition; Prefrontal Cortex; Process; Regulation; Role; Safety; Saliva; Salivary; Salvelinus; Sampling; Severities; Sex Differences; Specimen; Steroids; Stress; Sulfate; Symptoms; Testing; Urine; Variant; acute stress; associated symptom; base; biological adaptation to stress; boys; clinical investigation; dehydroepiandrosterone; girls; improved; male; mouse model; neuromechanism; neurosteroids; novel; novel therapeutics; patient response; perceived stress; potential biomarker; response; sex; sound; specific biomarkers; therapeutic target; tic suppression; trait; treatment strategy; urinary

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.

摘要 /项目摘要 Tourette综合征（TS）是一种残疾的神经发育障碍，其特征在于运动和音抽动。 由于我们对生物基础的了解有限，可用的治疗策略仍然不令人满意 这种疾病。本应用中提出的研究将探讨其中两种机制 TS的生物学特征最少，即其明显的男性优势和压力 可疑性。我们小组的研究表明，TS的这些特征是由神经活性类固醇贡献的， 一个涉及性和压力调节的调解人家族。 TS发作的典型年龄为6-7岁，与肾上腺肾上腺成熟的阶段相吻合 - 在肾上腺神经活性类固醇中的兴起，例如脱氢表甲酮（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TIC样反应。 有趣的是，在女性中引起类似TS的反应所需的DHEA剂量高于 男性，可能指出了TS中性别差异的机制。 压力降低了TS患者抑制抽动的能力，但潜在的机制仍然未知。我们的 动物模型中的研究表明，这一过程可能是由于神经活性类固醇同种的升高 妊娠（AP）在前额叶皮层中。通过抑制前额叶皮层抑制抽动的能力，AP 促进TIC执行。在一项试点研究中，我们发现TIC抑制是TS PA-的一项众所周知的压力任务 Timent，增加了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 合成导致抽动严重程度降低，并在压力大的情况下促进对抽动的自愿控制。 这些发现导致我们假设TS患者表现出其神经AC-组成的改变 Tive类固醇特征，包括：1）男性TS患者的基线DHEA水平增加 终身严重程度； 2）响应急性应激的AP升高。 该提案的两个目的将通过以下方式检验以下假设 受TS影响的男孩和女孩的性别和年龄匹配的对照； 2）绘制动态 响应TIC抑制作用的类固醇唾液谱的改变。这些研究将推动我们的不 在TS中阐述内分泌机制，并导致对潜在的生物标志物的识别 抽动和合并症状的严重程度。从长远来看，这些研究的结果可能为 开发针对TS的新疗法，这些疗法可能会降低抽动严重程度并提高患者的反应性 干预措施。