神经精神症状的性别差异是由于西罗莫司通过调节类固醇水平而产生的雌二醇/ERα依赖性转录调控所致

IF 3.3 3区 心理学 Q1 BEHAVIORAL SCIENCES Pharmacology Biochemistry and Behavior Pub Date : 2024-09-06 DOI:10.1016/j.pbb.2024.173875
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引用次数: 0

摘要

患者的性别往往会影响许多精神疾病的发病率、进展和严重程度。帕金森病和阿尔茨海默病是最常见的神经退行性疾病,其发病率、进展和严重程度也存在性别差异。在结节性硬化症复合体(TSC)中,自闭症谱系障碍(ASD)、注意缺陷多动障碍(ADHD)和焦虑症也存在性别差异。神经精神症状是TSC最重要的表现之一,多种神经精神症状统称为TSC相关神经精神障碍(TAND)。我们创建了TSC模型小鼠(Tsc2条件性基因敲除[cKO]小鼠),这些小鼠会患上癫痫和TAND。在患有 TAND 的 Tsc2 cKO 小鼠中,我们观察到了多动和认知功能障碍的性别差异,这表明雌性小鼠的症状比雄性小鼠更严重。TSC被认为是由雷帕霉素复合体1(mTORC1)机制靶点过度激活引起的,而mTORC1抑制剂几乎能改善所有TSC症状。使用mTORC1抑制剂西罗莫司治疗可改善Tsc2 cKO小鼠的TAND。我们的目的是利用 Tsc2 cKO 小鼠和西罗莫司阐明 TAND 基于性别差异的机制。我们发现雌二醇(E2)和雌激素受体(ER)α参与了神经精神症状的性别差异,并发现了西罗莫司的一种新功能。我们发现,西罗莫司可通过调节脑内类固醇水平和E2/ERα依赖性转录激活来改善TAND。这表明西罗莫司可能有益于治疗TAND以及由性别差异和类固醇水平引起的疾病。
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Sex-based differences in neuropsychiatric symptoms are due to estradiol/ERα-dependent transcriptional regulation via the modulation of steroid levels by sirolimus

The sex of the patient often affects the prevalence, progression, and severity of many psychiatric disorders. The incidence, progression, and severity of Parkinson's disease and Alzheimer's disease, the most common neurodegenerative diseases, also differ between the sexes. Sex differences in autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and anxiety are also observed in tuberous sclerosis complex (TSC). Neuropsychiatric symptoms are one of the most important manifestations of TSC, and the multiple neuropsychiatric symptoms are collectively referred to as TSC-associated neuropsychiatric disorders (TAND). We created TSC model mice (Tsc2 conditional knockout [cKO] mice) that developed epilepsy and TAND. Sex-based differences were observed for hyperactivity and cognitive dysfunctions in Tsc2 cKO mice with TAND, indicating more severe symptoms in female mice than in male mice. TSC is thought to be caused by the hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1), and mTORC1 inhibitors improve almost all TSC symptoms. Treatment with sirolimus, an mTORC1 inhibitor, improved TAND in Tsc2 cKO mice. We aimed to elucidate the mechanism underlying sex-based differences in TAND using Tsc2 cKO mice and sirolimus. We found that estradiol (E2) and estrogen receptor (ER)α are involved in sex differences in neuropsychiatric symptoms, and discovered a novel function of sirolimus. We showed that sirolimus ameliorated TAND by modulating brain steroid levels and regulating E2/ERα-dependent transcriptional activation. This indicates sirolimus may be beneficial for the treatment of TAND as well as diseases caused by sex-based differences and steroid levels.

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来源期刊
CiteScore
6.40
自引率
2.80%
发文量
122
审稿时长
38 days
期刊介绍: Pharmacology Biochemistry & Behavior publishes original reports in the areas of pharmacology and biochemistry in which the primary emphasis and theoretical context are behavioral. Contributions may involve clinical, preclinical, or basic research. Purely biochemical or toxicology studies will not be published. Papers describing the behavioral effects of novel drugs in models of psychiatric, neurological and cognitive disorders, and central pain must include a positive control unless the paper is on a disease where such a drug is not available yet. Papers focusing on physiological processes (e.g., peripheral pain mechanisms, body temperature regulation, seizure activity) are not accepted as we would like to retain the focus of Pharmacology Biochemistry & Behavior on behavior and its interaction with the biochemistry and neurochemistry of the central nervous system. Papers describing the effects of plant materials are generally not considered, unless the active ingredients are studied, the extraction method is well described, the doses tested are known, and clear and definite experimental evidence on the mechanism of action of the active ingredients is provided.
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