Brain Development & Sex Chromosomes: Imaging of Turner and Klinefelter Syndromes

大脑发育

• 批准号: 8653989
• 负责人: Allan L Reiss
• 金额: $ 19.63万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-18 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8653989
• 关键词: Academic achievement; Additional X Chromosome; Affect; Age; Amygdaloid structure; Aneuploidy; Area; Attention; Attention deficit hyperactivity disorder; Autistic Disorder; Behavior; Behavioral; Brain; Child; Childhood; Chromosome Deletion; Chromosomes, Human, Pair 2; Clinical; Clinical Treatment; Cognition; Cognitive; Cohort Studies; Control Groups; Corpus striatum structure; Development; Diagnosis; Diffusion weighted imaging; Disease; Emotions; Employee Strikes; Face; Female; Gene Expression; Genotype; Goals; Gonadal Steroid Hormones; Hereditary Disease; Human; Image; Impairment; Individual; Investigation; Klinefelter' s Syndrome; Laboratories; Language; Learning Disorders; Literature; Magnetic Resonance Imaging; Measures; Mental disorders; Nature; Neuroanatomy; Neurophysiology - biologic function; Occipital lobe; Outcome; Parietal; Pathway interactions; Pattern; Performance; Phenotype; Population; Prefrontal Cortex; Process; Production; Relative (related person); Research; Research Design; Risk; Role; Secondary to; Sex Characteristics; Sex Chromosomes; Structure; Symptoms; Temporal Lobe; Testing; Time; Tissue-Specific Gene Expression; Turner' s Syndrome; Variant; Visuospatial; X Chromosome; behavioral impairment; boys; brain behavior; brain morphology; brain volume; clinical Diagnosis; cohort; dosage; executive function; girls; improved; insight; male; neurodevelopment; neuroimaging; neuropsychiatry; prepuberty; prospective; public health relevance; relating to nervous system; resilience; sex; sexual dimorphism; skills; social cognition; white matter

DESCRIPTION (provided by applicant): Sex differences in rates and manifestations of mental illness have been receiving increasing attention for their potential to inform diagnosis, clinical course and treatment in a broad range of neuropsychiatric disorders. Recent literature suggests that underlying mechanisms for these sex dimorphisms arise from: (1) differential expression of genes on the sex chromosomes and, (2) extensive influence of sex hormones on the brain during critical windows of development. Though the independent and interactive effect of these influences on brain development and function are thought to contribute significantly to sexually dimorphic patterns of cognition and behavior, research in this area is limited. Further investigation is essential to increase our understanding of how sex chromosome gene expression and sex hormone exposure influence neural processes underlying sex differences in both typical development and in mental illness. Sex chromosome aneuploidies such as Turner syndrome ('TS', 45,X) and Klinefelter syndrome ('KS', 47,XXY) represent unique paradigms for elucidating the influences of sex chromosome gene expression and sex hormone exposure on neural development and function. Each condition is characterized by an abnormal number of X chromosomes and affected (genotypic non-mosaic) individuals typically demonstrate greatly reduced levels of sex hormone production. Because TS and KS are associated with specific profiles of neuroanatomical and cognitive-behavioral variation, the study of these conditions can potentially provide unique information about sexually dimorphic brain differences occurring in typical development (where males have 46,XY genotype and females have 46,XX genotype). Although TS and KS have been previously studied independently, there has been no prospective, direct comparison of these cohorts to date, and no studies have compared these groups singly or together to both typically developing male and female cohorts. Here we describe a first-of-its-kind study designed to directly examine differences in neuroanatomy and cognitive-behavioral function between prepubertal, age-matched cohorts of girls with TS, boys with KS and typically developing male and female controls. The proposed project builds on striking observations from previous research conducted by our group and others suggesting that spatial patterns of neuroanatomical variation in TS and KS may be largely complementary relative to typical development. The cross-sectional investigation we propose would be the first to directly compare TS and KS in the same study with the goal of elucidating the early (prepubertal) effects of varying sex chromosome gene expression and associated sex hormone exposure on neuroanatomy. This research holds great promise for improving our understanding of sex chromosome gene expression and sex hormone effects on neurodevelopment in young children and correspondingly, and for providing new insights into neural processes underlying sex differences related to risk and resilience for mental illness.

描述(由申请者提供)：精神疾病发病率和表现的性别差异越来越受到关注，因为它们有可能为广泛的神经精神疾病的诊断、临床过程和治疗提供信息。最近的文献表明，这些性别二型性的潜在机制来自：(1)性染色体上基因的差异表达，(2)性激素在发育的关键时期对大脑的广泛影响。尽管这些影响对大脑发育和功能的独立和交互作用被认为对认知和行为的性别二态模式有重要贡献，但这一领域的研究有限。进一步的研究对于增加我们对性染色体基因表达和性激素暴露如何影响典型发育和精神疾病中潜在的性别差异的神经过程的理解是至关重要的。性染色体非整倍体，如Turner综合征(TS，45，X)和Klinefelter综合征(KS，47，XXY)，为阐明性染色体基因表达和性激素暴露对神经发育和功能的影响提供了独特的范例。每种情况的特点是X染色体的数量异常，受影响的(遗传型非马赛克)个体通常表现出性激素水平的极大降低。由于TS和KS与神经解剖学和认知行为变异的特定特征相关联，对这些情况的研究可能会提供关于典型发育中发生的性别二态大脑差异的独特信息(男性具有46，XY基因，女性具有46，XX基因)。尽管先前对TS和KS进行了独立的研究，但到目前为止还没有对这些队列进行前瞻性的、直接的比较，也没有研究将这些组单独或一起与典型的男性和女性队列进行比较。在这里，我们描述了一项首创的研究，旨在直接检查青春期前、年龄匹配的TS女孩、KS男孩以及典型的男性和女性对照组之间的神经解剖学和认知行为功能的差异。这项拟议的项目建立在我们团队和其他人之前进行的研究的显著观察结果的基础上，表明TS和KS的神经解剖学变异的空间模式相对于典型发育可能在很大程度上是互补的。我们提出的横断面调查将是第一次在同一研究中直接比较TS和KS，目的是阐明不同的性染色体基因表达和相关的性激素暴露对神经解剖学的早期(青春期前)影响。这项研究有望提高我们对性染色体基因表达和性激素对幼儿神经发育的影响的理解，并相应地为揭示与精神疾病风险和韧性相关的性别差异背后的神经过程提供新的见解。

项目成果

Novel effects of Ras-MAPK pathogenic variants on the developing human brain and their link to gene expression and inhibition abilities.

Ras-MAPK 致病性变异对人类大脑发育的新影响及其与基因表达和抑制能力的联系。

• DOI: 10.21203/rs.3.rs-2580911/v1
• 发表时间: 2023
• 期刊: Research square
• 作者: Rai,Bhavana;Naylor,Paige;Sanchez,MonicaSiqueiros;Wintermark,Max;Raman,Mira;Jo,Booil;Reiss,Allan;Green,Tamar
• 通讯作者: Green,Tamar