Cellular, molecular, and functional imaging approaches to understanding early neurodevelopment in autism

了解自闭症早期神经发育的细胞、分子和功能成像方法

基本信息

批准号：
10240556
负责人：
KATARZYNA CHAWARSKA
金额：
$ 217.95万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-07 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10240556
关键词：
12 year old Address Affect Age Anatomy Attention Behavior Behavioral Biological Biological Models Birth Brain Brain imaging Cells Characteristics Child Childhood Data Development Diagnosis Diagnostic Disease Evaluation Female Fetal Development Functional Imaging Functional Magnetic Resonance Imaging Genetic Image Impairment Infant Intellectual functioning disability Interdisciplinary Study Intervention Investigation Learning Life Link Measures Methodology Methods Molecular Neonatal Neurobiology Neurology Neuronal Plasticity Neurons Neurosciences Newborn Infant Organizational Change Organoids Patients Pattern Perinatal Photons Play Pregnancy Prognostic Marker Prospective cohort Psychopathology Radiology Specialty Reporting Research Project Grants Resolution Risk Risk Factors Role School-Age Population Scientist Second Pregnancy Trimester Severities Sex Differences Siblings Social Values Symptoms Synapses System Testing Third Pregnancy Trimester Time Toddler Training autism spectrum disorder autistic children base behavioral study cellular imaging cohort connectome connectome based predictive modeling density diagnostic biomarker disorder risk efficacy testing executive function fetal high risk human model imaging approach induced pluripotent stem cell infancy inhibitory neuron innovation male molecular imaging multidisciplinary neonatal period neural model neural network neurodevelopment neuroimaging neuromechanism neurophysiology novel novel diagnostics outcome prediction predicting response predictive modeling prenatal prognostic programs protective factors recruit relating to nervous system resilience response risk sharing sex statistics stem cell biomarkers

项目摘要

The Yale Center represents a multidisciplinary research program consisting of five inter-related research projects and four cores dedicated to advancing understanding of early neurobiology of ASD. The proposal brings together a team of experts from the fields of developmental psychopathology and neurobiology, genetics, neurology, radiology, neuroscience, and statistics to identify the molecular, cellular, and neural mechanisms related to ASD from prenatal stages to childhood. We focus our investigation on two cohorts of younger siblings of children with ASD who, due to familial factors, are at high risk (HR) for developing the disorder: a prospective cohort recruited pre- and perinatally and followed through 24 months, and a cohort of HR siblings who was well-characterized at 24 months through our past studies and will reach the age of 12 years during the life of the Yale ACE. These cohorts enable our search for neural signatures of ASD during fetal, neonatal, and school-age periods, as well as to examine the connectome across the spectrum of risk for ASD both in males and females. Although neural and behavioral markers of ASD have been reported in 6- month-old infants later diagnosed with ASD, to our best knowledge, this is the first investigation into both fetal and neonatal functional connectivity in ASD. Emerging data suggest that male, but not female, ASD subjects demonstrate significant alterations in neural networks, and – for the first time – the proposed studies will identify not only the changes in connectivity in ASD but also the impact of fetal/neonatal sex upon these changes. Since recent studies demonstrate neuroplasticity in the developing brain across the late second and third trimesters of gestation, it is essential to understand if the factors associated with ASD are developing in this same time frame and to understand any sex differences that may be apparent even at that early age. The iPSC derived organoid system models human fetal development, allowing us to investigate neurobiological risk and protective factors that play a unique role in this period and may enable the discovery of patient-specific neuronal or stem cell biomarkers that could be used as predictors of risk or resilience in ASD. The Yale ACE aims rely on application of cutting-edge approaches to the analysis the connectome, fetal and neonatal imaging modeling neural development using the iPSC methodology with high resolution dual photon imaging approaches, the development of early markers for ASD, studying early attention and learning, novel predictive models relating brain organization to behavior, and statistical approaches for integrating the spectrum of data types across to address these aims. Results from the combined projects have a great potential to identify novel diagnostic and prognostic markers at the time of birth, identify neural, cellular, and molecular bases of risk and protective mechanisms in ASD, and clarify neural bases of sex differences in ASD.

耶鲁大学中心代表了一个多学科研究计划，该计划由五个相互关联的研究组成项目和四个核心致力于促进对ASD早期神经生物学的理解。提案汇集了来自发展心理病理学和神经生物学领域的专家团队，遗传学，神经病学，放射学，神经科学和统计数据，以鉴定分子，细胞和神经元与从产前阶段到童年的ASD有关的机制。我们将调查重点放在两个队列上 ASD儿童的年轻兄弟姐妹，由于家庭因素而有高风险（HR）障碍：前和围产期招募并遵循24个月的前瞻性队列，一群在过去的研究中，他在24个月内经过良好表征，并将达到12岁耶鲁王牌生命中的几年。这些队列使我们能够搜索ASD的神经签名胎儿，新生儿和学龄时期，以及检查跨风险的连接组男性和女性的ASD。尽管已在6-中报告了ASD的神经和行为标记据我们所知，后来被诊断为ASD的一个月大婴儿，这是两种胎儿的第一笔投资和ASD中的新生儿功能连通性。新兴数据表明男性而不是女性ASD受试者证明神经网络发生了重大变化，首次将不仅确定ASD中连通性的变化，还确定胎儿/新生儿对这些的影响更改。自最近的研究表明，在第二个末期发展大脑的神经可塑性和妊娠的第三个三个孕期，必须了解与ASD相关的因素是否正在发展至关重要同一时间框架，并了解即使在那个年龄的时候也可能显而易见的性别差异。这 IPSC衍生的器官系统模型人类胎儿发育，使我们能够研究神经生物学风险并保护在此期间起着独特作用的受保护因素，并可以发现患者特定的因素可以用作ASD风险或弹性预测指标的神经元或干细胞生物标志物。耶鲁王牌目的依赖于尖端方法的应用来分析连接组，胎儿和新生儿使用IPSC方法与高分辨率双光子成像进行成像建模神经发展方法，ASD早期标记的发展，研究早期注意力和学习，新颖的预测将大脑组织与行为相关的模型以及整合数据范围的统计方法各种类型以解决这些目标。合并项目的结果具有巨大的潜力来识别新颖出生时诊断和预后标记，确定风险的神经，细胞和分子基础 ASD中的保护机制，并阐明ASD性别差异的神经底座。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Low-motion fMRI data can be obtained in pediatric participants undergoing a 60-minute scan protocol.

DOI：
10.1038/s41598-020-78885-z
发表时间：
2020-12-14
期刊：
Scientific reports
影响因子：
4.6
作者：
Horien C;Fontenelle S 4th;Joseph K;Powell N;Nutor C;Fortes D;Butler M;Powell K;Macris D;Lee K;Greene AS;McPartland JC;Volkmar FR;Scheinost D;Chawarska K;Constable RT
通讯作者：
Constable RT

Hypoconnectivity between anterior insula and amygdala associates with future vulnerabilities in social development in a neurodiverse sample of neonates.

DOI：
10.1038/s41598-022-20617-6
发表时间：
2022-09-28
期刊：
SCIENTIFIC REPORTS
影响因子：
4.6
作者：
Scheinost, Dustin;Chang, Joseph;Lacadie, Cheryl;Brennan-Wydra, Emma;Foster, Rachel;Boxberger, Alexandra;Macari, Suzanne;Vernetti, Angelina;Constable, R. Todd;Ment, Laura R.;Chawarska, Katarzyna
通讯作者：
Chawarska, Katarzyna

Attention to audiovisual speech does not facilitate language acquisition in infants with familial history of autism