Probing Disrupted Cortico-thalamic Interactions in Autism Spectrum Disorders

探索自闭症谱系障碍中皮质丘脑相互作用的破坏

• 批准号: 7844347
• 负责人: Chinfei Chen
• 金额: $ 51.84万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7844347
• 关键词: Accounting; Address; Affect; Animal Model; Area; Behavior; Biological Models; Brain; Brain region; Child; Clinical; Communication; Data; Defect; Development; Disease; Environment; Exhibits; Feedback; Functional disorder; Genes; Grant; Hearing; Impaired cognition; Knockout Mice; Language; Methyl-CpG-Binding Protein 2; Modeling; Molecular; Mus; Neuraxis; Neurodevelopmental Disorder; Neurons; Phase; Phenotype; Play; Process; Proteins; Retina; Rett Syndrome; Role; Sensory; Smiling; Social Interaction; Structure; Synapses; Syndrome; System; Testing; Thalamic structure; Thinking; Time; Touch sensation; Vision; Visual; Visual Pathways; Visual system structure; autism spectrum disorder; autistic children; critical period; experience; feeding; information processing; interest; model development; mouse model; nervous system development; neural circuit; neurobehavioral; neurodevelopment; neuron development; neuropsychiatry; novel; public health relevance; retinogeniculate; sensory system; skills; social

DESCRIPTION (provided by applicant): Autism Spectrum Disorders (ASD) represents a group of severe, highly heritable, neurobehavioral syndromes with heterogeneous phenotype. The clinical features of autistic children are notable for an unawareness of their surrounding environment, impaired language and social interactions, and repetitive behaviors. They often exhibit relatively normal initial maturation followed by stagnation or regression. The underlying cause of this clinical course is unknown. Here, we propose to test a novel idea-- that disrupted interactions between the thalamus and the cortex during their circuit maturation underlie this developmental sequel. Recently, there has been increasing interest in the idea that ASD might involve dysfunction of experience- dependent circuit maturation and refinement. Sensory systems, such as the visual system, are thought to develop sequentially in a feed forward manner during sensitive periods in early development. However, this model for development has been challenged by our recent findings demonstrating overlap in the timing of refinement of thalamic and cortical critical periods. Our hypothesis is that cortical feedback to the thalamus drives the refinement of thalamic synaptic circuits, and the resulting thalamic function influences cortical development. Disruption of this interaction could result in the late developmental abnormalities observed in ASD. To test this hypothesis, we will take advantage of MeCP2 deficient mouse, an animal model of Rett Syndrome (RTT). RTT is a neurodevelopment disorder associated with ASD. The visual system will be used as an experimental system for understanding the developmental relationship between thalamus and cortex. MeCP2 null mice exhibit impaired development of visual function both at the thalamic and cortical level. In this proposal, we will selectively disrupt the expression of the MeCP2 gene either cortically or in the retino-thalamic circuitry and assess the functional maturation of retinogeniculate or cortical circuits respectively. If our hypothesis is true, selective cortical defect should affect the experience-dependent sensitive period for thalamic circuit plasticity and a focal deficit in the retino-thalamic circuitry will ultimately affect cortical development. Our results would transform the fundamental thinking of the mammalian central nervous system development. A feed forward and feedback interaction between the CNS structures would mean that defects in one area could affect the other and amplify over time. In addition, interaction between the two structures raises the possibility that changes in one structure can compensate for defects in the other. Thus, a deeper understanding of the developmental relationship between the thalamus and cortex could have implications in neurodevelopment disorders such as autism spectrum disorders. PUBLIC HEALTH RELEVANCE: Sensory information (such as vision, hearing and touch) is transmitted through various stations in the brain as it is relayed to the cortex. In this proposal we test a novel hypothesis that during development, the cortex sends information to guide the development of these stations. A feed-forward and feedback communication between different regions of the brain could result in a spreading of an initially focal abnormality. This could be the underlying cause of neurodevelopment diseases such as Rett Syndrome and Autism Spectrum Disorders. Thus it is important to understand the importance of communication between different areas of the brain during development.

描述(由申请人提供)：自闭症谱系障碍(ASD)代表一组严重的、高度可遗传的、具有异质性表型的神经行为综合征。自闭症儿童的临床特征是对周围环境的缺乏意识，语言和社交能力受损，以及重复的行为。它们通常表现出相对正常的初始成熟，随后是停滞或退化。这一临床病程的潜在原因尚不清楚。在这里，我们建议测试一个新的想法--在丘脑和皮质的回路成熟期间中断它们之间的相互作用是这一发育后遗症的基础。最近，越来越多的人对ASD可能涉及经验依赖的回路成熟和精炼功能障碍的想法越来越感兴趣。感觉系统，如视觉系统，被认为在早期发育的敏感期以前馈的方式按顺序发展。然而，我们最近的发现表明丘脑和大脑皮层关键期的精炼时间重叠，这一发育模型受到了挑战。我们的假设是，丘脑的皮质反馈驱动丘脑突触回路的精细化，由此产生的丘脑功能影响皮质的发育。这种相互作用的中断可能导致ASD观察到的晚期发育异常。为了验证这一假设，我们将利用MeCP2缺陷小鼠，这是一种Rett综合征(RTT)的动物模型。RTT是一种与ASD相关的神经发育障碍。视觉系统将被用作了解丘脑和皮质之间发育关系的实验系统。MeCP2基因缺失的小鼠表现出丘脑和皮质水平的视觉功能发育受损。在这个方案中，我们将选择性地干扰MeCP2基因在皮层或视网膜-丘脑回路中的表达，并分别评估视网膜原核或皮质回路的功能成熟度。如果我们的假设是正确的，选择性皮质缺陷应该影响丘脑回路可塑性的经验依赖敏感期，而视网膜-丘脑回路的局灶性缺陷最终将影响皮质发育。我们的结果将改变哺乳动物中枢神经系统发育的基本思维。CNS结构之间的前馈和反馈相互作用将意味着一个区域的缺陷可能会影响另一个区域，并随着时间的推移而放大。此外，两种结构之间的相互作用增加了一种结构中的变化可以弥补另一种结构中的缺陷的可能性。因此，更深入地了解丘脑和皮质之间的发育关系可能会对自闭症谱系障碍等神经发育障碍产生影响。 与公共健康相关：感觉信息(如视觉、听觉和触觉)在传递到大脑皮层时通过大脑中的不同站传递。在这项提议中，我们测试了一个新的假设，即在发育过程中，大脑皮层发送信息来指导这些站点的发育。大脑不同区域之间的前馈和反馈交流可能导致最初局灶性异常的扩散。这可能是雷特综合症和自闭症谱系障碍等神经发育疾病的根本原因。因此，了解大脑不同区域之间在发育过程中交流的重要性是很重要的。