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）代表一组具有异质表型的严重，高度可遗传的神经行为综合征。自闭症儿童的临床特征是对周围环境，语言和社交互动受损以及重复行为的不了解。它们通常表现出相对正常的初始成熟，然后停滞或回归。该临床过程的根本原因尚不清楚。在这里，我们建议测试一种新颖的想法 - 该想法破坏了丘脑在电路成熟过程中的相互作用，这是该发育续集的基础。最近，人们对ASD可能涉及经验依赖的电路成熟和改进的功能障碍的想法越来越兴趣。感觉系统（例如视觉系统）被认为在早期开发的敏感时期内以饲料向前的方式依次开发。但是，我们最近的发现表明，在丘脑和皮质关键时期的细化时间重叠的情况下，这种发展模型受到了挑战。我们的假设是，对丘脑的皮质反馈驱动了丘脑突触回路的完善，而所得的丘脑功能会影响皮质发育。这种相互作用的破坏可能导致ASD中观察到的晚期发育异常。为了检验这一假设，我们将利用MECP2缺乏小鼠（RETT综合征的动物模型（RTT））。 RTT是与ASD相关的神经发育障碍。视觉系统将用作了解丘脑和皮质之间的发育关系的实验系统。 MECP2无小鼠在丘脑和皮质水平上表现出视觉功能的发展受损。在此提案中，我们将分别在皮层或视网膜 - 丘脑回路中有选择地破坏MECP2基因的表达，并分别评估视网膜造成或皮质电路的功能成熟。如果我们的假设是正确的，那么选择性皮质缺陷应影响丘脑回路可塑性的经验依赖性敏感周期，而视网膜 - 丘脑回路的局灶性不足最终会影响皮质发育。我们的结果将改变对哺乳动物中枢神经系统发展的基本思维。中枢神经系统结构之间的馈电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扩大。另外，两种结构之间的相互作用增加了一种结构变化可以补偿另一个结构的可能性。因此，对丘脑和皮层之间的发展关系的更深入了解可能会影响神经发育障碍，例如自闭症谱系障碍。 公共卫生相关性：感官信息（例如视觉，听力和触摸）通过大脑中的各个站点传输，因为它被传递到皮层。在该提案中，我们检验了一个新的假设，即在开发过程中，皮层发送信息以指导这些站点的发展。大脑不同区域之间的前进和反馈交流可能会导致最初的局灶性异常传播。这可能是神经发育疾病（例如RETT综合征和自闭症谱系障碍）的根本原因。因此，重要的是要了解开发过程中大脑不同领域之间交流的重要性。