Probing Disrupted Cortico-thalamic Interactions in Autism Spectrum Disorders

描述（由申请人提供）：自闭症谱系障碍（ASD）是一组具有异质性表型的严重的、高度遗传性的神经行为综合征。自闭症儿童的临床特征是对周围环境缺乏意识，语言和社会交往受损，以及重复行为。它们通常表现出相对正常的初始成熟，随后停滞或退化。这一临床过程的根本原因尚不清楚。在这里，我们提出测试一个新颖的想法-丘脑和皮层之间的相互作用中断在他们的电路成熟的基础上，这种发展的后续。最近，人们对ASD可能涉及经验依赖回路成熟和完善功能障碍的观点越来越感兴趣。感觉系统，如视觉系统，被认为是在早期发育的敏感时期以前馈方式顺序发展的。然而，这一发展模式受到了挑战，我们最近的研究结果表明，丘脑和皮层的关键时期的改进时间重叠。我们的假设是皮层对丘脑的反馈驱动了丘脑突触回路的完善，由此产生的丘脑功能影响了皮层的发育。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。为了验证这一假设，我们将利用MeCP2缺陷小鼠，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。视觉系统将被用作理解丘脑和皮层之间发育关系的实验系统。MeCP2缺失小鼠在丘脑和皮层水平均表现出视觉功能发育受损。在这一提议中，我们将选择性地破坏MeCP2基因在皮层或视网膜丘脑回路中的表达，并分别评估视网膜环或皮层回路的功能成熟。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，视网膜-丘脑回路的局灶性缺陷最终会影响皮质发育。我们的研究结果将改变哺乳动物中枢神经系统发育的基本思路。中枢神经系统结构之间的前馈和反馈相互作用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的变化可以弥补另一种结构缺陷的可能性。因此，更深入地了解丘脑和皮层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。

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.