Mapping of Neuronal Placement in the Developing Cerebral Cortex

描述（由申请人提供）：大脑中神经元的适当布线需要皮质神经元的适当迁移和放置。神经元迁移和神经元的最终位置为神经元连接体或功能布线的出现提供了框架。神经元迁移中的区域特异性和神经元类型特异性缺陷以及随后的神经元连接性变化是广泛的神经系统疾病的根本原因，包括自闭症、精神分裂症、癫痫、精神发育迟滞和畸形，例如无脑回畸形、中脑回畸形、小脑畸形和大/小脑回畸形。然而，很少有人知道不同类别的神经元如何协调地从它们的出生地导航到发育中的大脑皮层中的最终层和区域特定目的地。了解不同类型的皮层神经元如何在正确的时间以正确的数量迁移到适当的皮层区域，对于理解神经发育和神经精神疾病的致病机制至关重要。因此，我们的目标是定义皮层神经元（即，投射神经元和中间神经元）在大脑皮层中实现其适当的位置。为了实现这一目标，我们将开发真实的时间，4-D共聚焦和多光子成像的遗传定义的亚型皮层神经元在发育中的大脑。使用这种方法，我们将映射不同类别的皮层神经元如何通过发育中的大脑壁导航，以到达其适当的区域和层状位置。总之，在大脑皮层发育期间中间神经元和投射神经元的协调迁移和放置的这种全面映射将定义用于形成脑连接体的神经元蓝图，促进新的体内活胚胎脑成像方法的开发，帮助描绘神经发育障碍谱中脑异常的基础，从而对正常和异常的大脑发育产生变革性的见解。

DESCRIPTION (provided by applicant): The appropriate wiring of neurons in the brain requires appropriate migration and placement of cortical neurons. Neuronal migration and the resultant placement of neurons provide the framework for the emergence of neuronal connectome or functional wiring. Area specific and neuronal type specific defects in neuronal migration and the subsequent changes in neuronal connectivity is an underlying cause of a wide spectrum of neurological disorders, including autism, schizophrenia, epilepsy, mental retardation, and malformations such as lissencephaly, schizencephaly, microencephaly, and macro/microgyria. However, very little is known about how distinct classes of neurons coordinately navigate from their sites of birth to their final laminar and areal specific destinations in the developing cerebral cortex. Understanding how the different types of cortical neurons migrate at the right time in right numbers to appropriate cortical areas will be essential to understand the pathogenic mechanisms that underlie neurodevelopmental and neuropsychiatric disorders. We therefore aim to define how cortical neurons (i.e., projection neurons and interneurons) achieve their appropriate placement in the cerebral cortex. Towards this goal, we will develop methods for real time, 4-D confocal and multiphoton imaging of genetically defined subtypes of cortical neurons in the developing brain. Using this approach, we will map how distinct classes of cortical neurons navigate through the developing cerebral wall to arrive at their appropriate areal and laminar positions. Together, this comprehensive mapping of coordinated migration and placement of interneurons and projection neurons during cerebral cortical development will define the neuronal blueprint used to form brain connectome, facilitate the development of new in vivo live embryonic brain imaging methods, help delineate the basis of brain abnormalities in a spectrum of neurodevelopmental disorders, and thus will generate transformative insights into normal and aberrant brain development.