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连接需要皮层神经元的适当迁移和放置。神经元迁移和由此产生的神经元位置为神经元连接组或功能性线路的出现提供了框架。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通性变化是广泛的神经系统疾病的潜在原因，包括自闭症、精神分裂症、癫痫、智力迟钝和畸形，如无脑畸形、分裂性脑畸形、小脑畸形和大/小脑回畸形。然而，对于不同种类的神经元如何协调地从它们的出生位置导航到它们在发育中的大脑皮层的最终层流和区域特定目的地，我们知之甚少。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）如何在大脑皮层中获得适当的位置。为了实现这一目标，我们将开发用于发育中的大脑皮层神经元遗传定义亚型的实时，4-D共聚焦和多光子成像的方法。使用这种方法，我们将绘制出不同种类的皮质神经元如何通过发育中的脑壁导航到适当的面状和层状位置。总之，这种对大脑皮层发育过程中中间神经元和投射神经元的协调迁移和放置的综合映射将定义用于形成大脑连接组的神经元蓝图，促进新的活体胚胎脑成像方法的发展，帮助描绘神经发育障碍谱系中大脑异常的基础，从而将产生对正常和异常大脑发育的革命性见解。

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.