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质神经元的适当迁移和放置。神经元的迁移和由此产生的神经元的位置为神经元连接体或功能连接的出现提供了框架。神经元迁移中特定区域和神经元类型的缺陷以及随后神经元连接性的改变是一系列神经疾病的潜在原因，包括自闭症、精神分裂症、癫痫、精神发育迟缓和畸形，如无脑畸形、脑裂脑畸形、小脑畸形和大/小脑回。然而，关于不同类别的神经元是如何从它们的出生地点协调导航到它们在发育中的大脑皮层的最终板层和区域特定目的地的，人们知之甚少。了解不同类型的皮质神经元如何在适当的时间以适当的数量迁移到适当的皮质区域，对于了解神经发育和神经精神障碍的致病机制至关重要。因此，我们的目标是定义皮质神经元(即投射神经元和中间神经元)如何实现其在大脑皮层的适当位置。为了实现这一目标，我们将开发实时、4-D共聚焦和多光子成像的方法，对发育中的大脑中遗传定义的皮质神经元亚型进行成像。使用这种方法，我们将绘制出不同类别的皮质神经元如何穿过发育中的脑壁，到达它们适当的区域和板层位置。总之，这张关于大脑皮层发育过程中中间神经元和投射神经元协调迁移和放置的全面图谱将定义用于形成大脑连接体的神经元蓝图，促进新的活体胚胎脑成像方法的开发，有助于在一系列神经发育障碍中描绘脑异常的基础，从而对正常和异常的脑发育产生革命性的见解。

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.