Lineage-Dependent Assembly of Neocortical Circuits

描述（由申请人提供）：在理解新皮层中精确的功能神经元回路是如何形成的方面存在一个基本的知识缺口，新皮层是大脑中最复杂的部分，控制着从感知到情感和认知的所有方面的行为。这种差距的持续存在代表了一个主要问题，因为它严重阻碍了对新皮层畸形和功能障碍的理解。长期目标是更好地理解发育中的新皮层中精确神经元回路的组装。目的是研究新皮层兴奋性神经元之间精确电突触形成的起源、基础和调控。核心假设是，谱系关系指导发育中的新皮层中兴奋性神经元之间精确的电突触形成。这一假设是根据申请人实验室产生的强有力的初步数据制定的。这项研究的基本原理是，神经发生和神经元迁移的过程调节了发育中的新皮层中兴奋性神经元之间特定电突触的形成。在强有力的初步数据的指导下，这一假设将通过追求三个具体目标来验证：1)揭示控制姐妹兴奋神经元之间强电突触形成特异性的机制；2)确定姐妹兴奋性神经元间电突触发育移除的调控机制；3)研究电偶联姐妹兴奋性神经元之间特定化学突触优先发育的机制。这种方法是创新的，因为它结合了许多尖端技术，包括逆转录病毒工程、子宫内标记、小鼠遗传学、四倍全细胞膜片钳记录和双光子/共聚焦激光扫描显微镜。这项提议的研究意义重大，因为它有望从根本上推进对精确神经元回路组装和新皮层功能发育的理解。最终，这些知识有可能为包括精神分裂症、癫痫、智力迟钝和自闭症在内的许多破坏性脑部疾病的早期诊断和治疗方法的开发提供信息。

DESCRIPTION (provided by applicant): There is a fundamental knowledge gap in understanding how precise functional neuronal circuits form in the neocortex, which is the most complex part of the brain and controls all aspects of behavior, from perception to emotion and cognition. The continuing existence of this gap represents a major problem because it severely hinders the understanding of malformation and malfunction of the neocortex. The long-term goal is to better understand the assembly of precise neuronal circuits in the developing neocortex. The objective in this particular application is to investigate the origin, basis and regulation of precise electrical synapse formation between neocortical excitatory neurons. The central hypothesis is that the lineage relationship guides precise electrical synapse formation between excitatory neurons in the developing neocortex. This hypothesis has been formulated on the basis of strong preliminary data produced in the applicant's laboratory. The rationale for the proposed research is that the processes of neurogenesis and neuronal migration regulate the formation of specific electrical synapses between excitatory neurons in the developing neocortex. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) to uncover the mechanisms that control the specificity of strong electrical synapse formation between sister excitatory neurons; 2) to determine the mechanisms that regulate the developmental removal of electrical synapses between sister excitatory neurons; and 3) to investigate the mechanisms that drive the preferential development of specific chemical synapses between electrically coupled sister excitatory neruons. The approach is innovative, because it combines a number of cutting-edge techniques including retroviral engineering, in utero labeling, mouse genetics, quadruple whole-cell patch clamp recording and two photon/confocal laser scanning microscopy. The proposed research is significant, because it is expected to fundamentally advance the understanding of precise neuronal circuit assembly and functional development of the neocortex. Ultimately, such knowledge has the potential to inform early diagnoses and the development of therapeutic treatments for many devastating brain disorders including schizophrenia, epilepsy, mental retardation and autism.