Developmental Mechanisms of Fine-scale Cortico-cortical Circuit Formation

精细皮质-皮质回路形成的发育机制

• 批准号: 10744933
• 负责人: Euiseok J Kim
• 金额: $ 44.06万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10744933
• 关键词: Adhesions; Anatomy; Anterolateral; Area; Axon; Birth; Brain; Cell Adhesion Molecules; Cells; Data; Date of birth; Defect; Development; Developmental Process; Disease; Dyslexia; Family; Feedback; Foundations; Gene Expression; Genetic; Goals; Human; In Situ Hybridization; Individual; Knowledge; Label; Link; Medial; Mediating; Mental disorders; Messenger RNA; Methods; Mission; Modeling; Molecular; Motor; Mus; Neurodevelopmental Disorder; Neurons; Neurosciences; Outcome; Output; Pattern; Phenotype; Process; Production; Projections and Predictions; Property; Regulation; Research; Role; Schizophrenia; Sensory; Solid; Source; Specific qualifier value; Specificity; Synapses; Testing; Therapeutic Intervention; Thymidine; United States National Institutes of Health; V1 neuron; Vision Disorders; Visual; Visual Cortex; Visual System; Work; analog; area striata; autism spectrum disorder; cell type; extrastriate visual cortex; genetic manipulation; innovation; insight; neural; neural circuit; neuromechanism; neuronal circuitry; neuronal patterning; new therapeutic target; novel therapeutics; presynaptic neurons; prevent; programs; public health relevance; rabies viral tracing; single molecule; synaptic pruning; virus genetics

Project Summary Cortico-cortical projection neurons (CCPNs) connect cortical areas with each other to facilitate sensory processing and execute appropriate motor actions. Defects in intra-cortical connectivity are associated with a variety of neural circuit disorders such as dyslexia, autism, and schizophrenia. Because these diseases have genetic components and potentially arise from altered brain development, it is important to understand how CCPNs know which area to target and which synaptic inputs to receive. The long-term goal of my research program is to gain mechanistic insights into cortical circuit assembly at the single cell level in an effort to understand underpinnings of neurodevelopmental disorders and develop new therapies. In doing so, we will be able to identify molecular and genetic mechanisms that link gene expression and neural activity to neuronal connectivity. The objective of this proposal is to identify mechanisms by which long-range cortico-cortical neuronal connectivity is established in the mammalian cortex using the mouse visual system as a model. Our central hypothesis is that V1 neurons, projecting to the AL (anterolateral: V1→AL) or the PM (posteromedial: V1→PM) higher visual areas, differ in timing and molecular regulation of their axonal projection development, and their input versus output connectivity is specified by two distinct rules: early specification and synaptic pruning mechanism, respectively. We will test this hypothesis with the following aims: 1) we will determine the patterns and timing of cortico-cortical neuronal projection development in the mouse visual cortex. 2) we will determine the roles of Teneurins, cell-adhesion molecules, in specifying the projection identities of V1→AL and V1→PM neurons. 3) we will determine developmental principles of ‘like-to-like’ cortico-cortical feedback circuit formation. This research is significant because elucidating the developmental mechanisms of neural circuit assembly will provide cell-type or circuit-specific therapeutic interventions for specific aspects of neurodevelopmental and psychiatric disorder phenotypes. The proposed research is innovative because we are using and developing the technical solutions to allow us to target gene expression and capture the rapid developmental connectivity dynamics of layer- and projection-specific cortical neurons. Results will provide a comprehensive understanding of how a long-range connectivity network arises at the cellular level. This new knowledge will have a positive impact on the neuroscience field as it will establish a solid foundation to provide connectivity-based therapeutic interventions for neurodevelopmental disorders.

项目摘要 皮质-皮质投射神经元（CCPN）将皮质区域彼此连接，以促进 感觉处理和执行适当的运动动作。皮质内连接缺陷 与多种神经回路障碍有关，如阅读障碍、自闭症和 精神分裂症因为这些疾病有遗传成分，可能是由 改变大脑发育，重要的是要了解CCPNs如何知道哪个区域的目标 以及接收哪些突触输入。我研究项目的长期目标是 在单细胞水平上对皮层电路组装的机械见解， 了解神经发育障碍的基础并开发新的治疗方法。在 这样做，我们将能够确定基因之间的分子和遗传机制， 表达和神经活动与神经元连接。这项建议的目的是 确定在大脑皮层中建立长距离皮质-皮质神经元连接的机制， 哺乳动物的大脑皮层使用小鼠的视觉系统作为模型。我们的核心假设是， V1神经元，投射到AL（前外侧：V1→AL）或PM（后内侧：V1→PM） 更高的视觉区域，在轴突投射的时间和分子调节方面不同 开发，它们的输入与输出连接由两个不同的规则指定： 规范和突触修剪机制。我们将测试这个假设与 以下目标：1）我们将确定皮质-皮质神经元的模式和时间 小鼠视觉皮层的投射发育。2)我们将决定特内鲁因的角色 细胞粘附分子，在指定的V1→AL和V1→PM神经元的投射身份。 3)我们将确定“相似”皮质-皮质反馈回路的发展原则 阵本研究具有重要意义，因为阐明了 神经回路组件将提供细胞类型或回路特异性治疗干预， 神经发育和精神障碍表型的特定方面。拟议 研究是创新的，因为我们正在使用和开发技术解决方案， 以基因表达为目标，捕捉层- 和投射特异性皮层神经元。结果将提供全面的了解 远程连接网络如何在蜂窝级别出现。这些新知识将 对神经科学领域的积极影响，因为它将建立一个坚实的基础， 基于连接性的神经发育障碍治疗干预。