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）相互连接皮质区域以促进 感官处理并执行适当的电机动作。皮质内连通性缺陷 与多种神经电路疾病有关，例如阅读障碍，自闭症和 精神分裂症。因为这些疾病具有遗传成分，并可能由 大脑发育改变了，重要的是要了解CCPN如何知道要针对哪个区域 以及要接收的突触输入。我的研究计划的长期目标是获得 在单细胞水平上对皮质电路组件的机械洞察力，以努力 了解神经发育障碍的基础并发展新疗法。 这样做，我们将能够鉴定连接基因的分子和遗传机制 对神经元连通性的表达和神经元活性。该提议的目的是 确定在远程皮质皮质神经元连接中建立的机制 使用鼠标视觉系统作为模型的哺乳动物皮质。我们的中心假设是 V1神经元，投影到AL（前外侧：V1→Al）或PM（后副元：V1→PM） 较高的视觉区域，其轴突投影的时机和分子调节不同 开发及其输入与输出连接由两个不同的规则指定：早期 规范和突触修剪机制。我们将用 以下目的：1）我们将确定皮质皮质神经元的模式和时机 小鼠视觉皮层中的投影发展。 2）我们将确定替析神经蛋白的作用， 在指定V1→Al和V1→PM神经元的投影身份时，细胞粘附分子。 3）我们将确定“类似于类似”的皮质皮层反馈电路的发展原理 形成。这项研究很重要，因为阐明了 神经电路组件将为细胞类型或电路特异性治疗干预措施 神经发育和精神障碍表型的特定方面。提议 研究具有创新性，因为我们正在使用并开发技术解决方案来允许我们 靶向基因表达并捕获层的快速发展连通性动力学 和投射特异性皮质神经元。结果将提供对 远程连接网络如何在细胞级别出现。这个新知识将有 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来提供 基于连通性的神经发育障碍的治疗干预措施。