Molecular analysis of neural circuit excitation and inhibition

神经回路兴奋和抑制的分子分析

• 批准号: 10322170
• 负责人: MICHAEL M FRANCIS
• 金额: $ 44.93万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10322170
• 关键词: Address; Adolescent; Adult; Area; Biological Models; Brain; Caenorhabditis elegans; Cell physiology; Cerebellum; Cholinergic Receptors; Chromatin; Defect; Dendrites; Dendritic Spines; Development; Developmental Process; Electron Microscopy; Ensure; Event; F-Actin; Foundations; Funding; Gene Targeting; Genes; Genetic; Genetic Models; Genetic Screening; Genetic Transcription; Genetic study; Goals; Health; Homologous Gene; Human; Investigation; Knowledge; Modeling; Molecular; Molecular Analysis; Molecular Genetics; Motor; Nematoda; Nervous system structure; Neurodevelopmental Disorder; Neurons; Pathway interactions; Patients; Pattern; Physiology; Positioning Attribute; Process; Regulation; Role; Schizophrenia; Shapes; Signal Transduction; Somatosensory Cortex; Specific qualifier value; Stimulus; Structure; Synapses; System; Testing; Therapeutic Intervention; Vertebral column; Visual system structure; Work; autism spectrum disorder; base; cholinergic; connectome; experimental study; genetic approach; homeodomain; in vivo; innovation; light microscopy; nervous system disorder; neural circuit; neuropsychiatric disorder; neuropsychiatry; new growth; novel; novel strategies; postsynaptic; presynaptic; programs; receptor; relating to nervous system; synaptogenesis; therapeutic candidate; tool; transcription factor; transcriptome sequencing

Developmental remodeling of circuit connectivity is a key process in shaping the mature organization of neural circuits in the brain, optimizing their connectivity in order to perform specific functions. Remodeling is triggered by both environmental stimuli and intrinsic genetic mechanisms, and deficits in remodeling processes are thought to be a primary factor underlying altered patterns of connectivity observed in a variety of neurodevelopmental and neuropsychiatric disorders. Despite the clear importance of these developmental processes for normal brain physiology and health, there are major gaps in our understanding of the cellular and molecular mechanisms that regulate neural circuit remodeling. Studies of genetic models have proven to be extremely fruitful for identifying fundamental mechanisms underlying neural circuit development and function. Our previous studies have pioneered new approaches for elucidating mechanisms for the specification of synaptic connectivity in a genetically tractable model, the nematode Caenorhabditis elegans. During the previous funding period, we demonstrated the remodeling of postsynaptic specializations located on GABAergic neurons in the C. elegans motor circuit, and showed that the formation of new synapses during remodeling is associated with the outgrowth of previously uncharacterized spines on GABAergic dendrites. Moreover, we uncovered a novel mechanism required for spine outgrowth and synapse assembly that depends on the synaptic organizer neurexin. These findings demonstrate the strength of this system for identifying key genes with conserved roles in shaping neural circuit connectivity and place us in a strong position for a deep investigation of in vivo molecular mechanisms. Indeed, in preliminary studies supporting this application we have identified the homeodomain transcription factor DVE-1, a homolog of mammalian chromatin organizers SATB1/2, as a key hub for regulation of synapse elimination during remodeling of the motor circuit. In Aim 1 of this proposal we investigate a novel transcriptional network controlling synapse disassembly and elimination. In Aim 2, we explore cellular and molecular mechanisms underlying the assembly of new synapses during circuit remodeling, focusing on the role of the conserved synaptic organizer neurexin. We expect that our studies of this experimentally tractable circuit in the worm will have a major impact on our understanding of the molecular processes involved in circuit remodeling. Additionally, we anticipate that the novel molecules and signaling mechanism we identify will be excellent candidates for therapeutic intervention to treat neurodevelopmental disorders involving disruptions in circuit connectivity.

电路连接的发展重塑是塑造成熟电路的关键过程 组织大脑中的神经回路，优化其连接以执行特定的任务 功能。重塑是由环境刺激和内在遗传共同触发的 机制和重塑过程中的缺陷被认为是潜在的主要因素 在各种神经发育和神经精神病学中观察到的连接模式改变 失调。尽管这些发育过程对于正常大脑具有明显的重要性 生理学和健康方面，我们对细胞和分子的理解存在重大差距 调节神经回路重塑的机制。 事实证明，遗传模型的研究对于识别基本原理非常富有成效。 神经回路发育和功能的机制。我们之前的研究有 开创了阐明突触规范机制的新方法 遗传易处理模型线虫秀丽隐杆线虫中的连接性。期间 在上一个资助期间，我们展示了位于以下位置的突触后专门化的重塑 对秀丽隐杆线虫运动回路中的 GABA 能神经元的影响，并表明新的形成 重塑过程中的突触与先前未表征的突触的生长有关 GABA能树突上有刺。此外，我们发现了脊柱所需的一种新机制 突触的生长和组装取决于突触组织者神经毒素。这些 研究结果证明了该系统在识别具有保守作用的关键基因方面的优势 塑造神经回路连接并使我们处于深入研究的有利位置 体内分子机制。事实上，在支持该应用的初步研究中，我们有 鉴定出同源域转录因子 DVE-1，哺乳动物染色质的同源物 组织者 SATB1/2，作为神经网络重塑过程中调节突触消除的关键枢纽 电机电路。在本提案的目标 1 中，我们研究了一种新颖的转录网络控制 突触拆卸和消除。在目标 2 中，我们探索细胞和分子机制 电路重塑过程中新突触组装的基础，重点关注突触的作用 保守的突触组织者神经毒素。 我们预计，我们对蠕虫中这种实验上易于处理的电路的研究将产生重大影响。 影响我们对电路重塑所涉及的分子过程的理解。 此外，我们预计我们确定的新分子和信号机制将是 治疗神经发育障碍的优秀候选人 电路连接中断。