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: 10519112
• 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/10519112
• 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; 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; 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; Work; autism spectrum disorder; cholinergic; connectome; experimental study; genetic approach; homeodomain; in vivo; innovation; light microscopy; nervous system disorder; neural; neural circuit; neuropsychiatric disorder; neuropsychiatry; new growth; novel; novel strategies; postsynaptic; presynaptic; programs; receptor; 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.

电路连接的发育重塑是塑造成熟的 组织大脑中的神经回路，优化它们的连接，以执行特定的功能。 功能协调发展的重塑是由环境刺激和内在遗传因素共同触发的。 机制和重建过程中的缺陷被认为是一个主要因素， 在各种神经发育和神经精神疾病中观察到的连接模式改变 紊乱尽管这些发育过程对正常大脑的重要性显而易见， 生理学和健康，我们对细胞和分子生物学的理解存在重大差距。 调节神经回路重塑的机制。 遗传模型的研究已被证明是非常富有成效的确定基本 神经回路发育和功能的潜在机制。我们以往的研究 开创了阐明突触特异性机制的新方法， 在一个遗传上易处理的模型中，线虫秀丽隐杆线虫的连接性。期间 在上一个资助期，我们证明了突触后特化的重塑， 对C. elegans运动电路，并表明，新的形成 突触在重塑过程中与以前未表征的 GABA能树突上的刺。此外，我们发现了一种新的机制， 生长和突触组装依赖于突触组织者neurexin。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。 塑造神经回路的连接性，并使我们处于深入调查的有利地位， 体内分子机制事实上，在支持这一应用的初步研究中， 鉴定了同源结构域转录因子DVE-1，一种哺乳动物染色质的同源物 组织者SATB 1/2，作为一个关键枢纽，调节突触消除过程中重塑的 电机电路在本提案的目的1中，我们研究了一种新的转录网络， 突触解体和消除。在目标2中，我们探索细胞和分子机制， 在电路重塑过程中新突触组装的基础上，重点关注 保守的突触组织者neurexin 我们希望我们对蠕虫中这种实验上易处理的电路的研究将有重大意义。 影响了我们对电路重塑所涉及的分子过程的理解。 此外，我们预计，新的分子和信号机制，我们确定将是 用于治疗神经发育障碍的治疗性干预的优秀候选者， 电路连接中断。