Dissecting Non-coding RNA Function in Critical Period Brain Development and Disor

剖析非编码 RNA 在大脑发育和紊乱关键期的功能

• 批准号: 7667960
• 负责人: Takao K Hensch
• 金额: $ 84.5万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7667960
• 关键词: Autistic Disorder; Behavioral; Biological Neural Networks; Brain; Brain Diseases; Cells; Dendrites; Development; Environment; Evolution; Functional RNA; Functional disorder; Gene Transfer; Genes; Genetic Translation; Genomics; Human; Imprisonment; Individual; Link; Methods; Mind; Molecular; Mus; Neurons; Parvalbumins; Physiologic pulse; Physiological; Pyramidal Cells; RNA Sequences; Role; Schizophrenia; Shapes; Social Behavior; Stem cells; Testing; Vertebral column; Vision; Work; behavior measurement; cell type; cohort; critical period; defective adenoviral vector; early experience; experience; gamma-Aminobutyric Acid; in utero; innovation; magnetic beads; mouse model; novel; optical imaging; therapeutic target

How does early experience shape ourselves? We have shown such critical period brain development is triggered by specific parvalbumin (PV)-positive GABA cells, then hard-wired by sequential re-configuration of spines and inputs upon pyramidal cell dendrites. At a genomic level, a far more widespread world of non-coding RNA (ncRNA) has been identified than previously anticipated. Accelerated regions of change in ncRNA sequences expressed in strategic cell types appear vital to human brain evolution. By rapidly regulating mRNA translation even distally, ncRNAs may be particularly adapted to respond to constantly changing environments, defining a unique milieu for maintaining the identity of individual neurons. Strikingly, the role of ncRNAs in brain function (and dysfunction) remains virtually unknown. We will explore their contribution to the onset and permanence of critical period brain development. Using replication-defective adenoviral vectors, we will develop ?pulse gene transfer? into specific progenitor cells in a neuronal birthdate-specific manner in mice. By covalently linking magnetic beads, innovative constructs containing specific ncRNA sequences or inducible Crerecombinases will be focused in utero for late over-expression or deletion of endogenous ncRNAs in PV-cells. Virally infected pyramidal cell cohorts will similarly be manipulated postnatally by their canonical inside-out laminar origins. An integrated assessment of electrophysiological, optical imaging, anatomical and behavioral measures of vision, audition and social behaviors will be performed on these various mouse models. We will then test the hypothesis that ncRNAs act as molecular switches to regulate gene networks within neural networks. By coordinating maturation of PV-cells and the propagation of well-orchestrated changes across cortical layers, ncRNA may establish the timecourse of experience-dependent brain plasticity. Behavioral and physiological reactivation in adulthood would elucidate the purpose of critical periods. Importantly, our work will identify novel methods and therapeutic targets for developmental brain disorders, like autism or schizophrenia, which tragically incarcerate the mind.

早期体验如何塑造自己？我们已经显示了如此关键的时期大脑 开发是由特定的白细胞蛋白（PV）阳性GABA细胞触发的，然后由 脊柱和输入在锥体细胞树突上的顺序重新配置。在基因组水平上 已经确定了比以前更广泛的非编码RNA（NCRNA）的世界 预期。在战略细胞类型中表达的NCRNA序列变化的加速区域 对于人脑的进化至关重要。通过迅速调节mRNA翻译甚至远端， NCRNA可能特别适应响应不断变化的环境，定义 保持单个神经元身份的独特环境。 令人惊讶的是，NCRNA在脑功能（和功能障碍）中的作用几乎是未知的。我们 将探索他们对关键时期大脑发育的发作和永久性的贡献。 使用复制缺陷的腺病毒载体，我们会发展脉冲基因转移？具体 祖细胞在小鼠中以神经元出生的特异性方式。通过共价连接磁性 珠子，含有特定NCRNA序列或诱导型凝集酶的创新构建体 将集中在子宫内，以进行过度表达或内源性缺失 PV细胞中的NCRNA。病毒感染的锥体细胞组将类似地被操纵 在产后通过其规范的内而外的层流起源。对 电生理，光学成像，视觉，试听和行为的衡量标准 社交行为将在这些各种鼠标模型上执行。 然后，我们将测试NCRNA充当分子开关以调节基因的假设 神经网络中的网络。通过协调PV细胞的成熟和传播 在皮层层之间进行了精心修整的变化，NCRNA可以建立 依赖经验的大脑可塑性。成年后的行为和生理重新激活 将阐明关键时期的目的。重要的是，我们的工作将确定新方法 以及用于发育性脑部疾病的治疗靶点，例如自闭症或精神分裂症， 悲惨地监禁思想。