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

早期经验如何塑造我们？我们已经展示了这样的关键时期大脑 发育由特定的小清蛋白（PV）阳性GABA细胞触发，然后由 棘和锥体细胞树突上的输入的顺序重新配置。在基因组水平上， 非编码RNA（ncRNA）的分布比以前广泛得多 预期。在战略细胞类型中表达的ncRNA序列的加速变化区域 似乎对人类大脑的进化至关重要通过快速调节mRNA的翻译， ncRNA可能特别适合于响应不断变化的环境，定义了一个新的环境。 维持单个神经元身份的独特环境。 引人注目的是，ncRNA在脑功能（和功能障碍）中的作用几乎仍然未知。我们 将探讨他们的贡献的发病和持久的关键时期大脑发育。 使用复制缺陷型腺病毒载体，我们将开发？脉冲基因转移？为具体 在小鼠中以神经元出生日期特异性的方式对祖细胞进行研究。通过共价连接磁性 珠粒，含有特异性ncRNA序列或诱导型Cre重组酶的创新构建体 将集中在子宫内的晚期过度表达或删除内源性 PV细胞中的ncRNA。病毒感染的锥体细胞群将类似地进行操作 出生后由其典型的由内而外的层状起源。综合评估 电生理学、光学成像、视觉、听觉和听觉的解剖和行为测量， 社会行为将在这些不同的小鼠模型上进行。 然后，我们将检验ncRNA作为分子开关调节基因表达的假设。 神经网络中的网络。通过协调PV细胞的成熟和 通过精心策划的皮质层变化，ncRNA可以建立时间进程， 经验依赖的大脑可塑性。成年期的行为和生理再激活 将阐明关键时期的目的。重要的是，我们的工作将确定新的方法， 和治疗大脑发育障碍的目标，如自闭症或精神分裂症， 可悲地禁锢了思想

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.