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

早期的经历如何塑造我们自己？我们展示了这样一个关键时期的大脑 发育是由特定的小白蛋白(PV)阳性GABA细胞触发的，然后通过 锥体细胞树突上的棘突和突起的顺序重新配置。在基因组水平上， 一个比以前更广泛的非编码rna(Ncrna)世界已经被发现。 已经预料到了。在战略细胞类型中表达的ncRNA序列的加速区 似乎对人类大脑进化至关重要。通过快速调节即使在远端的mRNA翻译， NcRNA可能特别适合于响应不断变化的环境，定义了一种 为维护单个神经元的身份提供了独特的环境。 令人惊讶的是，ncRNAs在大脑功能(和功能障碍)中的作用实际上仍然未知。我们 将探索它们对大脑发育关键期的开始和永久的贡献。 利用复制缺陷型腺病毒载体，我们将开发脉冲基因转移？变成了具体的 在小鼠中，祖细胞以神经元出生日期特异性的方式。通过共价连接磁性 含有特定ncRNA序列或可诱导的Crerecombinase的创新构建体 会集中在子宫中进行晚期过度表达或内源性缺失 PV细胞中的ncRNAs。受病毒感染的锥体细胞群同样会被操纵 出生后由其典型的由内向外的层状起源。一项综合评估 电生理、光学成像、解剖和行为测量视力、听力和 社会行为将在这些不同的老鼠模型上执行。 然后我们将检验ncRNAs作为分子开关来调节基因的假设。 神经网络中的网络。通过协调光伏细胞的成熟和细胞的繁殖 跨皮质层的精心安排的变化，ncRNA可能建立起 依赖经验的大脑可塑性。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 以及针对发育性大脑疾病的治疗目标，如自闭症或精神分裂症，这些 悲剧性地禁锢了心灵。

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.