The systems-level transcriptional architecture of song plasticity in songbirds

项目摘要摘要 学习运动技能，就像学习如何说话、走路或演奏乐器一样，是必不可少的一部分 行为发展的影响。过去广泛的研究以心理学中的运动学习为特征， 神经生理和细胞水平。然而，人们相对较少地理解 在行为可塑性过程中，支撑这种学习形式的神经系统会在分子水平上发生变化。 此外，对于多基因座神经系统内的可塑性如何反映在 基因表达的协调变化。这样从系统层面理解互联互通 行为可塑性和分子可塑性之间的关系对于更广泛地理解 神经系统疾病和促进或限制可塑性的分子条件的改变。在……里面 特别是，歌曲学习与人类的语音学习和一般运动技能高度相似。 获得，表现出相似的行为轨迹，并使用同源神经系统。 人类这些神经系统的紊乱与运动相关 神经退行性疾病，如帕金森氏症和亨廷顿病。这项提案将使用 鸣禽的鸣唱学习--一种易于驯化且与行为相关的运动技能学习模式 具有高度可控的输入、精确可测量的输出和定义的神经基质，以 描述作为运动技能获得和不稳定基础的转录状态。 这项工作的广泛的、长期的目标是了解有助于 复杂习得行为的可塑性，无论是在正常发育过程中还是在病理过程中 颠覆。这项提议将侧重于两个具体的假设。第一个目标将检验这样的假设 青少年的歌曲习得在歌曲系统中诱导了特定的转录反应。此外， 这一目标将检验这样一种假设，即最初的辅导歌曲接触和随后的歌曲学习会导致不同的 转录状态。第二个目标将检验这一假设，即成年鸟类的耳聋是一种操纵 这会导致歌曲不稳定，推动歌曲系统中的转录反应。过去的工作已经完成 证明了耳聋引起的歌唱不稳定需要来自皮质基底部的完整信号 作为歌曲学习基础的神经节系统。从这个结果来看，这个目标也将考验 假设这种依赖通过检查转录水平延伸到基因表达水平 缺乏完整皮质-基底节鸣声输出的聋鸟的鸣声系统反应 运动路径。为了使这项工作成为可能，我们开发了一种低成本和高通量的RNA测序 一种可以分析数百个单独激光显微切割的基因表达的方法 单个动物的样本。总而言之，这些实验将为理解 复杂行为变化的分子基础。

Project Summary Abstract Motor skill learning, like learning how to speak, walk, or play a musical instrument, is an essential part of behavioral development. Extensive past work has characterized motor learning at psychological, neurophysiological, and cellular levels. However, there is relatively poorer understanding of how the neural systems that underlie this form of learning change at the molecular level during behavioral plasticity. Moreover, there is little definition of how plasticity within a multi-locus neural system is reflected in coordinated alterations to gene expression. Such a systems-level understanding of the interconnections between behavioral and molecular plasticity is essential to broader understanding of the pathological alterations in neurological disease and the molecular conditions that promote or constrain plasticity. In particular, song learning is highly analogous to speech learning in humans and to general motor skill acquisition, exhibiting similar behavioral trajectories and employing homologous neural systems. Disruptions to these neural systems in humans are strongly associated with motor-associated neurodegenerative disease such as Parkinson's and Huntington's diseases. This proposal will use song learning in songbirds, a tractable and ethologically relevant model of motor skill learning with highly controllable inputs, precisely measurable outputs, and defined neural substrates, to characterize the transcriptional states that underlie motor skill acquisition and destabilization. The broad, long-term objective of this work is to understand the molecular mechanisms that contribute to plasticity in a complex learned behavior, both during normal development and during pathological disruption. This proposal will focus on two specific hypotheses. The first aim will test the hypothesis that song acquisition in juveniles induces specific transcriptional responses in the song system. Moreover, this aim will test the hypothesis that initial tutor song exposure and subsequent song learning induce distinct transcriptional states. The second aim will test the hypothesis that deafening in adult birds, a manipulation that drives song destabilization, drives transcriptional responses in the song system. Past work has demonstrated that deafening-induced song destabilization requires intact signaling from the cortical-basal ganglia system that underlies song learning. Following from this result, this aim will also test the hypothesis that this dependency extends to the level of gene expression by examining transcriptional responses in the song system in deafened birds that lack intact cortical-basal ganglia output to the song motor pathway. To enable this work, we have developed a low-cost and high-throughput RNA sequencing method that permits the analysis of gene expression in hundreds of individual laser microdissected samples from single animals. Together, these experiments will establish a framework for understanding the molecular basis of alterations in complex behaviors.