Retinoid Signaling in Songbirds: Learned Song, Gene Expression and Neurogenesis

描述（由申请人提供）：类维甲酸信号在神经元表型的发展和维持中很重要。如果在人类中被破坏，就会导致学习障碍。对鸣禽声音学习的研究已经确定了控制和发展鸣禽学习的关键大脑中心，适当的类维生素a信号是这些大脑通路充分发挥功能的必要条件。鸣禽通过听成人导师唱歌来学习它们的歌曲，并通过一段时间的试验和错误来完善它们——这一过程类似于人类小时候学习语言的过程。本研究的目的是阐明类维甲酸信号如何特异性地影响鸟类鸣叫途径。这将通过两个具体目标来实现。第一个目标是测量已知在类视黄醇信号传导中重要的基因的表达，并确定那些在歌唱途径中表达的基因。在歌唱系统中表达的基因将进一步在细胞水平上进行表征，以确定大脑中类视黄醇信号的细胞类型和潜在靶标区域。然后，我们将使用合成饮食模式，要么补充视黄酸，要么从饮食中去除所有视黄酸及其代谢前体，以测试这些已知在其他系统中对视黄酸有反应的基因如何对歌中枢的类视黄酸水平作出反应和调节。这些结果将为影响复杂学习行为的类视黄醇信号通路的生物信息学分析奠定基础。因为神经发生和神经元分化是由类视黄醛信号调节的一个显著特征，目的二将测试改变的类视黄醛信号对大脑中枢内神经元出生、迁移和建立速率的影响。维生素A缺乏是一个主要的人类健康问题，对认知发育有负面影响。类维生素a也用于治疗痤疮和减少早幼粒细胞白血病的增殖，但对人类发育有严重影响。啮齿动物模型能够测试对关系记忆和空间学习的影响，但这些物种不像人类那样表现出声音学习能力。像斑胸草雀这样的鸣禽确实表现出声音学习能力，并提供了一个合适的模型来测试类视黄醛信号在语言发育和学习障碍中的重要性。

DESCRIPTION (provided by applicant): Retinoid signaling is important in the development and maintenance of neuronal phenotypes. When disrupted in humans this results in learning disabilities. Work on vocal learning in song birds has identified the key brain centers responsible for the control and development of learned bird song, and proper retinoid signaling is one requirement for adequate function of these brain pathways. Songbirds learn their songs by listening to adult tutors, and perfect them through a period of trial and error- a process analogous to how humans learn language as children. This goal of this study is to elucidate how retinoid signaling specifically affects the avian song pathways. This will be achieved by two specific aims. The first aim is to measure the expression of genes known to be important in retinoid signaling and identify those that are expressed in the song pathway. Genes that show expression in the song system will be further characterized at the cellular level to identify the cell types and potential target areas of retinoid signaling in the brain. We will then use a synthetic diet paradigm to either supplement retinoic acid or remove all retinoic acid and its metabolic precursors from the diet to test how these genes, that are known to be retinoic responsive in other systems, respond to and regulate retinoid levels in the song centers. These results will seed a bio-informatics analysis of the retinoid signaling pathways that affect a complex learned behavior. Because neurogenesis and neuronal differentiation is a prominent trait that is regulated by retinoid signaling, aim two will test the effects that altered retinoid signaling has on rates of neuronal birth, migration and establishment within the song centers of the brain. PUBLIC HEALTH RELEVANCE Vitamin A deficiency is a major human health issue and has negative effects on cognitive development. Retinoids are also used therapeutically to treat acne and reduce the proliferation of promyelocytic leukemia, but with severe effects on human development. Rodent models are able to test effects on relational memory and spatial learning, but these species do not exhibit vocal learning as in humans. Songbirds such as the zebra finch do exhibit vocal learning and provide a suitable model to test the importance of retinoid signaling on speech development and learning disabilities.