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

描述(由申请人提供)：维甲酸信号在神经元表型的发展和维持中很重要。当在人类中受到干扰时，这会导致学习障碍。关于鸣禽发声学习的研究已经确定了负责控制和发展习得鸟类鸣叫的关键大脑中心，而适当的维甲酸信号是这些大脑通路充分发挥功能的必要条件之一。鸣禽通过听成人导师的话来学习它们的歌声，并通过一段时间的尝试和错误来完善它们--这一过程类似于人类小时候学习语言的过程。这项研究的目的是阐明维甲酸信号如何具体影响鸟类的鸣叫通路。这将通过两个具体目标来实现。第一个目标是测量已知在维甲酸信号中重要的基因的表达，并识别那些在歌曲通路中表达的基因。在SONG系统中表达的基因将在细胞水平上进一步表征，以确定大脑中维甲酸信号的细胞类型和潜在靶区。然后，我们将使用合成饮食范例来补充维甲酸或从饮食中移除所有维甲酸及其代谢前体，以测试这些已知在其他系统中对维甲酸反应的基因如何对歌曲中心的维甲酸水平做出反应并进行调节。这些结果将为影响复杂习得行为的维甲酸信号通路进行生物信息学分析。由于神经发生和神经元分化是由维甲酸信号调节的显著特征，目标二将测试改变的维甲酸信号对大脑歌曲中心神经元出生、迁移和建立的速度的影响。维生素A缺乏症是一个重大的人类健康问题，对认知发展有负面影响。维甲酸也被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发声学习。像斑马雀这样的鸣禽确实表现出发声学习，并提供了一个合适的模型来测试维甲酸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.