Gene Regulation in Auditory Learning

描述(申请人提供)：除了人类，鸣禽是极少数进化了发声学习的生物之一，它们的研究帮助揭示了发声交流和发声学习的神经元基础。为了学会产生自己的歌声，并执行需要个人识别的社会行为，鸣禽需要处理并形成对它们在生活中听到的歌曲的长期记忆。虽然关于鸟鸣的运动方面已经有了很大的进展，但我们对鸣鸟用来分析和存储歌声听觉信息的大脑区域和机制的了解仍然非常有限。对鸟鸣的听觉和知觉方面的重大洞察来自于以下发现：当鸟类听到鸣叫时，在尾侧新纹状体(NCM)中出现了明显的Zenk基因的诱导。Zenk编码一种与神经元可塑性有关的转录调节因子，而NCM是鸣禽大脑中枢听觉通路的一部分。来自分子、解剖学、电生理学和行为学研究的证据表明，NCM在歌曲的听觉加工中起着重要作用。特别是，在NCM中发现了歌曲音节的听觉表征的证据。这些研究还表明，在NCM中，由歌曲诱导的Zenk代表了基因调控级联中的早期事件，导致了长期的神经元变化，并可能形成和/或储存了歌曲听觉记忆。 这项研究的目的是描述NCM的功能和解剖结构，并确定NCM中发生的对歌曲的基因组反应的作用。其具体目标是：1)确定NCM对歌曲反应的关键决定因素的刺激参数，并确定NCM中的音节表示是与生俱来的还是依赖于经验的；2)通过小剂量注射神经束示踪剂来确定NCM的解剖组织，以检查NCM内的功能亚域具有不同连接性的程度；以及3)通过a)识别NCM中SONG调控的Zenk靶基因，以及b)确定Zenk在NCM神经元对歌曲的长期习惯性中的作用，来确定NCM中歌曲诱导表达的作用。拟议的研究结果将为脊椎动物的大脑如何处理和存储与行为相关的听觉信息提供基本见解，这最终将有助于我们了解与人类言语和语言障碍相关的大脑机制。

DESCRIPTION (provided by applicant): Songbirds are among the very few organisms that, besides humans, evolved vocal learning, and their study has helped uncover the neuronal basis of vocal communication and vocal learning. To learn to produce their own song and to perform social behaviors requiring individual recognition, songbirds need to process and to form long-lasting memories of the songs they hear in life. While there has been much progress with regards to motor aspects of birdsong, our understanding of the brain areas and mechanisms used by songbirds to analyze and store song auditory information is still very limited. Significant insight into auditory and perceptual aspects of birdsong has derived from the finding that a marked induction of the zenk gene occurs in the caudomedial neostriatum (NCM) when birds hear song. zenk encodes a transcriptional regulator linked to neuronal plasticity, and NCM is part of the central auditory pathway of the songbird brain. Evidence from molecular, anatomical, electrophysiological, and behavioral studies indicate that NCM plays a major role in song auditory processing. In particular, evidence has been uncovered for an auditory representation of song syllables in NCM. These studies also suggest that zenk induction by song in NCM represents an early event in a gene regulatory cascade that leads to long-lasting neuronal changes and possibly the formation and/or storage of song auditory memories. The objective of the proposed research is to characterize the functional and anatomical organization of NCM, and to determine the role of the genomic response to song that occurs in NCM. The specific aims are: 1) to identify stimulus parameters that are critical determinants of the NCM response to song and to determine whether the syllabic representation in NCM is innate or dependent on experience; 2) to determine the anatomical organization of NCM by using small injections of neuronal tract-tracers to examine the extent to which functional sub-domains within NCM have distinct connectivities; and 3) to determine the role of song-induced expression in NCM by a) identifying song regulated zenk target genes in NCM, and b) determining the role of zenk in the long-term habituation of NCM neurons to song. The outcomes of the proposed research will provide basic insights into how the brains of vertebrates process and store behaviorally relevant auditory information, which will eventually help us understand brain mechanisms associated with speech and language disorders in humans.