Synaptotagmin 4: Role in Vocal Motor Function and Parkinson's Disease.

描述（由申请人提供）：沟通障碍伴随着广泛的发育障碍和成人获得性神经系统疾病。这些缺陷的神经行为遗传基础知之甚少，使治疗具有挑战性，但激励实验研究。鸣禽是揭示人类声音交流的神经基础的有利模型，因为它们与人类在结构和功能上相似，并且能够进行人类不可行的分子，生理和行为操纵。该提案的重点是多巴胺（DA）的关键候选分子，突触结合蛋白4（Syt 4），在基底神经节电路专门学习发声鸣禽模型的调节。在鸣禽和人类基底神经节中，DA调节对行为重要的通路;当多巴胺丢失时，如帕金森病（PD）中发生的那样，发声和非发声运动症状出现。目前尚不清楚介导声音变化的分子途径，必须确定以补救疾病的这一方面。最近的证据表明Syt 4在这些途径中的重要性。我们对Syt 4基因表达的研究表明，它在鸣禽基底神经节的鸣禽专用亚区的水平与歌唱密切相关。来自实验室的生物信息学研究预测，Syt 4与DA途径中的其他基因相互作用，支持学习发声行为。其他发现暗示Syt 4在人类认知专业化，区分我们的物种从其他灵长类动物。因此，我假设多巴胺能调节Syt 4是功能特异性的声音 DA的丧失将Syt 4调节从与发声相关的模式化活动驱动转变为广义的非特异性活动。为了验证这一点，我将首先确定Syt 4是否受到DA的自然波动的调节，这种波动发生在不同社会背景下的发声行为和帕金森样状态下。随后的实验将测试DA的丢失，例如PD中发生的DA的丢失，是否将Syt 4调节切换到非发声区域中发现的调节。这些目标的结果将提供对基底神经节中分子机制的深入了解，以支持鸣禽和潜在人类的发声行为，并有望成为治疗发声障碍的新治疗靶点。 公共卫生相关性：沟通障碍是一系列发育障碍（如自闭症）和成人获得性神经系统疾病（如帕金森氏症）的一个衰弱组成部分，对心理健康有额外的负面影响。语言缺陷的神经和遗传基础尚不清楚。我的提议使用了一种有利的动物模型，即学习发声的鸣禽，来测试与鸟鸣相关的基因Synaptotagmin 4是否在正常发声的大脑通路中很重要，以及它是否在帕金森病样状态下受到错误调节。

DESCRIPTION (provided by applicant): Communication deficits accompany a wide array of developmental disorders and adult-acquired neurological diseases. The neurobehavioral genetic bases for these deficits are poorly understood, rendering treatment challenging yet motivating experimental investigation. Songbirds are advantageous models for uncovering the neural basis for human vocal communication given their structural and functional similarities to humans and the ability to conduct molecular, physiological, and behavioral manipulations not feasible in humans. This proposal focuses on dopaminergic (DA) regulation of a key candidate molecule, Synaptotagmin 4 (Syt4), in basal ganglia circuitry dedicated to learned vocalizations using the songbird model. In both songbird and human basal ganglia, DA regulates pathways important for behavior; when dopamine is lost as occurs in Parkinson's Disease (PD), vocal and non-vocal motor symptoms arise. The molecular pathways that mediate the vocal changes, currently unknown, must be determined in order to remediate this facet of the disease. Recent converging evidence highlights the importance of Syt4 in these pathways. Our studies on Syt4 gene expression show that its levels within the song-dedicated sub-region of the songbird basal ganglia are tightly linked to singing. Bioinformatic studies from the lab predict that Syt4 interacs with other genes in a DA pathway supporting learned vocal behavior. Additional findings implicate Syt4 in human cognitive specializations that distinguish our species from other primates. I thus hypothesize that dopaminergic regulation of Syt4 is functionally specific to vocal pathways, and that loss of DA converts Syt4 regulation from being driven by patterned activity associated with vocalizing to generalized non-specific activity. To test this, I will first determie whether Syt4 is regulated by natural fluctuations in DA that occur during vocal behavior under different social contexts and in a Parkinsonian-like state. Follow up experiments will then test whether loss of DA, such as occurs in PD, switches Syt 4 regulation to that found in non-vocal areas. Results from these aims will provide insight into molecular mechanisms operating in the basal ganglia to support vocal behavior in songbirds and potentially, humans, with the promise of new therapeutic targets to treat vocal disorders. PUBLIC HEALTH RELEVANCE: Communication deficits are a debilitating component in a wide range of developmental disorders (e.g. Autism Spectrum) and adult-acquired neurological diseases (e.g. Parkinson's) with additional negative effects on mental health. The neural and genetic bases for speech deficits are not well-understood. My proposal uses an advantageous animal model for speech, the vocal-learning songbird, to test whether a gene that is linked to birdsong, Synaptotagmin 4, is important in brain pathways for normal vocalization and whether it becomes misregulated in a Parkinsonian-like state.