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

描述(申请人提供)：沟通障碍伴随一系列发育障碍和成人获得性神经疾病。这些缺陷的神经行为遗传学基础还知之甚少，这使得治疗具有挑战性，但也激发了实验研究。鸣禽是揭示人类发声交流神经基础的有利模型，因为它们在结构和功能上与人类相似，而且进行分子、生理和行为操作的能力在人类身上是不可行的。这项建议的重点是多巴胺(DA)调节一个关键的候选分子，突触素4(Syt4)，在基础神经节回路专门用于学习发声使用鸣禽模型。在鸣禽和人类的基底节中，DA调节对行为重要的通路；当多巴胺丢失时，就会出现发声和非发声的运动症状，就像帕金森病(PD)一样。目前尚不清楚的是，调节发声改变的分子途径必须被确定，以补救疾病的这一方面。最近越来越多的证据表明了Syt4在这些途径中的重要性。我们对Syt4基因表达的研究表明，在鸣禽基底节的鸣叫专用亚区中，Syt4基因的水平与鸣叫密切相关。该实验室的生物信息学研究预测，Syt4与支持获得性发声行为的DA途径中的其他基因相互作用。更多的发现表明，Syt4与人类的认知特化有关，这种特化将我们物种与其他灵长类区分开来。因此，我假设Syt4的多巴胺能调节在功能上是声带特有的。 DA的缺失将Syt4的调节从与发声相关的模式活动转换为一般性的非特异性活动。为了测试这一点，我将首先确定Syt4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中，以及在类似帕金森的状态下。然后，后续实验将测试DA的丢失，如帕金森氏症，是否会将SYT4调节切换到非发声区域。这些目标的结果将为深入了解在基底节工作的分子机制，以支持鸣禽的发声行为，并有望为治疗发声障碍提供新的治疗靶点。 公共卫生相关性：沟通障碍是一系列发育障碍(如自闭症谱系障碍)和成人获得性神经疾病(如帕金森氏症)的衰弱因素，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还没有得到很好的理解。我的建议使用了一种有利的语音动物模型--发声学习鸣禽--来测试与鸟鸣相关的基因--synaptopagmin 4--是否在正常发声的大脑通路中发挥重要作用，以及在帕金森氏症患者的状态下，它是否会变得失控。

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.