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

描述（由申请人提供）：沟通缺陷伴随着一系列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，因为它们的结构和功能与人类相似，并且能够进行在人类中不可行的分子，生理和行为操作。本研究的重点是多巴胺能（DA）对一个关键候选分子Synaptotagmin 4 （Syt4）的调节，该分子在基底节区回路中致力于使用鸣禽模型学习发声。在鸣禽和人类基底神经节中，DA调节对行为重要的通路；当多巴胺像帕金森病（PD）那样丢失时，会出现声音和非声音运动症状。介导声音变化的分子途径，目前尚不清楚，必须确定，以纠正这方面的疾病。最近越来越多的证据强调了sy4在这些途径中的重要性。我们对Syt4基因表达的研究表明，它在鸣禽基底神经节歌唱专用亚区域内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，Syt4在支持习得发声行为的DA通路中与其他基因相互作用。其他的研究结果表明，Syt4在人类认知特化中起着区别于其他灵长类动物的作用。因此，我假设sy4的多巴胺能调节是语音功能特异性的

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.