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

Synaptotagmin 4：在发声运动功能和帕金森病中的作用。

• 批准号: 8445955
• 负责人: Julie Elizabeth Miller
• 金额: $ 7.7万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445955
• 关键词: Adult; Affect; Animal Model; Area; Autistic Disorder; Awareness; Basal Ganglia; Behavior; Behavior Control; Behavioral; Bioinformatics; Cognitive; Communication; Communication impairment; Development; Disease; Dopamine; Gene Expression; Gene Mutation; Genes; Genetic; Human; Indium; Individual; Investigation; Lead; Learning; Link; Maintenance; Measures; Mediating; Mental Depression; Mental Health; Messenger RNA; Metrazole; Modeling; Molecular; Motor; Motor output; Neurotoxins; Oxidopamine; Parkinson Disease; Parkinsonian Disorders; Pathway Analysis; Pathway interactions; Pattern; Performance; Physiological; Play; Primates; Public Health; Refractory; Regulation; Research; Rewards; Role; Seizures; Social Environment; Social isolation; Solutions; Songbirds; Speech; Stuttering; Symptoms; System; Techniques; Testing; Verbal Dyspraxia; Voice; Weight; Work; autism spectrum disorder; base; bird song; brain pathway; developmental disease; follow-up; gene therapy; improved; insight; mRNA Expression; nervous system disorder; neurobehavioral; neurobiological mechanism; neurogenetics; neuromechanism; neuroregulation; new therapeutic target; novel; programs; relating to nervous system; research study; social; synaptotagmin IV; trait; vocal learning; vocalization; zebra finch

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.

描述（由申请人提供）：沟通障碍伴随着多种发育障碍和成人获得性神经系统疾病。人们对这些缺陷的神经行为遗传基础知之甚少，这使得治疗具有挑战性，但也激发了实验研究的兴趣。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，并且具有进行人类不可行的分子、生理和行为操作的能力。该提案重点关注基底神经节电路中关键候选分子 Synaptotagmin 4 (Syt4) 的多巴胺能 (DA) 调节，该电路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；当帕金森病 (PD) 中多巴胺丢失时，就会出现发声和非发声运动症状。目前尚不清楚介导声音变化的分子途径，为了治疗该疾病的这一方面，必须确定。最近的一致证据强调了 Syt4 在这些途径中的重要性。我们对 Syt4 基因表达的研究表明，其在鸣禽基底神经节专门鸣叫的亚区域内的水平与歌唱紧密相关。实验室的生物信息学研究预测 Syt4 与 DA 通路中的其他基因相互作用，支持习得的发声行为。其他发现表明 Syt4 与人类认知特化有关，这些特化将我们的物种与其他灵长类动物区分开来。因此我推测 Syt4 的多巴胺能调节在功能上是针对发声的 DA 的缺失将 Syt4 调节从与发声相关的模式活动驱动转变为广义的非特异性活动。为了测试这一点，我将首先确定 Syt4 是否受到 DA 自然波动的调节，这种波动在不同社会背景下和帕金森样状态下的发声行为中发生。后续实验将测试 DA 的丧失（例如 PD 中发生的情况）是否会将 Syt 4 调节切换到非发声区域的调节。这些目标的结果将深入了解基底神经节中运作的分子机制，以支持鸣禽甚至人类的发声行为，并有望为治疗发声疾病提供新的治疗靶点。 公共健康相关性：沟通缺陷是多种发育障碍（例如自闭症谱系）和成人获得性神经系统疾病（例如帕金森病）的一个令人衰弱的组成部分，并对心理健康产生额外的负面影响。言语缺陷的神经和遗传基础尚不清楚。我的建议使用一种有利的语言动物模型，即学习声音的鸣禽，来测试与鸟鸣相关的基因 Synaptotagmin 4 在正常发声的大脑通路中是否重要，以及在帕金森样状态下是否会出现失调。