The Role of Striatal Cholinergic Interneurons in Dystonia

纹状体胆碱能中间神经元在肌张力障碍中的作用

基本信息

批准号：
10543837
负责人：
Scott Allen Norris
金额：
$ 61.69万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10543837
关键词：
Address Adult Adult-Onset Dystonias Affect Age Analysis of Variance Animal Model Binding Biochemical Blepharospasm Body Regions Brain Brain region Cerebellum Cervical Characteristics Cholinergic Receptors Clinical Control Groups Corpus striatum structure Data Development Disease Dopamine Drug Targeting Dystonia Employment Status Focal Dystonias Functional Magnetic Resonance Imaging Functional disorder Future Genotype Goals Heterogeneity Human Interneuron function Interneurons Knowledge Larynx Limb Dystonia Magnetic Resonance Imaging Measurement Measures Mediating Methods Mission Modeling Molecular Multimodal Imaging Muscle Neurons Neurotransmitters Participant Pathogenicity Pathway interactions Persons Pharmaceutical Preparations Phenotype Play Positron-Emission Tomography Public Health Quality of life Research Research Personnel Research Priority Rest Role Severities Signal Transduction Subgroup System Testing Thalamic structure Therapeutic Intervention Translating United States National Institutes of Health Upper Extremity acetylcholine transporter cholinergic comparison control comparison group disability effective therapy gene discovery in vivo innovation interest motor control network dysfunction neuroimaging neuroimaging marker new therapeutic target novel presynaptic radioligand regional difference sex symptomatic improvement therapeutic target uptake

项目摘要

PROJECT SUMMARY There is a fundamental gap in understanding the pathophysiology of isolated adult-onset dystonia due to genotypic and phenotypic heterogeneity. Determining common pathophysiologic mechanisms across dystonia subtypes is a critical step toward developing more generalizable and effective therapies. Emerging evidence points to striatal cholinergic interneurons (ChIs) playing a key role in the pathophysiology of dystonia, including biochemical and network-level dysfunction. In addition to offering a common therapeutic target, our findings are likely to benefit gene discovery and research on other disabling, less common forms of dystonia. Over the long term, results could guide researchers to perform greater in depth histopathological and biochemical studies in the brain that can lead to identification of new targets for therapeutic intervention. Our goal is to apply a recently developed PET radioligand, [18F]VAT, which possesses high selectivity for vesicular acetylcholine transporters, to investigate striatal ChIs. Structural and resting state functional MRI will examine the relationship of striatal ChIs to related brain networks across different focal dystonia subtypes. Identification of network-level changes across dystonia subtypes will provide better understanding of common pathophysiology and could potentially provide means to assess target engagement for future therapeutic interventions. The central hypothesis is that striatal ChIs contribute to a common pathophysiological mechanism in humans with isolated adult-onset focal dystonia, and that cholinergic integrity relates to striatal functional connectivity and clinical features of dystonia. The rationale for the proposed research is the likely involvement of striatal ChIs in a) normal motor control and b) animal models of dystonia. ChIs are autonomously active and mediate a baseline presynaptic inhibitory tone on striatal medium spiny neurons against the excitatory cortical drive, likely via modulation of dopamine release via presynaptic cholinergic receptors on nigrostriatal dopaminergic terminals. They also receive input from intralaminar thalamic neurons innervated by cerebellar afferents, that when dysfunctional may contribute to dystonic phenotypes. Thus, ChIs may contribute to a common pathogenic mechanism involving cortico-striata-thalamic or cerebello-thalamo-striatal networks. This hypothesis will be tested by pursuing three specific aims: Determine if 1) dysfunction of striatal ChIs is a common mechanism across isolated dystonia subtypes; 2) common aberrations in functional striatal brain networks underlie the isolated dystonia subtypes; 3) clinical characteristics relate to markers of ChIs and brain network dysfunction across different isolated adult-onset focal dystonias. This approach is innovative as it uses comprehensive multimodal imaging to investigate novel PET- measured cholinergic integrity and related functional networks. The proposed research is significant because it is expected to critically advance the understanding of dystonia. Ultimately, such knowledge may provide critical rationale to identify and test new therapeutic targets and better understand other disabling forms of dystonia.

项目概要由于以下原因，对孤立性成人发病的肌张力障碍的病理生理学的理解存在根本性的差距：基因型和表型异质性。确定肌张力障碍的常见病理生理机制亚型是开发更普遍和更有效的疗法的关键一步。新出现的证据指出纹状体胆碱能中间神经元 (ChIs) 在肌张力障碍的病理生理学中发挥着关键作用，包括生化和网络水平功能障碍。除了提供共同的治疗目标之外，我们的研究结果可能有利于基因发现和其他致残、不太常见形式的肌张力障碍的研究。超过从长远来看，结果可以指导研究人员进行更深入的组织病理学和生化研究在大脑中，可以识别治疗干预的新目标。我们的目标是应用一个最近开发的PET放射性配体[18F]VAT，对囊泡乙酰胆碱具有高选择性转运蛋白，以研究纹状体 ChI。结构和静息状态功能 MRI 将检查不同局灶性肌张力障碍亚型纹状体 ChIs 与相关大脑网络的关系。鉴定肌张力障碍亚型之间的网络水平变化将有助于更好地理解常见的病理生理学并有可能提供评估未来治疗干预目标参与度的方法。这中心假设是纹状体 ChIs 有助于人类常见的病理生理机制孤立的成人发病的局灶性肌张力障碍，胆碱能完整性与纹状体功能连接和肌张力障碍的临床特征。拟议研究的基本原理是纹状体 ChIs 可能参与 a) 正常运动控制和 b) 肌张力障碍动物模型。 ChI 自主活跃并调节基线纹状体中型多棘神经元的突触前抑制音对抗兴奋性皮质驱动，可能通过通过黑质纹状体多巴胺能末端的突触前胆碱能受体调节多巴胺释放。它们还接收来自小脑传入神经支配的层内丘脑神经元的输入，当功能失调可能导致肌张力障碍表型。因此，ChI 可能导致一种常见的致病性涉及皮质-纹状体-丘脑或小脑-丘脑-纹状体网络的机制。这个假设将是通过追求三个特定目标进行测试：确定 1) 纹状体 ChI 功能障碍是否是一种常见现象跨孤立肌张力障碍亚型的机制； 2）功能纹状体的常见畸变大脑网络是孤立的肌张力障碍亚型的基础； 3) 临床特征相关不同孤立的成人发病病灶的 ChIs 和脑网络功能障碍的标志物肌张力障碍。这种方法具有创新性，因为它使用全面的多模态成像来研究新型 PET- 测量胆碱能完整性和相关功能网络。拟议的研究意义重大，因为它预计将极大地增进对肌张力障碍的理解。最终，这些知识可能提供关键的确定和测试新的治疗靶点并更好地了解肌张力障碍的其他致残形式的基本原理。