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.

项目摘要理解由于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具普遍和有效疗法的关键一步。新兴证据指出纹状体胆碱能中间神经元（CHI）在肌张力障碍的病理生理学中起着关键作用，包括生化和网络级功能障碍。除了提供常见的治疗靶点外，我们的发现对于其他残疾，不常见的肌张力障碍形式的基因发现和研究可能会受益。在长期，结果可以指导研究人员在深度组织病理学和生化研究中执行更大的作用在大脑中，可以鉴定出新的治疗干预靶标。我们的目标是应用最近开发的PET放射性物体[18F]增值税，其对囊泡乙酰胆碱具有很高的选择性转运蛋白，研究纹状体CHI。结构和静止状态功能MRI将检查纹状体CHI与不同局灶性肌张力障碍亚型的相关大脑网络的关系。识别肌张力障碍子类型的网络级变化将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措施的目标参与的手段。这中心假设是纹状体CHI有助于人类的常见病理生理机制孤立的成年局灶性肌张力障碍，胆碱能完整性与纹状体功能连通性和肌张力障碍的临床特征。拟议的研究的理由是纹状体CHI可能参与 a）正常运动控制和b）肌张力障碍动物模型。 CHI是自主活动的，并介导基线纹状体培养基神经元对兴奋性皮质驱动的纹状体介质神经元上的突触前抑制性张力，可能通过通过突触前胆碱能受体对多巴胺能量释放的调节，对骨纹状体多巴胺能末端进行调节。他们还收到小脑传入的腔内丘脑神经元的输入，功能障碍可能导致肌张力型表型。因此，CHI可能有助于常见的致病性涉及皮质 - 纹状体 - 丘脑或小脑 - thalamo-纹状体网络的机制。这个假设将是通过追求三个特定目标测试：确定1）纹状体CHI的功能障碍是常见的分离的肌张力障碍亚型的机制； 2）功能性纹状体的常见畸变脑网络是孤立的肌张力障碍亚型的基础； 3）临床特征与 CHIS和大脑网络功能障碍的标记跨不同的孤立成人发行焦点肌张力障碍。这种方法具有创新性，因为它使用全面的多模式成像来研究新型PET- 测量的胆碱能完整性和相关的功能网络。拟议的研究很重要，因为它预计将严格提高对肌张力障碍的理解。最终，这些知识可能会提供关键识别和测试新的治疗靶标并更好地了解其他残疾肌张力障碍形式的理由。