The Role of Striatal Cholinergic Interneurons in Dystonia

项目总结 对孤立的成人起病肌张力障碍的病理生理学理解有一个根本的差距，这是由于 基因异质性和表型异质性。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有效的治疗方法的关键一步。新出现的证据 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关键作用，包括 生化和网络层面的功能障碍。除了提供共同的治疗靶点外，我们的发现 这可能有利于基因发现和对其他致残的、不太常见的肌张力障碍形式的研究。超过了 从长远来看，研究结果可能会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，这可以导致识别新的治疗干预目标。我们的目标是将 新开发的PET放射性配体[18F]VAT，它对囊泡性乙酰胆碱具有高选择性 转运蛋白，以研究纹状体脑出血。结构和静息状态的功能磁共振将检查 纹状体CHI与不同局灶性肌张力障碍亚型相关脑网络的关系。身份识别 跨肌张力障碍亚型的网络水平变化将提供对常见病理生理学的更好理解 并可能为未来的治疗干预提供评估目标参与度的手段。这个 中心假说是纹状体CHI与人类共同的病理生理机制有关。 孤立的成人起病的局灶性肌张力障碍，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点。这项拟议的研究的基本原理是纹状体CHI可能参与了 A)正常运动控制；b)肌张力障碍动物模型。CHI是自主活动的，并调节基线 纹状体中棘神经元上的突触前抑制音对抗兴奋性皮质驱动，可能通过 黑质纹状体多巴胺能终末上突触前胆碱能受体对多巴胺释放的调节。 他们也接受由小脑传入神经支配的丘脑层内神经元的输入，当 功能障碍可能与肌张力障碍表型有关。因此，CHIS可能与一种常见的致病因素有关 涉及皮质-纹状体-丘脑或小脑-丘脑-纹状体网络的机制。这一假设将是 通过追求三个具体目标进行测试：确定1)纹状体智商功能障碍是否常见 跨孤立肌张力障碍亚型的机制；2)功能性纹状体常见的异常 脑神经网络是孤立的肌张力障碍亚型的基础；3)临床特征与 不同孤立的成人发病灶的CHIS和脑网络功能障碍的标志物 声门困难。这种方法是创新的，因为它使用了综合的多模式成像来研究新型的PET- 测量胆碱能完整性和相关的功能网络。这项拟议的研究意义重大，因为它 有望极大地促进人们对肌张力障碍的理解。最终，这种知识可能会提供关键的 确定和测试新的治疗靶点并更好地了解其他致残形式的肌张力障碍的基本原理。

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.