Multi-scale functional connectivity in preclinical models of Parkinson's disease

项目摘要/摘要： 帕金森氏病是一种进行性神经退行性疾病，与显著的运动和 非运动性症状，可追溯到黑质多巴胺神经元的丢失以及广泛的电路 功能障碍延伸到垂死的黑质纹状体束之外。基于成像的生物标记物在 评估帕金森相关的病理变化，但目前的生物标记物在诊断和 预测能力，特别是在疾病的早期阶段，干预将是最有益的。功能性 磁共振成像(FMRI)能够研究大脑的激活，并已被广泛应用于研究 帕金森氏病的全球功能网络变化。然而，标准的功能磁共振成像在其能力方面是有限的 强健地测量疾病的细微变化，部分原因是敏感性和特异性较低；此外， 由于神经元功能和磁共振信号之间的间接联系，对标准功能磁共振成像的解释具有挑战性。 变化。缺乏强有力的直接生物标志物是一个关键的缺口，最终限制了我们理解 潜在的病理变化，以及评估新出现的治疗方法。为了克服这些限制，我们 建议利用先进的多对比功能磁共振成像方法，提供高对比度敏感度，以及 明显的微血管敏感性。通过将这种方法与药理学和化学遗传学相结合 操作，基于fMRI的功能网络和潜在的神经元功能之间的直接联系可以是 推断出来的。更具体地说，该项目旨在a)表征多对比(总血管和微血管) 两个互补的临床前模型中的功能连接网络概括了 帕金森病-进行性PFF联核症模型和急性6-OHDA模型；b)评估 急性和慢性治疗中药物多巴胺调节对功能网络的影响 范例，类似于标准治疗范例；以及c)调查内源性 中缝背侧5-羟色胺能环路和蓝斑去甲肾上腺素能环路的调制 被认为参与了某些非运动性症状--关于使用化学发生学的功能网络 方法：研究方法。这些研究将提供对不同血管上发生的功能网络变化的洞察 规模和通过不同的神经递质群体。与核磁共振相关的生物标记物的研究进展 多巴胺能、5-羟色胺能和去甲肾上腺素能回路的功能和功能障碍也可能为深入了解 帕金森氏症的多面性，导致运动和非运动症状。作为功能性的 脑网络功能障碍在帕金森病中被广泛观察到，这种综合方法将使 帕金森氏病的强健生物标记物的开发 这是当前技术的一个严重缺陷。

PROJECT SUMMARY / ABSTRACT: Parkinson’s disease is a progressive neurodegenerative disorder and is associated with significant motor and non-motor symptoms, traceable to the loss of nigral dopamine neurons in addition to widespread circuit dysfunction extending beyond the dying nigrostriatal tract. Imaging-based biomarkers play a critical role in assessing Parkinson’s-related pathological changes, but current biomarkers are limited in their diagnostic and prognostic ability, particularly in early disease stages when intervention would be most beneficial. Functional magnetic resonance imaging (fMRI) enables the study of brain activation and has been widely used to study global functional network changes in Parkinson’s disease. However, standard fMRI is limited in its ability to robustly measure subtle changes with disease, in part due to low sensitivity and specificity; furthermore, interpretation of standard fMRI is challenging due to the indirect link between neuronal function and MRI signal change. This lack of robust direct biomarkers is a critical gap that ultimately limits our ability to understand the underlying pathological changes, as well as evaluate emerging therapies. To overcome these limitations, we propose to leverage an advanced multi-contrast fMRI method that provides high contrast sensitivity, as well as distinct microvascular sensitivity. By coupling this method with pharmacological and chemogenetic manipulations, a direct link between fMRI-based functional networks and underlying neuronal function can be inferred. More specifically, this project aims to a) characterize multi-contrast (total vascular and microvascular) functional connectivity networks in two complementary preclinical models that recapitulate classic hallmarks of Parkinson’s disease - the progressive PFF synucleinopathy model and the acute 6-OHDA model; b) assess the effect of pharmacological dopamine modulation on functional networks, using both acute and chronic treatment paradigms, analogous to the standard treatment paradigm; and c) investigate the effect of endogenous modulation of the dorsal raphe serotonergic circuit and the locus coeruleus noradrenergic circuit – both of which are proposed to be involved in certain non-motor symptomology – on functional networks using chemogenetic methods. These studies will provide insight into functional network changes that occur over different vascular scales and via different neurotransmitter populations. The development of robust MRI biomarkers that relate to dopaminergic, serotonergic, and noradrenergic circuit function and dysfunction may also provide insight into the multifaceted nature of Parkinson’s disease that contributes to both motor and non-motor symptoms. As functional brain network dysfunction is widely observed in Parkinson’s disease, this integrative approach will enable the development of robust biomarkers of Parkinson’s disease with well-characterized pathophysiological origins, which is a critical shortcoming of current technologies.