Evolution of aberrant brain-wide spatiotemporal dynamics of resting-state networks in a Huntington's disease mouse model

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2024-10-18 DOI:10.1002/ctm2.70055

Tamara Vasilkovska, Marlies Verschuuren, Dorian Pustina, Monica van den Berg, Johan Van Audekerke, Isabel Pintelon, Roger Cachope, Winnok H. De Vos, Annemie Van der Linden, Mohit H. Adhikari, Marleen Verhoye

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引用次数: 0

Abstract

Background

Huntington's disease (HD) is marked by irreversible loss of neuronal function for which currently no availability for disease-modifying treatment exists. Advances in the understanding of disease progression can aid biomarker development, which in turn can accelerate therapeutic discovery.

Methods

We characterised the progression of altered dynamics of whole-brain network states in the zQ175DN mouse model of HD using a dynamic functional connectivity (FC) approach to resting-state fMRI and identified quasi-periodic patterns (QPPs) of brain activity constituting the most prominent resting-state networks.

Results

The occurrence of the normative QPPs, as observed in healthy controls, was reduced in the HD model as the phenotype progressed. This uncovered progressive cessation of synchronous brain activity with phenotypic progression, which is not observed with the conventional static FC approaches. To better understand the potential underlying cause of the observed changes in these brain states, we further assessed how mutant huntingtin (mHTT) protein deposition affects astrocytes and pericytes – one of the most important effectors of neurovascular coupling, along phenotypic progression. Increased cell-type dependent mHTT deposition was observed at the age of onset of motor anomalies, in the caudate putamen, somatosensory and motor cortex, regions that are prominently involved in HD pathology as seen in humans.

Conclusion

Our findings provide meaningful insights into the development and progression of altered functional brain dynamics in this HD model and open new avenues in assessing the dynamics of whole brain states, through QPPs, in clinical HD research.

Highlights

Hyperactivity in the LCN-linked regions within short QPPs observed before motor impairment onset.
DMLN QPP presents a progressive decrease in DMLN activity and occurrence along HD-like phenotype development.
Breakdown of the LCN DMLN state flux at motor onset leads to a subsequent absence of the LCN DMLN QPP at an advanced HD-like stage.

查看原文本刊更多论文

亨廷顿氏病小鼠模型全脑静息态网络时空动态的异常演变

背景亨廷顿舞蹈症（Huntington's disease，HD）以不可逆转的神经元功能丧失为特征，目前尚无可改变病情的治疗方法。对疾病进展的进一步了解有助于生物标志物的开发，进而加快治疗方法的发现。方法我们使用动态功能连接（FC）方法对静息态 fMRI 进行研究，确定了构成最突出静息态网络的大脑活动准周期模式（QPPs），从而描述了 zQ175DN HD 小鼠模型中全脑网络状态动态改变的进展。结果在健康对照组中观察到的标准 QPPs 在 HD 模型中随着表型的进展而减少。这揭示了随着表型的发展，大脑同步活动逐渐停止，而传统的静态 FC 方法却观察不到这一点。为了更好地了解观察到的这些大脑状态变化的潜在根本原因，我们进一步评估了突变型亨廷汀（mHTT）蛋白沉积如何随着表型进展影响星形胶质细胞和周细胞--神经血管耦合的最重要效应因子之一。在尾状核、躯体感觉皮层和运动皮层运动异常的发病年龄段，观察到了细胞类型依赖性 mHTT 沉积的增加，而这些区域正是人类 HD 病理学的主要涉及区域。结论我们的研究结果为了解这种 HD 模型中大脑功能动态变化的发展和进程提供了有意义的见解，并为在临床 HD 研究中通过 QPP 评估整个大脑状态的动态变化开辟了新的途径。研究亮点在运动障碍发生之前，在短QPP内观察到LCN连接区域的过度活跃。 DMLN QPP 随着 HD 类表型的发展，DMLN 活性和发生率逐渐降低。在运动障碍发病时，LCN DMLN 状态通量的破坏导致随后在类似 HD 的晚期阶段 LCN DMLN QPP 的缺失。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.