脑小血管病默认网络-海马神经环路失连接引起混合性痴呆的机制研究

脑小血管病（CSVD）是一组由小血管病变引起的脑实质损伤综合征，是血管性认知障碍的主因。然而，绝大多数CSVD患者同时伴有阿尔茨海默病（AD）病理改变，最终进展为混合性痴呆。文献报道默认网络-海马神经环路对记忆的形成有重要作用，也是AD的主要靶点。我们前期研究发现，CSVD患者存在默认网络内部激活降低且与控制网络失连接。但是控制网络通过默认网络对海马的调控机制尚未明确。因此，本项目将采用CSVD小鼠模型（慢性缺血造模）、AD小鼠模型（APP/PS1）及混合模型，联合9.4T磁共振（DTI、fMRI）和化学遗传学在体调控神经活动，研究抑制默认网络、激活控制网络后小鼠海马的功能连接改变，并进一步研究持续抑制默认网络后小鼠海马Aβ病理改变，及其与神经电生理和认知行为学的关系。研究结果将加深理解CSVD引起AD病理改变的机制，为临床筛查存在混合性痴呆风险的CSVD患者提供关键靶点及理论基础。

Cerebral small vessel disease (CSVD) refers to a group of pathological processes that affect the small arteries and microvessels of the brain. It is the major contributor to vascular cognitive impairment. However, the high prevalence of mixed cerebrovascular and Alzheimer disease (AD) pathology result in severely increased risk of mixed dementias in patients with CSVD. Default mode network (DMN) and hippocampus, both are crucial for memory formation, are major sites of AD pathology. Decreased intra and inter network connectivity of DMN and executive control network (ECN), based on our previous study, are pervasive in patients with CSVD. However, whether ECN modulate hippocampal activity via DMN remain unclear. Therefore, this study intend to use a CSVD mouse model (BCAS mice), an AD mouse model (APP/PS1 mice) and a hybrid model (BCAS+APP/PS1) to investigate the effect of DMN deactivation and ECN activation on hippocampal activities and hippocampal Aβ accumulation by combining chemogenetic modulations with resting-state fMRI. Furthermore, to investigate the effect of continuous DMN deactivation on hippocampal activities and its relationship to behavioral and electrophysiological changes. In summary, this study may provide insights on the AD-like pathogenesis in CSVD and to identify novel imaging markers for the detection and prevention of mixed dementias.