利用锰增强磁共振技术多层次研究5XFAD小鼠记忆神经环路和网络功能

Exploring the characteristics of brain function is one of the research hotspots in Alzheimer’s disease, basing on the change of neural activity and network function. Compared with functional MRI in clinics, manganese enhanced magnetic resonance imaging (MEMRI) is an excellent non-invasive tool with more accurate biological information, higher spatial resolution and signal-to-noise ratio, less artifact and influence by anesthesia. Previous studies with MEMRI in 5XFAD mice at early ages (1, 2, 3 and 5-month) have shown that increased signal intensity in the brain regions involved in spatial cognition, including entorhinal cortex and hippocampus, as early as 2-month. In the study, it will be studied the conduction of neuronal circuits by injecting manganese entorhinal cortex and hippocampus under stereotactic instrument. In addition, the abnormalities of memorial network were analyzed with topology structure by MEMRI basing on the water maze and routine state longitudinally. Moreover, the effect of different Aβ pathology on the brain function were studied with immunofluorescence and Western blot in 5XFAD mice. At last, basing on the results, increasing Aβ in entorhinal cortex and hippocampus under stereotactic instrument in wild mice could understand the relationship between Aβ and brain function. Consequently, it could improve the comprehension of the regulation and characteristics of brain function in AD and the relationship with Aβ.

立足脑区神经活动和脑网络功能变化，探索阿尔兹海默症（AD）的脑功能特征已成为研究热点。与临床功能磁共振成像相比，锰增强磁共振（MEMRI）有获取生物信息学准确，空间分辨率和信噪比高，不易变形，不受麻醉药物影响等优势，已用于动物认知功能研究。课题组前期研究对5转基因AD（5XFAD）小鼠MEMRI显示脑区活性的纵向研究，发现2月龄Aβ轻度沉积时，已有海马、内嗅皮层神经活性升高。本项目拟进一步对2月龄小鼠海马、内嗅皮层定向增强，研究5XFAD小鼠记忆环路传导功能的变化。联合水迷宫任务态和日常生化状态MEMRI，构建记忆网络，系统纵向研究其拓扑属性。利用免疫荧光法和蛋白免疫印迹法细化Aβ不同时期病理在记忆网络核心脑区的变化，明确其对5XFAD小鼠脑功能影响。对野生型小鼠内嗅皮层、海马微量注射，提高Aβ相关病理水平，明确其对记忆网络功能的影响。以加深对“AD脑功能变化规律及其与Aβ关系”的理解。

本研究基于阿尔兹海默症的神经环路机制，采用MEMRI等小鼠结构和功能MRI技术，分析其神经环路中脑区机构功能变化，为进一步明确AD模式动物神经环路的动态变化，寻找生物学机制研究切入点提供证据。目前得到了以下结果：1. 5XFAD小鼠Ab病理沉积前期即有记忆功能受损，病程中无明确焦虑抑郁样行为；2. 5XFAD小鼠海马、杏仁核等脑区病程中MEMRI信号持续升高；内嗅皮层活性有升高趋势，随月龄增加而持续存在；5月龄时压后皮层（RSC）、尾壳核（CPu）神经活性显著增强。3. 后嗅皮层和腹外侧前额叶及其相关脑区环路中背侧海马、后嗅皮层等脑区晚期升高，其神经环路连接形式改变，与空间记忆损伤相关。4. 5XFAD小鼠海马的t2值自2月龄起，有明显降低，其中背侧海马的改变早于腹侧海马改变，可能是MEMRI改变病理基础之一。