网格细胞空间导航神经环路的衰老和退变特征及其预测AD转化的机制

The ability of spatial navigation decreases with aging, severally damages in mild cognitive impairment(MCI) and Alzheimer’s Disease(AD), which performs as getting lost. Therefore, the exploration of neural mechanism of spatial navigation impairment might be the breakthrough point of the pathological mechanism of aging and AD. In rodents, the grid cells in entorhinal cortex and place cells in hippocampal contribute spatial navigation function coordinately. Recent studies indicate that grid cells also exist in entorhinal cortex of human brain, and the spatial navigation task-bold functional MRI based on six-fold rotational symmetry properties of the motion direction response can activate the grid cells neural network in macroscopic scale, while the activation decreases in risk gene carriers, such as APOEε4 or APOEε3/TOMM40 carriers. Our pre-study showed that the spatial navigation impairment is associated with the atrophy of hippocampus and entorhinal cortex, the demyelination of fiber and the disruption of functional connectivity. However, the early changes and the regulatory mechanism of grid-cell spatial navigation neural circuit among different ages and cognitive status are worth further investigating. We will combine gene, behavior, improved grid-cell-activated functional MRI, mediation analysis and advanced algorithm of pattern identification to state the causal mechanism of ‘genetics and aging→ the structure and function of brain→ AD’. At the same time, we hope this study could lay the foundation of mechanism of brain aging and the early-diagnosis of high- AD risk MCI.

空间导航能力随衰老而降低，在轻度认知障碍(MCI)和阿尔茨海默病(AD)中损害逐渐加重，表现为迷路和走失。因而空间导航神经环路的研究可能是阐明衰老和AD病理机制的突破点。大鼠脑中由海马位置细胞和内嗅皮层网格细胞协调完成空间导航，近年来人脑网格细胞研究也取得突破进展，基于运动方向响应的六倍旋转对称特性的任务态功能磁共振(fMRI)可在宏观尺度激活网格细胞，且在APOEε4和APOEε3/TOMM40风险基因携带者中激活减低。我们前期发现衰老、MCI和AD中，空间导航障碍与内嗅皮层/海马的萎缩、纤维脱髓鞘和功能连接破坏有关，但不同年龄和认知状态人群中网格细胞空间导航神经环路的早期改变和调控机制还需深入研究。我们将联合基因、行为、改进的网格细胞激活fMRI和中介分析、模式识别先进算法，阐述“基因和衰老→脑结构和功能→AD”转化的因果机制通路，为探寻脑衰老机制和早期诊断高AD风险MCI奠定基础。

空间导航能力随衰老而降低，在轻度认知障碍(MCI)和阿尔茨海默病(AD)中损害逐渐加重，表现为迷路和走失。因而空间导航神经环路的研究可能是阐明衰老和AD病理机制的突破点。大鼠脑中由海马位置细胞和内嗅皮层网格细胞协调完成空间导航，近年来人脑网格细胞研究也取得突破进展，基于运动方向响应的六倍旋转对称特性的任务态功能磁共振(fMRI)可在宏观尺度激活网格细胞，且在APOEε4和APOEε3/TOMM40风险基因携带者中激活减低。我们前期发现衰老、MCI和AD中，空间导航障碍与内嗅皮层/海马的萎缩、纤维脱髓鞘和功能连接破坏有关，但不同年龄和认知状态人群中网格细胞空间导航神经环路的早期改变和调控机制还需深入研究。本项目中，我们首先成功改进了网格细胞激活的fMRI范式，并在70名年轻健康人数据中进行验证，同时，我们联合基因、行为、改进的网格细胞激活fMRI和中介分析、模式识别先进算法，发现AD风险基因对年轻健康人和衰老及MCI患者的空间导航环路的影响，进一步我们还探究了糖尿病等AD高风险人群的内嗅皮层受损机制，并优化和验证了一些功能磁共振成像算法。总体来说，本项目发现了衰老和MCI患者的“基因和衰老→脑结构和功能→AD”转化的因果机制通路，为探寻脑衰老机制和早期诊断高AD风险MCI奠定了基础。