Department of Biochemistry, College of Medicine, Konyang University, 158, Gwanjeodong-ro, Seo-gu, Daejeon 35365, Korea.
Department of Occupational Therapy, Konyang University, 158, Gwanjeodong-ro, Seo-gu, Daejeon 35365, Korea.
Int J Mol Sci. 2019 Aug 16;20(16):3992. doi: 10.3390/ijms20163992.
It is widely known that the degeneration of neural circuits is prominent in the brains of Alzheimer's disease (AD) patients. The reciprocal connectivity of the medial septum (MS) and hippocampus, which constitutes the septo-hippocampo-septal (SHS) loop, is known to be associated with learning and memory. Despite the importance of the reciprocal projections between the MS and hippocampus in AD, the alteration of bidirectional connectivity between two structures has not yet been investigated at the mesoscale level. In this study, we adopted AD animal model, five familial AD mutations (5XFAD) mice, and anterograde and retrograde tracers, BDA and DiI, respectively, to visualize the pathology-related changes in topographical connectivity of the SHS loop in the 5XFAD brain. By comparing 4.5-month-old and 14-month-old 5XFAD mice, we successfully identified key circuit components of the SHS loop altered in 5XFAD brains. Remarkably, the SHS loop began to degenerate in 4.5-month-old 5XFAD mice before the onset of neuronal loss. The impairment of connectivity between the MS and hippocampus was accelerated in 14-month-old 5XFAD mice. These results demonstrate, for the first time, topographical evidence for the degradation of the interconnection between the MS and hippocampus at the mesoscale level in a mouse model of AD. Our results provide structural and functional insights into the interconnectivity of the MS and hippocampus, which will inform the use and development of various therapeutic approaches that target neural circuits for the treatment of AD.
众所周知，神经回路的退化在阿尔茨海默病（AD）患者的大脑中很明显。内侧隔核（MS）和海马体的相互连接构成了隔海马隔（SHS）回路，已知与学习和记忆有关。尽管 MS 和海马体之间的相互投射对 AD 很重要，但两个结构之间双向连接的改变尚未在中尺度水平上进行研究。在这项研究中，我们采用 AD 动物模型，5XFAD 小鼠，以及顺行和逆行示踪剂，BDA 和 DiI，分别可视化 5XFAD 大脑中 SHS 回路拓扑连接的与病理学相关的变化。通过比较 4.5 个月大和 14 个月大的 5XFAD 小鼠，我们成功确定了 5XFAD 大脑中改变的 SHS 回路的关键电路组件。值得注意的是，SHS 回路在神经元丢失之前，在 4.5 个月大的 5XFAD 小鼠中开始退化。在 14 个月大的 5XFAD 小鼠中，MS 和海马体之间的连接损伤加速。这些结果首次在 AD 小鼠模型中提供了 SHS 回路在中尺度水平上的连接退化的拓扑证据。我们的结果为 MS 和海马体的互连提供了结构和功能上的见解，这将为针对 AD 治疗目标神经回路的各种治疗方法的使用和开发提供信息。
