■控制认知过程的神经回路受损与阿尔茨海默病和相关疾病(ADRD)的病理生理学有关。然而,目前还不清楚ADRD中具体更改了哪些电路,特别是在早期阶段。
■我们的研究目标是揭示内嗅皮层(EC)回路的功能变化,大脑皮层和海马体之间的界面,在AD。
■电生理,光遗传学和化学遗传学方法用于检查和操纵淀粉样β家族性AD模型(5×FAD)和tau蛋白病模型(P301STau)中的内嗅皮层回路。
■我们发现,与野生型小鼠相比,EC的电刺激在5×FAD小鼠(6月龄)的下膜(海马输出)中引起明显较小的反应,表明在此AD模型中,EC到下膜回路中的突触通讯被特别阻断。此外,来自前额叶皮质(PFC)的谷氨酸能末端的光遗传学刺激在5×FAD和P301STau小鼠(6月龄)的EC中引起较小的反应,这表明在两种ADRD模型中PFC到EC通路中的突触通信都受到损害。在5×FAD小鼠中,PFC对EC途径的化学活化不影响EC神经元的爆发活性,但部分恢复了P301STau小鼠EC神经元活动的减少。
■这些数据表明,5×FAD小鼠具有特定的短程海马通道(EC至下丘)损伤,这可能是由淀粉样蛋白-β沉积引起的;而两种ADRD模型对长程皮质至海马回路(PFC至EC)有共同的损害,这可能是由基于微管/tau的运输缺陷引起的。这些回路缺陷为ADRD条件下各种认知过程的独特和常见损伤提供了病理生理学基础。
UNASSIGNED: The impairment of neural circuits controlling cognitive processes has been implicated in the pathophysiology of Alzheimer\'s disease and related disorders (ADRD). However, it is largely unclear what circuits are specifically changed in ADRD, particularly at the early stage.
UNASSIGNED: Our goal of this study is to reveal the functional changes in the circuit of entorhinal cortex (EC), an interface between neocortex and hippocampus, in AD.
UNASSIGNED: Electrophysiological, optogenetic and chemogenetic approaches were used to examine and manipulate entorhinal cortical circuits in amyloid-β familial AD model (5×FAD) and tauopathy model (P301S Tau).
UNASSIGNED: We found that, compared to wild-type mice, electrical stimulation of EC induced markedly smaller responses in
subiculum (hippocampal output) of 5×FAD mice (6-month-old), suggesting that synaptic communication in the EC to
subiculum circuit is specifically blocked in this AD model. In addition, optogenetic stimulation of glutamatergic terminals from prefrontal cortex (PFC) induced smaller responses in EC of 5×FAD and P301S Tau mice (6-month-old), suggesting that synaptic communication in the PFC to EC pathway is compromised in both ADRD models. Chemogenetic activation of PFC to EC pathway did not affect the bursting activity of EC neurons in 5×FAD mice, but partially restored the diminished EC neuronal activity in P301S Tau mice.
UNASSIGNED: These data suggest that 5×FAD mice has a specific impairment of short-range hippocampal gateway (EC to
subiculum), which may be caused by amyloid-β deposits; while two ADRD models have a common impairment of long-range cortical to hippocampal circuit (PFC to EC), which may be caused by microtubule/tau-based transport deficits. These circuit deficits provide a pathophysiological basis for unique and common impairments of various cognitive processes in ADRD conditions.