Effects of optogenetic stimulation of basal forebrain parvalbumin neurons on Alzheimer's disease pathology
Effects of optogenetic stimulation of basal forebrain parvalbumin neurons on Alzheimer's disease pathology
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基底前脑小清蛋白神经元光遗传学刺激对阿尔茨海默病病理学的影响
DOI：
10.1101/2020.04.26.062950
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Wilson C
中科院分区：
文献类型：
--
作者：
Wilson C
神经元活动可以改变阿尔茨海默病的病理学。在小鼠模型中，神经元的过度兴奋可以促进疾病进展，而皮质γ振荡的诱导可以减少淀粉样蛋白负荷并改善认知功能。尽管先前的研究已经通过皮质小白蛋白阳性（PV+）神经元的光遗传学激活或感觉刺激诱导皮质γ振荡，但是仍然不清楚诱导γ振荡的其他方法是否也可以是有益的。我们在基底前脑（BF）中PV+神经元的光遗传学激活增加淀粉样蛋白负荷，而不是减少它。我们通过在5xFAD小鼠的PV+神经元中表达通道视紫红质-2（ChR 2）在BF中应用40 Hz光刺激。在3天内诱导皮质γ振荡1小时后，我们观察到额叶皮质区淀粉样蛋白β42浓度增加，但淀粉样蛋白β40没有增加。淀粉样斑块在内侧前额叶皮质和隔核中积累较多，这两者都是BF PV+神经元的靶点。这些结果表明，皮质γ振荡对阿尔茨海默病病理学的有益影响可以取决于皮质γ振荡的诱导机制。
Neuronal activity can modify Alzheimer’s disease pathology. Overexcitation of neurons can facilitate disease progression whereas the induction of cortical gamma oscillations can reduce amyloid load and improve cognitive functions in mouse models. Although previous studies have induced cortical gamma oscillations by either optogenetic activation of cortical parvalbumin-positive (PV+) neurons or sensory stimuli, it is still unclear whether other approaches to induce gamma oscillations can also be beneficial. Here we show that optogenetic activation of PV+ neurons in the basal forebrain (BF) increases amyloid burden, rather than reducing it. We applied 40 Hz optical stimulation in the BF by expressing channelrhodopsin-2 (ChR2) in PV+ neurons of 5xFAD mice. After 1-h induction of cortical gamma oscillations over three days, we observed the increase in the concentration of amyloid-β42 in the frontal cortical region, but not amyloid-β40. Amyloid plaques were accumulated more in the medial prefrontal cortex and the septal nuclei, both of which are targets of BF PV+ neurons. These results suggest that beneficial effects of cortical gamma oscillations on Alzheimer’s disease pathology can depend on the induction mechanisms of cortical gamma oscillations.