Gamma Visual Stimulation Induces a Neuroimmune Signaling Profile Distinct from Acute Neuroinflammation
Gamma Visual Stimulation Induces a Neuroimmune Signaling Profile Distinct from Acute Neuroinflammation
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DOI：
10.1523/jneurosci.1511-19.2019
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发表时间：
2020-02-05
影响因子：
5.3
通讯作者：
Singer, Annabelle C.
中科院分区：
文献类型：
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作者：
Garza, Kristie M.;Zhang, Lu;Singer, Annabelle C.
许多神经退行性疾病和神经系统疾病的根源在于神经免疫系统的功能障碍;因此，操纵该系统具有很强的治疗潜力。先前的研究表明，将小鼠暴露在40 Hz的闪烁灯光下会驱动伽马频率（类似于40 Hz）的神经活动，并招募小胶质细胞（大脑的主要免疫细胞），揭示了一种操纵神经免疫系统的新方法。然而，40 Hz神经活动和免疫募集之间的生化信号机制仍然未知。在这里，我们将野生型雄性小鼠暴露于5-60分钟的40 Hz或对照闪烁，并评估已知在免疫功能中发挥作用的细胞因子和磷蛋白网络。我们发现，40 Hz闪烁导致细胞因子的表达增加，促进小胶质细胞吞噬状态，如IL-6和IL-4，和小胶质细胞趋化因子的表达增加，如巨噬细胞集落刺激因子和干扰素-γ诱导的单核细胞因子。有趣的是，细胞因子的作用作为刺激频率的函数而不同，揭示了刺激的一系列神经免疫作用。为了确定潜在的细胞因子表达的可能机制，我们量化了闪烁对已知调节细胞因子水平的细胞内信号传导途径的影响。我们发现，40 Hz的闪烁上调活化B细胞核因子κ轻链增强子（NF-κ B）和丝裂原活化蛋白激酶（MAPK）通路内的磷酸化信号。虽然细胞因子的表达增加后1小时的40赫兹闪烁刺激，在NF-κ B途径中的蛋白磷酸化在几分钟内上调。重要的是，由40 Hz闪烁诱导的细胞因子表达谱与响应于由脂多糖诱导的急性神经炎症的细胞因子变化不同。据我们所知，这些结果是第一个显示视觉刺激如何在健康动物中快速诱导关键神经免疫信号的结果。
Many neurodegenerative and neurological diseases are rooted in dysfunction of the neuroimmune system; therefore, manipulating this system has strong therapeutic potential. Prior work has shown that exposing mice to flickering lights at 40 Hz drives gamma frequency (similar to 40 Hz) neural activity and recruits microglia, the primary immune cells of the brain, revealing a novel method to manipulate the neuroimmune system. However, the biochemical signaling mechanisms between 40 Hz neural activity and immune recruitment remain unknown. Here, we exposed wild-type male mice to 5-60 min of 40 Hz or control flicker and assessed cytokine and phosphoprotein networks known to play a role in immune function. We found that 40 Hz flicker leads to increases in the expression of cytokines which promote microglial phagocytic states, such as IL-6 and IL-4, and increased expression of microglial chemokines, such as macrophage-colony-stimulating factor and monokine induced by interferon-gamma. Interestingly, cytokine effects differed as a function of stimulation frequency, revealing a range of neuroimmune effects of stimulation. To identify possible mechanisms underlying cytokine expression, we quantified the effect of the flicker on intracellular signaling pathways known to regulate cytokine levels. We found that a 40 Hz flicker upregulates phospho-signaling within the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) and mitogen-activated protein kinase (MAPK) pathways. While cytokine expression increased after 1 h of 40Hz flicker stimulation, protein phosphorylation in the NF-kappa B pathway was upregulated within minutes. Importantly, the cytokine expression profile induced by 40 Hz flicker was different from cytokine changes in response to acute neuroinflammation induced by lipopolysaccharides. These results are the first, to our knowledge, to show how visual stimulation rapidly induces critical neuroimmune signaling in healthy animals.