Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, 510006, China.
South China Normal University-Panyu Central Hospital Joint Laboratory of Translational Medical Research, Panyu Central Hospital, Guangzhou, 511400, China.
Mol Neurobiol. 2022 Nov;59(11):6874-6895. doi: 10.1007/s12035-022-03018-8. Epub 2022 Sep 1.
Stress-induced neuroinflammation is a hallmark of modern society and has been linked to various emotional disorders, including anxiety. However, how microglia-associated neuroinflammation under chronic unpredictable mild stress (CUMS) alters mitochondrial function and subsequent medial prefrontal cortex-hippocampus (mPFC-HIPP) connectivity remains obscure. We speculated that CUMS might induce neuroinflammation, which involves altered mitochondrial protein levels, blockade of neuroinflammation by a microglial modulator, minocycline, protects against CUMS-induced alterations. Mice were exposed to CUMS for 3 weeks and received minocycline (50 mg/kg) intraperitoneally for 7 consecutive days during the 3 week of CUMS. Novelty-suppressed feeding test and contextual anxiety test assessed anxiety-like behavior. Western blotting and immunofluorescent staining were employed to evaluate levels of proteins involved in neuroinflammation and mitochondrial function. In vivo dual-site extracellular recordings of local field potential (LFP) were conducted to evaluate the oscillatory activity and brain connectivity in mPFC-HIPP circuitry. We show that CUMS results in excessive microglial activation accompanied by aberrant levels of mitochondrial proteins, such as ATP-5A and the fission protein, Drp-1, increased oxidative stress indicated by elevated levels of nitrotyrosine, and decreased Nrf-2 levels. Furthermore, CUMS causes downregulation of α1 subunit of GABAR, vesicular GABA transporter (Vgat), and glutamine synthetase (GS), leading to impaired LFP and connectivity of the mPFC-HIPP circuitry. Strikingly, blockage of microglial activation by minocycline ameliorates CUMS-induced aberrant levels of mitochondrial and GABAergic signaling proteins and prevents CUMS-induced anxiety-like behavior in mice. To the end, the study revealed that microglia is critically involved in stress-induced neuroinflammation, which may underlie the molecular mechanism of CUMS-induced anxiety behavior.
应激诱导的神经炎症是现代社会的一个标志，与各种情绪障碍有关，包括焦虑。然而，慢性不可预测轻度应激（CUMS）下小胶质细胞相关的神经炎症如何改变线粒体功能，以及随后的前额叶皮层-海马（mPFC-HIPP）连接仍不清楚。我们推测，CUMS 可能会引起神经炎症，涉及改变线粒体蛋白水平，小胶质细胞调节剂米诺环素阻断神经炎症，可防止 CUMS 引起的改变。小鼠暴露于 CUMS 3 周，并在 CUMS 的 3 周内连续 7 天腹腔内给予米诺环素（50mg/kg）。新奇抑制喂养试验和情境焦虑试验评估焦虑样行为。Western blot 和免疫荧光染色用于评估神经炎症和线粒体功能相关蛋白的水平。在体双部位局部场电位（LFP）记录用于评估 mPFC-HIPP 回路中的振荡活动和脑连接。我们发现，CUMS 导致过度的小胶质细胞激活，伴有线粒体蛋白水平异常，如 ATP-5A 和分裂蛋白 Drp-1，氧化应激增加，硝基酪氨酸水平升高，Nrf-2 水平降低。此外，CUMS 导致 GABAAR 的 α1 亚基、囊泡 GABA 转运体（Vgat）和谷氨酰胺合成酶（GS）下调，导致 LFP 和 mPFC-HIPP 回路的连接受损。引人注目的是，米诺环素阻断小胶质细胞激活可改善 CUMS 引起的线粒体和 GABA 能信号蛋白的异常水平，并防止 CUMS 引起的小鼠焦虑样行为。总之，该研究表明小胶质细胞在应激诱导的神经炎症中起着关键作用，这可能是 CUMS 引起焦虑行为的分子机制。
