SIRT1 mediates hypoxic postconditioning- and resveratrol-induced protection against functional connectivity deficits after subarachnoid hemorrhage
SIRT1 mediates hypoxic postconditioning- and resveratrol-induced protection against functional connectivity deficits after subarachnoid hemorrhage
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DOI：
10.1177/0271678x221079902
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发表时间：
2022-02-09
影响因子：
6.3
通讯作者：
Zipfel, Gregory J.
中科院分区：
文献类型：
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作者：
Clarke, Julian, V;Brier, Lindsey M.;Zipfel, Gregory J.
功能连接 (FC) 是一种敏感指标，可提供小鼠模型中整个皮层坐标神经活动的读数。我们通过三个关键问题来研究通过血管内穿孔建模的实验性 SAH 的影响，以及后续治疗对 FC 的有效性：1）SAH 的血管内穿孔模型是否会导致 FC 缺陷？ 2) 暴露于低氧条件下是否可以针对这些 FC 缺陷提供保护，如果可以，这种神经血管保护是否是 SIRT1 介导的； 3) 单独使用 SIRT1 激活剂白藜芦醇治疗是否可以预防这些 FC 缺陷？将颅窗粘附在颅骨完整的小鼠上，然后对其进行假手术或 SAH 手术，并且不进行治疗或用缺氧后处理（有或没有 EX527）或白藜芦醇治疗 3 天。 SAH/假手术后 3 天对小鼠进行成像，时间与小鼠主要 SAH 后遗症的发生一致。在这里，我们表明 SAH 的血管内穿孔模型在第 3 天诱导 FC 的全局和网络特异性缺陷，这与小鼠 DCI 的时间范围相对应。低氧调节提供了 SIRT1 介导的保护，以对抗 SAH 后这些网络特异性 FC 缺陷，白藜芦醇治疗也是如此。基于调节的策略为实验性蛛网膜下腔出血提供多方面的神经血管保护。
Functional connectivity (FC) is a sensitive metric that provides a readout of whole cortex coordinate neural activity in a mouse model. We examine the impact of experimental SAH modeled through endovascular perforation, and the effectiveness of subsequent treatment on FC, through three key questions: 1) Does the endovascular perforation model of SAH induce deficits in FC; 2) Does exposure to hypoxic conditioning provide protection against these FC deficits and, if so, is this neurovascular protection SIRT1-mediated; and 3) does treatment with the SIRT1 activator resveratrol alone provide protection against these FC deficits? Cranial windows were adhered on skull-intact mice that were then subjected to either sham or SAH surgery and either left untreated or treated with hypoxic post-conditioning (with or without EX527) or resveratrol for 3 days. Mice were imaged 3 days post-SAH/sham surgery, temporally aligned with the onset of major SAH sequela in mice. Here we show that the endovascular perforation model of SAH induces global and network-specific deficits in FC by day 3, corresponding with the time frame of DCI in mice. Hypoxic conditioning provides SIRT1-mediated protection against these network-specific FC deficits post-SAH, as does treatment with resveratrol. Conditioning-based strategies provide multifaceted neurovascular protection in experimental SAH.