Focused ultrasound (FUS) mediated blood–brain barrier disruption (BBBD) targets the delivery of systemically‐administered therapeutics to the central nervous system. Preclinical investigations of BBBD have been performed on different anesthetic backgrounds; however, the influence of the choice of anesthetic on the molecular response to BBBD is unknown, despite its potential to critically affect interpretation of experimental therapeutic outcomes. Here, using bulk RNA sequencing, we comprehensively examined the transcriptomic response of both normal brain tissue and brain tissue exposed to FUS‐induced BBBD in mice anesthetized with either isoflurane with medical air (Iso) or ketamine/dexmedetomidine (KD). In normal murine brain tissue, Iso alone elicited minimal differential gene expression (DGE) and repressed pathways associated with neuronal signaling. KD alone, however, led to massive DGE and enrichment of pathways associated with protein synthesis. In brain tissue exposed to BBBD (1 MHz, 0.5 Hz pulse repetition frequency, 0.4 MPa peak‐negative pressure), we systematically evaluated the relative effects of anesthesia, microbubbles, and FUS on the transcriptome. Of particular interest, we observed that gene sets associated with sterile inflammatory responses and cell–cell junctional activity were induced by BBBD, regardless of the choice of anesthesia. Meanwhile, gene sets associated with metabolism, platelet activity, tissue repair, and signaling pathways, were differentially affected by BBBD, with a strong dependence on the anesthetic. We conclude that the underlying transcriptomic response to FUS‐mediated BBBD may be powerfully influenced by anesthesia. These findings raise considerations for the translation of FUS‐BBBD delivery approaches that impact, in particular, metabolism, tissue repair, and intracellular signaling.

中文翻译：

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脑组织对聚焦超声介导的血脑屏障破坏的转录组反应很大程度上取决于麻醉


聚焦超声（FUS）介导的血脑屏障破坏（BBBD）的目标是向中枢神经系统输送全身治疗药物。 BBBD 的临床前研究是在不同的麻醉背景下进行的；然而，麻醉剂的选择对 BBBD 分子反应的影响尚不清楚，尽管它可能严重影响实验治疗结果的解释。在这里，我们使用批量 RNA 测序，全面检查了使用异氟烷医用空气 (Iso) 或氯胺酮/右美托咪定 (KD) 麻醉的小鼠中正常脑组织和暴露于 FUS 诱导的 BBBD 的脑组织的转录组反应。在正常小鼠脑组织中，单独的 Iso 会引发最小差异基因表达 (DGE) 并抑制与神经元信号传导相关的通路。然而，单独的 KD 会导致大量的 DGE 和与蛋白质合成相关的途径的富集。在暴露于 BBBD（1 MHz、0.5 Hz 脉冲重复频率、0.4 MPa 峰值负压）的脑组织中，我们系统地评估了麻醉、微泡和 FUS 对转录组的相对影响。特别有趣的是，我们观察到，无论选择何种麻醉，BBBD 都会诱导与无菌炎症反应和细胞-细胞连接活性相关的基因组。同时，与新陈代谢、血小板活性、组织修复和信号通路相关的基因组受到 BBBD 的不同影响，并且对麻醉剂有很强的依赖性。我们的结论是，FUS 介导的 BBBD 的潜在转录组反应可能受到麻醉的强烈影响。 这些发现引起了人们对 FUS-BBBD 递送方法转化的考虑，尤其是影响新陈代谢、组织修复和细胞内信号传导。