Table_1_Differences in the neural basis and transcriptomic patterns in acute and persistent pain-related anxiety-like behaviors.XLSX

BackgroundBoth acute and persistent pain is associated with anxiety in clinical observations, but whether the underlying neural mechanisms differ is poorly understood.
MethodsWe used formalin or complete Freund’s adjuvant (CFA) to induce acute or persistent pain. Behavioral performance was assessed by the paw withdrawal threshold (PWT), open field (OF), and elevated plus maze (EPM) tests. C-Fos staining was used to identify the activated brain regions. Chemogenetic inhibition was further performed to examine the necessity of brain regions in behaviors. RNA sequencing (RNA-seq) was used to identify the transcriptomic changes.
ResultsBoth acute and persistent pain could lead to anxiety-like behavior in mice. The c-Fos expression indicates that the bed nucleus of the stria terminalis (BNST) is activated only in acute pain, whereas the medial prefrontal cortex (mPFC) is activated only in persistent pain. Chemogenetic manipulation reveals that the activation of the BNST excitatory neurons is required for acute pain-induced anxiety-like behaviors. In contrast, the activation of the prelimbic mPFC excitatory neurons is essential for persistent pain-induced anxiety-like behaviors. RNA-seq reveals that acute and persistent pain induces differential gene expression changes and protein–protein interaction networks in the BNST and prelimbic mPFC. The genes relevant to neuronal functions might underline the differential activation of the BNST and prelimbic mPFC in different pain models, and be involved in acute and persistent pain-related anxiety-like behaviors.
ConclusionDistinct brain regions and gene expression patterns are involved in acute and persistent pain-related anxiety-like behaviors.

背景：临床观察显示，急性疼痛与持续性疼痛均与焦虑存在关联，但二者潜在的神经机制是否存在差异，目前仍尚不明确。方法：本研究采用福尔马林（formalin）或完全弗氏佐剂（complete Freund’s adjuvant, CFA）构建小鼠急性疼痛与持续性疼痛模型。通过缩爪阈值（paw withdrawal threshold, PWT）、旷场实验（open field, OF）及高架十字迷宫实验（elevated plus maze, EPM）评估小鼠行为学表现；采用c-Fos染色鉴定被激活的脑区；进一步通过化学遗传学抑制实验，探究相关脑区在行为学中的必要性；利用RNA测序（RNA-seq）分析转录组变化。结果：急性疼痛与持续性疼痛均可诱发小鼠产生焦虑样行为。c-Fos表达结果显示，仅在急性疼痛模型中，终纹床核（bed nucleus of the stria terminalis, BNST）被激活；而仅在持续性疼痛模型中，内侧前额叶皮层（medial prefrontal cortex, mPFC）被激活。化学遗传学操控实验表明，终纹床核兴奋性神经元的激活是急性疼痛诱发焦虑样行为的必要条件；与之相反，内侧前额叶皮层前边缘亚区（prelimbic mPFC）兴奋性神经元的激活，是持续性疼痛诱发焦虑样行为的关键因素。RNA测序结果显示，急性疼痛与持续性疼痛可在终纹床核及内侧前额叶皮层前边缘亚区内诱导出差异的基因表达变化与蛋白质相互作用网络。与神经元功能相关的基因，可能是不同疼痛模型下终纹床核与内侧前额叶皮层前边缘亚区差异化激活的分子基础，并参与急性与持续性疼痛相关的焦虑样行为调控。结论：急性疼痛与持续性疼痛相关的焦虑样行为，涉及不同的脑区与基因表达模式。