Neuroscience Program, Zhongshan School of Medicine, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhongshan Rd. 2, Guangzhou, China.
Zhongshan Medical School and Guangdong Province Key Laboratory of Brain Function and Disease, Sun Yat-Sen University, 510080, Guangzhou, China.
J Neuroinflammation. 2022 Jun 11;19(1):144. doi: 10.1186/s12974-022-02503-0.
The adaption of brain region is fundamental to the development and maintenance of nervous system disorders. The prelimbic cortex (PrL) participates in the affective components of the pain sensation. However, whether and how the adaptation of PrL contributes to the comorbidity of neuropathic pain and depression are unknown.
Using resting-state functional magnetic resonance imaging (rs-fMRI), genetic knockdown or overexpression, we systematically investigated the activity of PrL region in the pathogenesis of neuropathic pain/depression comorbid using the combined approaches of immunohistochemistry, electrophysiology, and behavior.
The activity of PrL and the excitability of pyramidal neurons were decreased, and the osteoclastic tartrate-resistant acid phosphatase 5 (Acp5) expression in PrL neurons was upregulated following the acquisition of spared nerve injury (SNI)-induced comorbidity. Genetic knockdown of Acp5 in pyramidal neurons, but not parvalbumin (PV) neurons or somatostatin (SST) neurons, attenuated the decrease of spike number, depression-like behavior and mechanical allodynia in comorbidity rats. Overexpression of Acp5 in PrL pyramidal neurons decreased the spike number and induced the comorbid-like behavior in naïve rats. Moreover, the expression of interleukin-6 (IL-6), phosphorylated STAT3 (p-STAT3) and acetylated histone H3 (Ac-H3) were significantly increased following the acquisition of comorbidity in rats. Increased binding of STAT3 to the Acp5 gene promoter and the interaction between STAT3 and p300 enhanced acetylation of histone H3 and facilitated the transcription of Acp5 in PrL in the modeled rodents. Inhibition of IL-6/STAT3 pathway prevented the Acp5 upregulation and attenuated the comorbid-like behaviors in rats.
These data suggest that the adaptation of PrL mediated by IL-6/STAT3/Acp5 pathway contributed to the comorbidity of neuropathic pain/depression induced by SNI.
脑区的适应对于神经系统疾病的发生和维持至关重要。额前皮质（PrL）参与疼痛感觉的情感成分。然而，PrL 的适应是否以及如何导致神经病理性疼痛和抑郁症的共病尚不清楚。
我们使用静息态功能磁共振成像（rs-fMRI）、基因敲低或过表达，通过免疫组织化学、电生理学和行为学相结合的方法，系统地研究了 PrL 区域在神经病理性疼痛/抑郁共病发病机制中的活动。
在 spared nerve injury（SNI）诱导的共病获得后，PrL 神经元的活性和锥体神经元的兴奋性降低，并且 PrL 神经元中的破骨细胞抗酒石酸酸性磷酸酶 5（Acp5）表达上调。在锥体神经元中基因敲低 Acp5，但不在 PV 神经元或 SST 神经元中，可减轻共病大鼠的尖峰数减少、抑郁样行为和机械性痛觉过敏。PrL 锥体神经元中 Acp5 的过表达会降低尖峰数并诱导正常大鼠出现共病样行为。此外，在大鼠获得共病后，白细胞介素 6（IL-6）、磷酸化 STAT3（p-STAT3）和乙酰化组蛋白 H3（Ac-H3）的表达显著增加。STAT3 与 Acp5 基因启动子的结合增加以及 STAT3 与 p300 之间的相互作用增强了组蛋白 H3 的乙酰化，促进了 PrL 中 Acp5 的转录。抑制 IL-6/STAT3 通路可防止 Acp5 上调并减轻大鼠的共病样行为。
这些数据表明，IL-6/STAT3/Acp5 通路介导的 PrL 适应导致了 SNI 诱导的神经病理性疼痛/抑郁共病。
