Department of Neurobiology and Acupuncture Research, The Third School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
Key Laboratory of Acupuncture and Neurology of Zhejiang Province, The Third School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
Mol Neurobiol. 2024 Sep;61(9):6934-6949. doi: 10.1007/s12035-024-04027-5. Epub 2024 Feb 16.
Neurons within the anterior cingulate cortex (ACC) orchestrate the co-occurrence of chronic pain and anxiety. The ACC hyperactivity plays a crucial role in the emotional impact of neuropathic pain. Astrocyte-mediated neuroinflammatory is responsible for regulating the balance between excitation-inhibition (E/I) in the brain. However, there is limited understanding of the possible contributions of astrocytes in the ACC to comorbidity of anxiety and chronic inflammatory pain. This paper aims to investigate the possible contribution of astrocytes in the ACC to the comorbidity between anxiety and chronic inflammatory pain, as well as their involvement in the E/I imbalance of pyramidal cells. Our results show that CFA rats displayed allodynia and anxiety-like behaviors. The E/I balance in the ACC shifts to excitement in comorbidity of chronic pain and anxiety by western blotting, and electrophysiological recording. Result of RNA-Seq also indicated that E/I imbalance and neuroinflammation of ACC were involved in pain-anxiety comorbidity. Then, positive cells of GFAP but not Iba1 in the contralateral ACC were increased; the mRNA expression of GFAP and its activation-related proinflammatory cytokines (TNF-α, IL-6, and IL-1β) in the contralateral ACC were also elevated. Furthermore, specific chemogenic inhibition of ACC astrocytes reversed comorbid pain and anxiety and suppressed high ACC excitability. Our data suggest that astrocytes participate in comorbid pain and anxiety and excitation-inhibition imbalance in ACC. Inhibition astrocyte activation can reduce anxiety related to pain and restore the imbalance in the ACC. These findings shed light on the involvement of astrocytes in comorbid conditions, offering valuable insights into a potential therapeutic approach for the co-occurrence of chronic pain and anxiety.
前扣带皮层（ACC）内的神经元协调慢性疼痛和焦虑的同时发生。ACC 的过度活跃在神经病理性疼痛的情绪影响中起着关键作用。星形胶质细胞介导的神经炎症负责调节大脑中兴奋-抑制（E/I）之间的平衡。然而，对于星形胶质细胞在 ACC 中对焦虑和慢性炎症性疼痛共病的可能贡献，人们的理解有限。本文旨在研究 ACC 中的星形胶质细胞对焦虑和慢性炎症性疼痛共病的可能贡献，以及它们在锥体神经元 E/I 失衡中的作用。我们的结果表明，CFA 大鼠表现出痛觉过敏和焦虑样行为。通过 Western blot 和电生理记录，发现慢性疼痛和焦虑共病时，ACC 中的 E/I 平衡向兴奋转移。RNA-Seq 的结果也表明，ACC 的 E/I 失衡和神经炎症参与了疼痛-焦虑共病。然后，对侧 ACC 中 GFAP 阳性细胞而非 Iba1 增加；对侧 ACC 中 GFAP 的 mRNA 表达及其激活相关的促炎细胞因子（TNF-α、IL-6 和 IL-1β）也升高。此外，特异性化学遗传抑制 ACC 星形胶质细胞可逆转共病性疼痛和焦虑，并抑制高 ACC 兴奋性。我们的数据表明，星形胶质细胞参与共病性疼痛和焦虑以及 ACC 中的 E/I 失衡。抑制星形胶质细胞激活可以减轻与疼痛相关的焦虑，并恢复 ACC 中的失衡。这些发现揭示了星形胶质细胞在共病状态中的参与，为慢性疼痛和焦虑的共病提供了有价值的治疗方法。
