Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, United States.
Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
Pain. 2021 May 1;162(5):1322-1333. doi: 10.1097/j.pain.0000000000002149.
Pain experience can change the central processing of nociceptive inputs, resulting in persistent allodynia and hyperalgesia. However, the underlying circuit mechanisms remain underexplored. Here, we focus on pain-induced remodeling of the projection from the mediodorsal thalamus (MD) to the anterior cingulate cortex (ACC), a projection that relays spinal nociceptive input for central processing. Using optogenetics combined with slice electrophysiology, we detected in male mice that 7 days of chronic constriction injury (CCI; achieved by loose ligation of the sciatic nerve) generated AMPA receptor (AMPAR)-silent glutamatergic synapses within the contralateral MD-to-ACC projection. AMPAR-silent synapses are typically GluN2B-enriched nascent glutamatergic synapses that mediate the initial formation of neural circuits during early development. During development, some silent synapses mature and become "unsilenced" by recruiting and stabilizing AMPARs, consolidating and strengthening the newly formed circuits. Consistent with these synaptogenic features, pain-induced generation of silent synapses was accompanied by increased densities of immature dendritic spines in ACC neurons and increased synaptic weight of GluN2B-containing NMDA receptors (NMDARs) in the MD-to-ACC projection. After prolonged (∼30 days) CCI, injury-generated silent synapses declined to low levels, which likely resulted from a synaptic maturation process that strengthens AMPAR-mediated MD-to-ACC transmission. Consistent with this hypothesis, viral-mediated knockdown of GluN2B in ACC neurons, which prevented pain-induced generation of silent synapses and silent synapse-mediated strengthening of MD-to-ACC projection after prolonged CCI, prevented the development of allodynia. Taken together, our results depict a silent synapse-mediated mechanism through which key supraspinal neural circuits that regulate pain sensitivity are remodeled to induce allodynia and hyperalgesia.
疼痛体验可以改变伤害性感受输入的中枢处理，导致持续性的痛觉过敏和痛觉超敏。然而，其潜在的电路机制仍未得到充分探索。在这里，我们专注于疼痛引起的中脑背侧丘脑（MD）到前扣带皮层（ACC）投射的重塑，该投射将脊髓伤害性传入信息中继到中枢进行处理。使用光遗传学结合切片电生理学，我们在雄性小鼠中检测到，7 天的慢性缩窄性损伤（CCI；通过坐骨神经的松绑结扎来实现）在对侧 MD-ACC 投射中产生了 AMPA 受体（AMPAR）沉默的谷氨酸能突触。AMPAR 沉默突触通常是富含 GluN2B 的新生谷氨酸能突触，在早期发育过程中介导神经网络的初始形成。在发育过程中，一些沉默突触成熟并通过招募和稳定 AMPAR 而变得“不沉默”，从而巩固和加强新形成的回路。与这些突触发生特征一致，疼痛诱导的沉默突触的产生伴随着 ACC 神经元中不成熟树突棘密度的增加和 MD-ACC 投射中含有 GluN2B 的 NMDA 受体（NMDAR）的突触权重增加。在长时间（约 30 天）CCI 后，损伤产生的沉默突触减少到低水平，这可能是由于一个突触成熟过程，该过程加强了 AMPAR 介导的 MD-ACC 传递。与这一假设一致，ACC 神经元中病毒介导的 GluN2B 敲低阻止了疼痛诱导的沉默突触的产生和长时间 CCI 后沉默突触介导的 MD-ACC 投射的增强，从而防止了痛觉过敏的发生。综上所述，我们的结果描绘了一种沉默突触介导的机制，通过该机制，调节疼痛敏感性的关键皮质上神经回路被重塑，导致痛觉过敏和痛觉超敏。
