Neuropathic pain generates silent synapses in thalamic projection to anterior cingulate cortex
Neuropathic pain generates silent synapses in thalamic projection to anterior cingulate cortex
复制标题
神经病理性疼痛在丘脑向前扣带皮质的投射中产生沉默突触
DOI：
10.1097/j.pain.0000000000002149
复制
发表时间：
2021-05-01
期刊：
影响因子：
7.4
通讯作者：
Dong, Yan
中科院分区：
文献类型：
--
作者：
Wang, Yao Q.;Wang, Junshi;Dong, Yan
疼痛体验可以改变伤害性信息的中枢处理，导致持续性异常性疼痛和痛觉过敏。然而，潜在的电路机制仍有待探索。在这里，我们专注于疼痛引起的重塑的投影从mediodorsal丘脑（MD）的前扣带皮层（ACC），一个投影，中继脊髓伤害性输入的中央处理。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天的慢性压迫性损伤（CCI;通过坐骨神经的松散结扎实现）在对侧MD到ACC投射内产生AMPA受体（AMPAR）沉默的神经元突触。AMPAR沉默突触是典型的富含GluN 2B的新生突触，其在早期发育期间介导神经回路的初始形成。在发育过程中，一些沉默的突触成熟，并通过招募和稳定AMPAR，巩固和加强新形成的回路而变得“不沉默”。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神经元中未成熟树突棘的密度增加和MD至ACC投射中含GluN 2B的NMDA受体（NMDARs）的突触重量增加。在长时间（类似于30天）CCI后，损伤产生的沉默突触下降到低水平，这可能是由于突触成熟过程加强了AMPAR介导的MD到ACC的传递。与这一假设一致，病毒介导的ACC神经元中GluN 2B的敲低，其防止了疼痛诱导的沉默突触的产生和沉默突触介导的延长CCI后MD到ACC投射的加强，防止了异常性疼痛的发展。总之，我们的研究结果描绘了一个沉默的突触介导的机制，通过该机制，调节疼痛敏感性的脊髓上神经回路被重塑，以诱导异常性疼痛和痛觉过敏。
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 (similar to 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.