Identification of a Glutamatergic Claustrum-Anterior Cingulate Cortex Circuit for Visceral Pain Processing.
Identification of a Glutamatergic Claustrum-Anterior Cingulate Cortex Circuit for Visceral Pain Processing.
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用于内脏疼痛处理的谷氨酸能克劳斯特鲁姆-前扣带皮层电路的识别。
DOI：
10.1523/jneurosci.0779-22.2022
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Xu Guang-Yin
中科院分区：
文献类型：
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作者：
Qi-Ya Xu;Hai-Long Zhang;Han Du;Yong-Chang Li;Fu-hai Ji;Rui Li;Xu Guang-Yin
慢性内脏疼痛是患者和医疗服务提供者面临的主要挑战。虽然大脑的中枢敏感化被认为在内脏痛的发展中起重要作用，但详细的神经回路在很大程度上仍然未知。使用一个成熟的慢性内脏高敏感性模型诱导的新生儿母亲剥夺（NMD）的雄性小鼠，我们确定了一个独特的途径，即屏状核（CL）的前扣带皮层（ACC）的神经元投射是至关重要的内脏痛，但不是CFA诱发的炎性疼痛。通过结合在体电路解剖细胞外电生理方法和内脏痛相关的肌电图记录，我们证明了光遗传学抑制CL神经元活性抑制NMD小鼠的ACC神经活动和内脏高敏感性，而选择性激活CL神经元活性增强对照小鼠的ACC神经活动并诱发内脏痛。此外，光遗传学研究证明了这种神经元活动和内脏疼痛行为之间的因果关系。化学遗传学激活或抑制ACC神经活动逆转了CL神经活动的光遗传学操纵对内脏疼痛反应的影响。重要的是，分子检测显示NMD显著增强ACC突触后致密区N-甲基-D-天冬氨酸受体的表达和激活的CaMKIIα。总之，我们的数据建立了CL→ACC神经元门控内脏痛的功能作用，从而提供了一个潜在的治疗策略内脏pain. Significance声明：研究表明，前扣带皮层（ACC）的敏化在慢性疼痛中起着重要作用。然而，目前还不清楚是否有一个特定的大脑区域和一个独特的神经回路，帮助ACC区分内脏和躯体疼痛。本研究表明，屏状核（CL）神经元可能对结直肠扩张而不是躯体刺激作出反应，并且CL神经元向ACC神经元的投射调节小鼠内脏痛。此外，慢性内脏痛小鼠ACC突触后致密区N-甲基-D-天冬氨酸受体和CaMKIIα过度活跃。总之，这些发现揭示了一种新的神经回路的慢性内脏痛的中枢敏感化。
Chronic visceral pain is a major challenge for both patients and health providers. Although the central sensitization of the brain is thought to play an important role in the development of visceral pain, the detailed neural circuits remain largely unknown. Using a well-established chronic visceral hypersensitivity model induced by neonatal maternal deprivation (NMD) in male mice, we identified a distinct pathway whereby the claustrum (CL) glutamatergic neuron projecting to the anterior cingulate cortex (ACC) is critical for visceral pain but not for CFA-evoked inflammatory pain. By a combination of in vivo circuit-dissecting extracellular electrophysiological approaches and visceral pain related electromyographic recordings, we demonstrated that optogenetic inhibition of CL glutamatergic activity suppressed the ACC neural activity and visceral hypersensitivity of NMD mice whereas selective activation of CL glutamatergic activity enhanced the ACC neural activity and evoked visceral pain of control mice. Further, optogenetic studies demonstrate a causal link between such neuronal activity and visceral pain behaviors. Chemogenetic activation or inhibition of ACC neural activities reversed the effects of optogenetic manipulation of CL neural activities on viscera pain responses. Importantly, molecular detection showed that NMD significantly enhances the expression of N-methyl-D-aspartate receptors and activated CaMKIIα in the ACC postsynaptic density region. Together, our data establish a functional role for CL→ACC glutamatergic neurons in gating visceral pain, thus providing a potential treatment strategy for visceral pain.SIGNIFICANCE STATEMENT:Studies have shown that sensitization of anterior cingulate cortex (ACC) plays an important role in chronic pain. However, it is as yet unknown whether there is a specific brain region and a distinct neural circuit that helps the ACC to distinguish visceral and somatic pain. The present study demonstrates that claustrum (CL) glutamatergic neurons maybe responding to colorectal distention rather than somatic stimulation and that a CL glutamatergic projection to ACC glutamatergic neuron regulates visceral pain in mice. Furthermore, excessive N-methyl-D-aspartate receptors and overactive CaMKIIα in the ACC postsynaptic density region were observed in mice with chronic visceral pain. Together, these findings reveal a novel neural circuity underlying the central sensitization of chronic visceral pain.