Cervical Epidural Electrical Stimulation Increases Respiratory Activity through Somatostatin-Expressing Neurons in the Dorsal Cervical Spinal Cord in Rats.
Cervical Epidural Electrical Stimulation Increases Respiratory Activity through Somatostatin-Expressing Neurons in the Dorsal Cervical Spinal Cord in Rats.
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DOI：
10.1523/jneurosci.1958-21.2022
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发表时间：
2023-01-18
影响因子：
5.3
通讯作者：
Lu, Daniel C.
中科院分区：
文献类型：
--
作者：
Galer, Erika L.;Huang, Ruyi;Madhavan, Meghna;Wang, Emily;Zhou, Yan;Leiter, James C.;Lu, Daniel C.
我们测试的假设，背颈硬膜外电刺激（CEES）增加呼吸活动的男性和女性麻醉大鼠。当CEES背侧应用于颈脊髓的C2-C6区域时，呼吸频率和每分钟通气量显著增加。通过将伪狂犬病病毒注入膈肌，用c-Fos活性鉴定CEES过程中激活的神经元，我们发现在颈髓后角有c-Fos和伪狂犬病共同定位的神经元，这些神经元表达生长抑素（SST）。使用双重病毒感染表达抑制性设计师受体专门激活的设计师药物（DREADD），hM 4D（Gi），选择性地在SST阳性细胞，我们抑制SST表达神经元给予氯氮平N-氧化物（CNO）。在β-受体介导的表达SST的颈脊髓神经元抑制期间，CEES引起的呼吸兴奋减弱。因此，颈背部硬膜外刺激激活了颈髓中表达SST的神经元，可能是中间神经元，其与呼吸模式产生网络通信以影响通气的变化。脑干内的脑桥延髓神经元网络产生呼吸行为，这些呼吸行为易受各种输入的调节;脊髓感觉和运动回路调节和适应这种输出，以满足对呼吸系统的需求。我们探讨了背颈硬膜外电刺激（CEES）兴奋脊髓回路，以增加大鼠的通气。我们确定了背侧生长抑素（SST）的表达神经元在颈脊髓激活（c-Fos阳性）CEES。CEES不再刺激通气抑制SST表达脊髓神经元的活动，从而表明脊髓SST神经元参与激活受CEES影响的呼吸回路。这项工作建立了一个机械的基础，重新利用临床上可获得的神经调节治疗，以激活呼吸回路和刺激通气。
We tested the hypothesis that dorsal cervical epidural electrical stimulation (CEES) increases respiratory activity in male and female anesthetized rats. Respiratory frequency and minute ventilation were significantly increased when CEES was applied dorsally to the C2–C6 region of the cervical spinal cord. By injecting pseudorabies virus into the diaphragm and using c-Fos activity to identify neurons activated during CEES, we found neurons in the dorsal horn of the cervical spinal cord in which c-Fos and pseudorabies were co-localized, and these neurons expressed somatostatin (SST). Using dual viral infection to express the inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADD), hM4D(Gi), selectively in SST-positive cells, we inhibited SST-expressing neurons by administering Clozapine N-oxide (CNO). During CNO-mediated inhibition of SST-expressing cervical spinal neurons, the respiratory excitation elicited by CEES was diminished. Thus, dorsal cervical epidural stimulation activated SST-expressing neurons in the cervical spinal cord, likely interneurons, that communicated with the respiratory pattern generating network to effect changes in ventilation. SIGNIFICANCE STATEMENT A network of pontomedullary neurons within the brainstem generates respiratory behaviors that are susceptible to modulation by a variety of inputs; spinal sensory and motor circuits modulate and adapt this output to meet the demands placed on the respiratory system. We explored dorsal cervical epidural electrical stimulation (CEES) excitation of spinal circuits to increase ventilation in rats. We identified dorsal somatostatin (SST)-expressing neurons in the cervical spinal cord that were activated (c-Fos-positive) by CEES. CEES no longer stimulated ventilation during inhibition of SST-expressing spinal neuronal activity, thereby demonstrating that spinal SST neurons participate in the activation of respiratory circuits affected by CEES. This work establishes a mechanistic foundation to repurpose a clinically accessible neuromodulatory therapy to activate respiratory circuits and stimulate ventilation.
影响因子：
5.3
作者：
Kowalski, Krzysztof E.;Hsieh, Yee-Hsee;Dick, Thomas E.;DiMarco, Anthony F.
通讯作者：
DiMarco, Anthony F.