CD38/催产素通路调控的室旁核-杏仁核神经环路在局麻药惊厥中的作用

Seizure is one of the most serious local anesthetic systemic toxicity. Amygdala is the key brain area mediating local anesthetics seizures. Oxytocin secreted by the paraventricular nucleus of hypothalamus (PVN) is an important neuromodulator closely related to the function of amygdala. Our previous studies have found that blocking the CD38/oxytocin pathway in the PVN-amygdala neural circuit can significantly alleviate local anesthetics seizures. Thus, we hypothesized that the CD38/oxytocin pathway may regulate PVN-amygdala neural circuit and play a critical role in the pathogenesis of local anesthetics seizures. In this study, we employ neural tracer technique, optogenetics, electrophysiology and other experimental approach to clarify the role of PVN-amygdala circuit in local anesthetics seizures, and further analyze the neurological and molecular mechanisms of the CD38/oxytocin pathway, so as to clarify the mechanisms of CD38/oxytocin-mediated paraventricular nucleus-amygdala pathway in local anesthetic seizures, and to provide a new target for its prevention and treatment.

局麻药惊厥是最严重的局麻药不良反应之一。杏仁核是介导局麻药惊厥的关键脑区，下丘脑室旁核分泌的催产素是调控杏仁核功能的重要神经调质。我们前期研究发现抑制室旁核-杏仁核环路CD38/催产素通路可明显缓解局麻药惊厥，据此我们提出假说：CD38/催产素通路可能通过调控室旁核-杏仁核神经环路，在局麻药惊厥中起到了重要作用。本研究将通过神经示踪、光遗传学、电生理等技术探索下丘脑室旁核-杏仁核神经环路在局麻药惊厥中的作用，并深入分析催产素在局麻药惊厥中涉及的神经分子机制，从而阐明CD38/催产素通路调控的室旁核-杏仁核神经环路在局麻药惊厥中的作用机制，为局麻药惊厥的防治提供新靶点。

丘脑室旁核（PVT）在内的丘脑中线背侧核在癫痫发作的诱导和扩散中起着关键的作用。我们研究了局部麻醉剂给药对PVT中c-Fos蛋白的表达和钙信号的影响。PVT发出到伏隔核（NAc）的投射，这已被本实验中PVT中逆行荧光金标记的神经元所揭示。此外，我们证明，在PVT中对NAc投射的CaMK II神经元的特异性抑制足以抑制NAc中神经元的活动，从而减少由局部麻醉剂系统毒性（LAST）引起的神经毒性行为。这些结果揭示了一个调节局部麻醉剂神经毒性的专用PVT-NAc回路，并为治疗和预防LAST提供了一个潜在的机制解释。