LC-BLA重塑参与局麻药惊厥后的负性情绪

Local anesthetics-related serious convulsion is a common adverse event with highest incidence rate in medical practice. Moreover, the patients usually suffer from negative emotions, such as anxiety or depression, after convulsion. The neuronal synaptic plasticity in the basolateral amygdala (BLA) is the foundation of negative emotions induced by nociceptive stimulus and that is specific to local anesthetics-induced convulsion. Our previous studies showed that locus coeruleus (LC)-noradrenaline (NA) projections are widely spread in the BLA and the convulsion induced by local anesthetics can be attenuated by inhibiting LC-NA neurons, suggesting that LC-NA projections participate in the neuronal activation and synaptic plasticity in the BLA. However, the specific cellular and molecular mechanisms remain uncertain. Therefore, in the present study, we focus on the BLA region and LC-BLA pathway to investigate the relationship between neuronal activation and synaptic plasticity with the negative emotion by using a combination of pharmacological, behavioral, microscopy, molecular, and optogenetics approaches in a ropivacaine-induced convulsive model in rats. The goal of this study is to provide the theoretical basis for illustrating the central mechanism of negative emotions after local anesthetics-induced convulsion and the new target for clinical prevention and treatment.

惊厥是局麻药相关不良事件中最先发生且发病率最高的不良反应，且惊厥缓解后，患者常伴有极不愉快的情绪改变，如焦虑或抑郁等。基底外侧杏仁核（BLA）内神经元重塑是伤害性刺激相关负性情绪产生和维持的基础，课题组前期发现，蓝斑（LC）-去甲肾上腺素（NA）能神经元在BLA内分布极广，且选择性抑制LC-NA能神经元的活化可改善局麻药惊厥后的负性情绪，提示其可能参与了BLA内神经元重塑，但具体细胞分子机制尚不明确。本课题拟采用罗哌卡因诱导的惊厥模型，以BLA为研究靶点、LC-BLA通路为切入点，综合应用行为学、形态学、分子生物学、以及光遗传学的技术和方法，探讨LC-BLA重塑与惊厥后负性情绪的关系及其分子机制，为阐明局麻药惊厥后情绪变化的中枢机制提供新思路，为临床防治提供新靶点。

惊厥是局麻药相关不良事件中最先发生且发病率最高的不良反应，且惊厥缓解后，患者常伴有极不愉快的情绪改变，如焦虑或抑郁等。基底外侧杏仁核（BLA）内神经元重塑是伤害性刺激相关负性情绪产生和维持的基础，课题组前期发现，蓝斑（LC）-去甲肾上腺素（NA）能神经元在BLA内分布极广，且选择性抑制LC-NA能神经元的活化可改善局麻药惊厥后的负性情绪，提示其可能参与了BLA内神经元重塑，但具体细胞分子机制尚不明确。本项目综合采用罗哌卡因诱导的惊厥模型，以BLA为研究靶点、LC-BLA通路为切入点，综合应用行为学、神经影像、转录组学、形态学、分子生物学、流行细胞分析、以及化学遗传学的技术和方法，探讨LC-BLA重塑与惊厥后负性情绪的关系及其分子机制。结果表明：LC存在大量投射至BLA的NA能神经纤维，惊厥后可引起LC-BLA神经环路活化、激活并诱导BLA内小胶质细胞促炎和促吞噬表型转化，维持并扩大神经元NF-κB - NLRP3 - CASP-1 - IL-1β炎症信号通路的持续表达，最终导致LC-BLA突触重塑产生负性情绪样行为，喂食PLX5622删除小胶质细胞或CNO诱导hSyn-hM4D(Gi)-eGFP抑制神经元活化，可有效逆转惊厥后的负性情绪行为。本研究结果为阐明局麻药惊厥后情绪变化的中枢机制提供新思路，为临床防治提供新靶点。