Li Junhua, Wen Jinbei, Zeng Meigu, Mei Jinghong, Zeng Cong, Liufu Ning, Li Yujuan
Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
CNS Neurosci Ther. 2025 May;31(5):e70443. doi: 10.1111/cns.70443.
Perioperative neurocognitive disorders (PND) are common and costly complications in elderly surgical patients, yet the involvement of specific neural circuits in their etiology remains poorly understood. We hypothesized that neural projections from the medial prefrontal cortex (mPFC) to the amygdala contribute to PND pathogenesis.
Using chemogenetic approaches, we selectively suppressed or excited the mPFC and its projections to the amygdala in a murine model exposed to sevoflurane. We assessed cognitive deficits, synaptic plasticity (AMPA receptor activity, long-term potentiation [LTP]), mitochondrial stress, neuroinflammatory markers, and neuronal apoptosis in the amygdala. Additional interventions included pharmacological suppression of AMPA receptors, glutamate biosynthesis, and mitochondrial stress within the amygdala.
Sevoflurane exposure activated the mPFC-amygdala circuit. Chemogenetic suppression of the mPFC attenuated sevoflurane-induced cognitive deficits, AMPA receptor hyperexcitation, mitochondrial dysfunction, neuroinflammation, and neuronal apoptosis in the amygdala. Retrograde inhibition of mPFC projections to the amygdala alleviated cognitive impairments, whereas retrograde excitation exacerbated them. Suppressing AMPA receptors, glutamate synthesis, or mitochondrial stress in the amygdala similarly reduced cognitive deficits and pathological alterations. Notably, mPFC suppression rescued sevoflurane-induced LTP impairment in the amygdala.
These findings demonstrate that sevoflurane activates the mPFC-amygdala circuit, driving PND-associated cognitive deficits and neuropathological changes. Targeting this circuit or downstream mechanisms (AMPA signaling, mitochondrial stress) may mitigate sevoflurane-induced PND. This study provides empirical evidence implicating specific neural circuitry in anesthetic-related neurocognitive dysfunction.
围手术期神经认知障碍（PND）是老年外科患者常见且代价高昂的并发症，但其病因中特定神经回路的参与情况仍知之甚少。我们假设从内侧前额叶皮质（mPFC）到杏仁核的神经投射促成了PND的发病机制。
我们采用化学遗传学方法，在暴露于七氟醚的小鼠模型中选择性抑制或兴奋mPFC及其向杏仁核的投射。我们评估了杏仁核中的认知缺陷、突触可塑性（AMPA受体活性、长时程增强[LTP]）、线粒体应激、神经炎症标志物和神经元凋亡。额外的干预措施包括对杏仁核内AMPA受体、谷氨酸生物合成和线粒体应激的药理学抑制。
七氟醚暴露激活了mPFC-杏仁核回路。对mPFC的化学遗传学抑制减轻了七氟醚诱导的认知缺陷、AMPA受体过度兴奋、线粒体功能障碍、神经炎症和杏仁核中的神经元凋亡。对mPFC向杏仁核投射的逆行抑制减轻了认知障碍，而逆行兴奋则使其加重。抑制杏仁核中的AMPA受体、谷氨酸合成或线粒体应激同样减少了认知缺陷和病理改变。值得注意的是，mPFC抑制挽救了七氟醚诱导的杏仁核LTP损伤。
这些发现表明，七氟醚激活了mPFC-杏仁核回路，导致与PND相关的认知缺陷和神经病理变化。靶向该回路或下游机制（AMPA信号传导、线粒体应激）可能减轻七氟醚诱导的PND。本研究提供了经验证据，表明特定神经回路与麻醉相关的神经认知功能障碍有关。
