taVNS Alleviates Sevoflurane-Induced Cognitive Dysfunction in Aged Rats Via Activating Basal Forebrain Cholinergic Neurons

Postoperative cognitive dysfunction (POCD) is a common complication of central nervous system after anesthesia or surgery. Sevoflurane, an inhalation anesthetic, may inhibit cholinergic pathway that induce neuronal death and neuroinflammation, ultimately leading to POCD. Transauricular vagus nerve stimulation (taVNS) has neuroprotective effects in POCD rats, but the mechanisms related to cholinergic system have not been revealed. Sprague-Dawley rats were anesthetized with sevoflurane to construct the POCD model. The immunotoxin 192-IgG-saporin (192-sap) selectively lesioned cholinergic neurons in the basal forebrain, which is the major source of cholinergic projections to hippocampus. After lesion, rats received 5 days of taVNS treatment (30 min per day) starting 24 h before anesthesia. Open field test and Morris water maze were used to test the cognitive function. In this study, rats exposed to sevoflurane exhibited cognitive impairment that was attenuated by taVNS. In addition, taVNS treatment activated cholinergic system in the basal forebrain and hippocampus, and downregulated the expression of apoptosis- and necroptosis-related proteins, such as cleaved Caspase-3 and p-MLKL, in the hippocampus. Meanwhile, the activation of Iba1(+) microglial by sevoflurane was reduced by taVNS. 192-sap blocked the cholinergic system activation in the basal forebrain and hippocampus and inhibited taVNS-mediated neuroprotection and anti-inflammation effects in the hippocampus. Generally, our study indicated that taVNS might alleviate sevoflurane-induced hippocampal neuronal apoptosis, necroptosis and microglial activation though activating cholinergic system in the basal forebrain.

Automated summary

Postoperative cognitive dysfunction (POCD) is a common complication of anesthesia or surgery, which can be induced by sevoflurane inhibiting the cholinergic pathway. Transauricular vagus nerve stimulation (taVNS) has been shown to have neuroprotective effects in rats with POCD, but the mechanisms related to the cholinergic system have not been fully revealed. In this study, sevoflurane-exposed rats showed cognitive impairment, which was attenuated by taVNS treatment. TaVNS treatment activated the cholinergic system, reduced apoptosis and necroptosis in the hippocampus, and decreased microglial activation caused by sevoflurane. However, blocking the cholinergic system inhibited the neuroprotection and anti-inflammation effects of taVNS in the hippocampus. Overall, taVNS may alleviate sevoflurane-induced hippocampal neuronal apoptosis, necroptosis, and microglial activation by activating the cholinergic system.