Preoperative Pain Facilitates Postoperative Cognitive Dysfunction Through PAG-DR Neural Circuit

Background:Postoperative cognitive dysfunction(POCD)refers to a type of clinical problem in which patients undergoing surgical procedure have cognitive,emotional or mental states that are different from normal.This type of dysfunction may last for a long time therefore not only affects patients’ rehabilitation and quality of life but also causes a burden on both the patient’s family and society.There is no recognized treatment to solve this problem so it is very important to prevent it.That is,to identify rick factors and actively avoid them during perioperative period.As one of the pre-existing conditions,the relationship between pain and POCD has not yet been clear and its role in facilitating POCD needs further study.Dorsal raphe(DR)serotonin(5-HT)energy neurons are the most important source of 5-HT in most nucleus related cognitive function.The changes of 5-HT neurons in DR region can affect cognitive function.The periaqueductal gray(PAG)region next to DR region is a key part of pain signaling pathway and whether PAG and DR have functional connectivity and neuronal changes in PAG can affect the 5-HTergic neurons in DR region and then affect cognitive function is the topic we want to study.Purpose:To explore the mechanism of PAG-DR neural circuit in preoperative pain facilitating postoperative cognitive dysfunction.Methods:1)Formalin and CFA were injected to male SD rats to construct pain model,sevoflurane was used to simulate surgery anesthesia procedure,and immunofluorescence was used to study the state of 5-HT neurons in DR region under pain or/with anesthesia condition.2)Anterograde and retrograde AAV and electrophysiology were used to study the possible connection between PAG and DR region.3)Neurotoxin and chemogenetic AAV combined with Morris water maze were used to study the cognitive function of rats,and whether the changes of PAG neurons can affect DR region and further affect cognitive function.Results:1)The activation of 5-HT neurons in DR region of rats reduces after anesthesia treatment but can recover gradually.The number and activation of 5-HT neurons in DR region of rats under acute pain state have no change whether with or without anesthesia treatment.The number and activation of 5-HT neurons in DR region of rats under chronic pain state reduce significantly after anesthesia treatment.2)There is a direct projection from vl PAG region to DR region.3)Inhibiting the vl PAG region neurons projecting to DR region by chemogenetic AAV can affect the cognitive function of rats.Conclusion:The 5-HT neurons in DR region can be significantly inhibited by anesthesia treatment under chronic pain state.There is a direct projection from PAG region to DR region.Regulating this part of neurons in PAG region can affect cognitive function.The “PAGDR” neural circuit may be one of the mechanisms in preoperative pain facilitating postoperative cognitive dysfunction.