The Study About The Role Of Hippocampus-mPFC Connectivity In Postoperative Cognitive Dysfunction And Its Underlying Mechanisms

Objective: Postoperative cognitive dysfunction(POCD)occurs in 25%to 40% of elderly postoperative patients.Studies about the mechanisms of POCD mainly focus on the postoperative neuroinflammation,nutritional disorders,and molecular changes such as Aβ,Tau,glutamate and their receptors in the hippocampus and prefrontal cortex.But changes of these molecules are difficult to explain the persistence of long-term POCD symptoms,so we speculate that there are other mechanisms involving structural changes in the occurrence and development of POCD.Studies have shown that injury of the hippocampus-medial prefrontal cortex(mPFC)connectivity is closely related to cognitive dysfunction in various neurodegenerative diseases.But little is known about whether there is hippocampus-mPFC connectivity injury in patients with POCD.In this study,the relationship between hippocampus-mPFC connectivity and POCD will be explored.And its potential molecular targets will be explored as well.We aim to provide a new theoretical basis for the prevention and treatment of POCD.Methods: The POCD model was established with rat by general anesthesia and partial hepatic lobectomy.The effect of HDAC6 was inhibited by AAV9-hsyn-Sh RNA-HDAC6 or Tubastatin A.The Barnes maze test and the delayed position-matching task water maze test were used to detect the short-term and long-term cognitive functions of experimental rats,respectively.The hippocampus-mPFC connectivity was evaluated by BDA tracer.WB technology was used to detect HDAC6 and Ac-tubulin expression levels in hippocampus and mPFC.Immunohistochemistry and PCR techniques were used to detect inflammatory levels in the hippocampus and mPFC.Results:(1)The number of errors in the Barnes maze test in elderly rats after surgery was significantly more than that in the control group.(2)The difference both in escape time and escape distance of searching for a platform in the water maze test of elderly rats after surgery were significantly lower than those in the control group.(3)The BDA-positive cell number of mPFC in elderly rats after surgery was significantly lower than that in the control group.(4)AAV9-hsyn-Sh RNA-HDAC6 or TBA reversed the increase in HDAC6 expression of hippocampus and mPFC in elderly rats.(5)AAV9-hsyn-Sh RNA-HDAC6 or TBA reversed the increasing number of errors in the Barnes maze test in elderly rats after surgery.(6)AAV9-hsyn-Sh RNA-HDAC6 or TBA reversed the reduction of the difference of escape time and escape distance during searching for platform in the delayed position task matching water maze test in elderly rats after surgery.(7)AAV9-hsyn-Sh RNA-HDAC6 or TBA reversed the reduction of the BDA-positive cell number in elderly rats after surgery.(8)AAV9-hsyn-Sh RNA-HDAC6 or TBA reversed the reduction of Ac-tubulin both in hippocampus and mPFC in elderly rats after surgery.(9)AAV9-hsyn-Sh RNA-HDAC6 or TBA reversed the increasing inflammation levels both of hippocampus and mPFC in elderly rats after surgery.Conclusion:Through the above experiments,we have proved that injury of hippocampus-mPFC connectivity may be involved in the pathogenesis of POCD.And HDAC6 is a potential drug target for preventing POCD.Specific inhibition of HDAC6 can increase the Actubulin level both in hippocampus and mPFC,while decrease the inflammation level at the same time.Then it will enhance the injured hippocampus-mPFC connectivity to alleviate POCD.