Psilocybin facilitates fear extinction in mice by promoting hippocampal neuroplasticity  

作　　者：Yingjie Du Yunfeng Li Xiangting Zhao Yishan Yao Bin Wang Liming Zhang Guyan Wang 

机构地区：[1]Department of Anesthesiology,Beijing Tongren Hospital,Capital Medical University,Beijing 100730,China [2]Beijing Institute of Pharmacology and Toxicology,State Key Laboratory of Toxicology and Medical Countermeasures,Beijing Key Laboratory of Neuropsychopharmacology,Beijing 100850,China [3]Beijing Institute of Basic Medical Sciences,Beijing 100850,China [4]Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases Basic Medical College of Jiamusi University,Jiamusi,Heilongjiang 154000,China

出　　处：《Chinese Medical Journal》2023年第24期2983-2992,共10页中华医学杂志（英文版）

基　　金：supported by grants from the STI2030-Major Projects(Nos.2021ZD0200900 and 2021ZD0202000);National Natural Science Foundation of China(Nos.81773708,82270411 and 81970344);Beijing Hospitals Authority's Ascent Plan(No.DFL20220203);Beijing Hospitals Authority Clinical Medicine Development of Special Funding Support(No.ZYLX202103)

摘　　要：Background:Posttraumatic stress disorder(PTSD)and depression are highly comorbid.Psilocybin exerts substantial therapeutic effects on depression by promoting neuroplasticity.Fear extinction is a key process in the mechanism of first-line exposure-based therapies for PTSD.We hypothesized that psilocybin would facilitate fear extinction by promoting hippocampal neuroplasticity.Methods:First,we assessed the effects of psilocybin on percentage of freezing time in an auditory cued fear conditioning(FC)and fear extinction paradigm in mice.Psilocybin was administered 30 min before extinction training.Fear extinction testing was performed on the first day;fear extinction retrieval and fear renewal were tested on the sixth and seventh days,respectively.Furthermore,we verified the effect of psilocybin on hippocampal neuroplasticity using Golgi staining for the dendritic complexity and spine density,Western blotting for the protein levels of brain derived neurotrophic factor(BDNF)and mechanistic target of rapamycin(mTOR),and immunofluorescence staining for the numbers of doublecortin(DCX)-and bromodeoxyuridine(BrdU)-positive cells.Results:A single dose of psilocybin(2.5 mg/kg,i.p.)reduced the increase in the percentage of freezing time induced by FC at 24 h,6th day and 7th day after administration.In terms of structural neuroplasticity,psilocybin rescued the decrease in hippocampal dendritic complexity and spine density induced by FC;in terms of neuroplasticity related proteins,psilocybin rescued the decrease in the protein levels of hippocampal BDNF and mTOR induced by FC;in terms of neurogenesis,psilocybin rescued the decrease in the numbers of DCX-and BrdU-positive cells in the hippocampal dentate gyrus induced by FC.Conclusions:A single dose of psilocybin facilitated rapid and sustained fear extinction;this effect might be partially mediated by the promotion of hippocampal neuroplasticity.This study indicates that psilocybin may be a useful adjunct to exposure-based therapies for PTSD and other mental disorders characte

关 键 词：Brain-derived neurotrophic factor BROMODEOXYURIDINE Depression Doublecortin domain proteins Extinction psychological Freezing Hippocampus Neuronal plasticity PSILOCYBIN Stress disorders post-traumatic 

分 类 号：R285.5[医药卫生—中药学]